1. Name Of The Medicinal Product
Clarithromycin 125 mg/5ml granules for oral suspension
Clarithromycin 250 mg/5ml granules for oral suspension
2. Qualitative And Quantitative Composition
Clarithromycin 125 mg/5ml granules for oral suspension
After reconstitution 1 ml oral suspension contains 25 mg clarithromycin, 5 ml oral suspension contain 125 mg clarithromycin.
Clarithromycin 250 mg/5ml granules for oral suspension
After reconstitution 1 ml oral suspension contains 50 mg clarithromycin, 5 ml oral suspension contain 250 mg clarithromycin.
These products contain 2,4 g sucrose per 5 ml ready- for- use suspension.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Granules for oral suspension.
White to beige granules.
4. Clinical Particulars
4.1 Therapeutic Indications
Clarithromycin 25 and 50 mg/ml granules for oral suspension is indicated for the treatment of the following acute and chronic infections, when caused by clarithromycin susceptible organisms.
• Infections of the upper respiratory tract such as tonsillitis/pharyngitis, as an alternative when beta lactam antibiotics are not appropriate.
• Acute otitis media in children.
• Infections of the lower respiratory tract such as community acquired pneumonia.
• Sinusitis and acute exacerbation of chronic bronchitis in adults and adolescents over 12 years of age
• Skin infections and soft tissue infections of mild to moderate severity.
In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer healing medicinal product for the eradication of Helicobacter pylori in adult patients with H. pylori associated ulcers. See section 4.2.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
The dosage of Clarithromycin 25 mg/ml and 50 mg/ml granules for oral suspension depends on the clinical condition of the patient and has to be defined in any case by the physician.
Adults and adolescents:
Standard dosage: The usual dose is 250 mg twice daily.
High dosage treatment (severe infections): The usual dose may be increased to 500 mg twice daily in severe infections.
Elimination of Helicobacter pylori in adults:
In patients with gastro-duodenal ulcers due to H. pylori infection clarithromycin as part of the first line triple therapy is given in a dosage of 500 mg twice daily. The national recommendations for Helicobacter pylori eradication have to be considered.
Dosage in renal functional impairment:
The maximum recommended dosages should be reduced proportionately to renal impairment.
At creatinine clearance rate of less than 30 ml/min, the dosage should be halved to 250 mg daily or in the most severe infections to 250 mg twice daily. The duration of treatment should not exceed 14 days in these patients.
Children up to 12 years of age:
The recommended dose is 7,5 mg/kg twice a day.
Weight | Age | Dosage 125 mg/5ml | Dosage 250 mg/5ml |
8 – 11 kg | 1 – 2 years | 2.5 ml twice daily | n/a |
12 – 19 kg | 2 – 4 years | 5.0 ml twice daily | 2.5 ml twice daily |
20 – 29 kg | 4 – 8 years | 7.5 ml twice daily | 3.75 ml twice daily |
30 – 40 kg | 8 – 12 years | 10.0 ml twice daily | 5.0 ml twice daily |
Children weighing less than 8 kg should be treated based on their bodyweight.
There is limited experience of treatment of children below 6 months of age.
For the indication community acquired pneumonia effect in children under 3 years of age is not documented.
In renal insufficiency, especially if the creatinine clearance is < 30 ml/min, the dose must be halved, i.e. 7,5 mg/kg once a day, and the duration of treatment should not exceed 14 days..
Duration of therapy:
The duration of therapy with Clarithromycin 25 mg/ml and 50 mg/ml granules for oral suspension depends on the clinical condition of the patient. The duration of therapy has in any case to be determined by the physician.
• The usual duration of treatment of children up to 12 years of age is 5 to 10 days.
• The usual duration of treatment of adults and adolescents is 6 to 14 days.
• Therapy should be continued at least for 2 days after symptoms have subsided.
• In streptococcus pyogenes (as a beta-haemolytic streptococcal) infections the duration of therapy should be at least 10 days.
• Combination therapy for the eradication of H. pylori infection, e.g. clarithromycin 500 mg twice daily in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily should be continued for 7 days.
Method of administration:
Before administration the granules must be reconstituted with water, see section 6.6. For administration after reconstitution an oral PE/PP-measuring syringe or a PP-measuring spoon are used.
Granules of the oral suspension can cause a bitter aftertaste when remaining in the mouth. This can be avoided by eating or drinking something immediately after the intake of the suspension
Clarithromycin may be given irrespective of food intake. Food does not affect the extent of bioavailability. Food does only slightly delay the onset of absorption of clarithromycin.
4.3 Contraindications
Clarithromycin 25 mg/ml and 50 mg/ml granules for oral suspension must not be used in patients with a hypersensitivity to the active substance, other macrolide antibiotics or to any of the excipients.
Clarithromycin and ergot derivatives should not be co-administered.
Concomitant administration of clarithromycin and any of the following active substances is contraindicated: cisapride, pimozide and terfenadine. Elevated cisapride, pimozide and terfenadine levels have been reported in patients receiving either of these active substances and clarithromycin concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes. Similar effects have been observed with concomitant administration of astemizole and other macrolides (see section 4.5).
Clarithromycin 25 mg/ml and 50 mg/ml granules for oral suspension should not be administered to hypokalemic patients (prolongation of QT-time, see section 4.4).
4.4 Special Warnings And Precautions For Use
This medicinal product contains 2.4 g powdered sucrose per 5 ml ready-for-use suspension. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Clarithromycin is mainly excreted by the liver. Therefore, caution should be taken in administering clarithromycin to patients with impaired hepatic function.
When renal function is poor, dosage of clarithromycin should be suitably reduced depending on the degree of the impairment (see section 4.2). In elderly patients, the possibility of renal impairment should be considered.
Clarithromycin therapy for H. pylori may select for drug-resistant organisms.
Patients who are hypersensitive to lincomycin or clindamycin may also be hypersensitive to clarithromycin. Therefore, caution is required when prescribing clarithromycin for such patients.
Prolonged or repeated use of clarithromycin may result in superinfections with insusceptible organisms. In case of superinfection, clarithromycin therapy should be stopped.
Pseudomembranous colitis has been reported with the use of broad-spectrum antibiotics. Therefore, it is important to consider its diagnosis in patients who develop severe diarrhoea during or after therapy with clarithromycin.
Due to a risk of increased QT-interval, clarithromycin should be used with caution in patients with a coronary vessel disease, a history of ventricular arrhythmia, severe cardiac insufficiency, non-compensated hypokalemia and/or hypomagnesemia, bradycardia (< 50 bpm), or when co-administered with other medicinal products with a QT-prolonging effect. Clarithromycin should not be used in patients with congenital or documented acquired QT prolongation (see section 4.5).
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5).
Clarithromycin should be used with caution whenever indicated for use in patients receiving treatment with an inducer of CYP3A4 (see section 4.5).
Clarithromycin is an inhibitor of CYP3A4, and concomitant use with other medicinal products that are metabolised to a large extent by this enzyme should be restricted to situations where it is clearly indicated (see section 4.5).
Exacerbation or aggravation of Myasthenia gravis may occur.
Clarithromycin inhibits the metabolism of some HMG-CoA reductase inhibitors, which results in increased plasma concentrations of these medicinal products (see section 4.5).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The effect of Clarithromycin suspension on other medicinal products
Clarithromycin is an inhibitor of the metabolising enzyme CYP3A4 and the transport protein P-glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence, clarithromycin should not be used during treatment with other medicinal products that are substrates for CYP3A4, unless plasma levels, therapeutic effect or adverse events of the CYP3A4 substrate can be closely monitored. A dose reduction may be necessary for medicinal products that are substrates for CYP3A4 if co-administered with clarithromycin. Alternatively, treatment with these products may be interrupted during clarithromycin treatment.
Medicinal products with a potential to prolong QT-interval
Clarithromycin has been reported to inhibit the metabolism of cisapride and terfenadine, with a 2 to 3-fold increase in plasma levels reported for terfenadine. This has been associated with QT-prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrilation and torsades de pointes. Similar symptoms have been described for patients treated with pimozid when combined with clarithromycin. Concomitant administration of clarithromycin and terfenadine, cisapride, pimozide or astemizole is contraindicated (see section 4.3).
Cases with torsades de pointes has been reported in patients where clarithromycin has been co-administered with quinidine or disopyramid. These combinations should therefore be avoided, or plasma levels of quinidine or disopyramid closely monitored to allow dose adjustment.
Caution is warranted when clarithromyin is administered to patients treated taking other medicinal products with the potential to prolong QT (see section 4.4).
Colchicin
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).
HMG-CoA reductase inhibitors
Clarithromycin inhibits the metabolism of some HMG-CoA reductase inhibitors, which results in increased plasma concentrations of these medicinal products. Rhabdomyolysis in association with increased plasma concentrations have in rare cases been reported in patients treated with clarithromycin and simvastatin or lovastatin. Clarithromycin may produce a similar interaction with atorvastatin and cerivastatin. When treatment with clarithromycin is indicated in patients receiving treatment with either simvastatin, lovastatin, atorvastatin, or cerivastatin patients should be monitored for signs and symptoms of myopathy (see section 4.4).
Ergot vasoconstrictors (e.g. dihydroergotamine, ergotamine)
Cases of ergotism due to increased plasma levels of ergot alkaloids have been reported when these products have been co-administered with macrolides. The combination is contraindicated (see section 4.3).
Benzodiazepines
When midazolam was co-administered with clarithromycin tablets (250 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A4, especially triazolam but also alprazolam. For benzodiazepines which are not metabolised by CYP3A4 (temazepam, nitrazepam, lorazepam) an interaction with clarithromycin is unlikely.
Cyclosporin, tacrolimus and sirolimus
Concomitant use of oral clarithromycin and cyclosporin or tacrolimus have resulted in more than a 2-fold increase of the Cmin-levels of both cyclosporin and tacrolimus. Similar effects are also expected for sirolimus. When initiating treatment with clarithromycin in patients already receiving any of these immunosuppressive agents, cyclosporin, tacrolimus or sirolimus plasma levels must be closely monitored and their doses decreased as necessary. When clarithromycin is discontinued in these patients, close monitoring of plasma levels of cyclosporin, tacrolimus or sirolimus, is again necessary to guide dose adjustment.
Digoxin and other active substances transported by P-glycoprotein
Claritromycin is a potent inhibitor of the transport protein P-glycoprotein (Pgp). This could give rise to increased plasma concentrations of active substances which are transported by this transporter and may also increase distribution of such active substances to organs having Pgp as an distribution barrier eg CNS. The concentration of the Pgp substrate digoxin may be increased when co-administered with clarithromycin. Monitoring of plasma levels of digoxin should be considered when co-treatment with clarithromycin is initiated or terminated since a dose adjustment may be warranted.
Warfarin
The use of clarithromycin in patients receiving warfarin may result in potentiation of the effects of warfarin. Prothrombin time should be frequently monitored in these patients.
Carbamazepin
Clarithromycin may potentiate the effects of carbamazepine due to a reduction in the rate of excretion.
Theophylline
The administration of clarithromycin to patients who are receiving theophylline has been associated with an increase in serum theophylline levels and potential theophylline toxicity.
Zidovudine
Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV infected adult patients may result in decreased steady-state zidovudine levels. This can be largely avoided by staggering the doses of clarithromycin and zidovudine by 1-2 hours. No such reaction has been reported in children.
Fluconazole
Clarithromycin may increase plasma fluconazole levels
The effect of other medicinal products on Clarithromycin supension
Clarithromycin is metabolised by the enzyme CYP3A4. Hence, strong inhibitors of this enzyme may inhibit the metabolism of clarithromycin, resulting in increased plasma concentrations of clarithromycin.
Although the plasma concentrations of clarithromycin and omeprazole may be increased when they are administered concurrently, no adjustment to the dosage is necessary. Increased plasma concentrations of clarithromycin may also occur when it is co-administered with antacids or ranitidine. No adjustment to the dosage is necessary.
Ritonavir (200 mg three times daily) have been shown to inhibit the metabolism of clarithromycin (500 mg twice daily), with an increase in Cmax, Cmin and AUC of 31, 182 and 77%, respectively, when co-administered with ritonavir. Formation of the active 14-OH-hydroxy metabolite was almost completely inhibited. A general dose reduction is probably not required in patients with normal renal function, but the daily dose of clarithromycin should not exceed 1 g. Dose reduction should be considered in patients with renal impairment. For patients with a creatinine clearance of 30 to 60 ml/min, the clarithromycin dose should be reduced with 50%, and at a creatinine clearance of < 30 ml/min the dose should be reduced with 75%.
Products that are inducers of CYP3A4 (e.g. rifampicin, phenytoin, carabamazepin, phenobarbital, St. Johns wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to a reduced efficacy. When clarithromycin is clearly indicated it might be necessary to increase the dose of clarithromycin and monitor the efficacy and safety of clarithromycin carefully . Furthermore monitoring the plasma levels of the CYP3A4 inducer might be necessary because the latter could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered).
Concomitant administration of rifabutin and clarithromycin resulted in an increase and decrease, respectively, in serum levels, followed by an increased risk of uveitis.
A 39% reduction in AUC for clarithromycin and a 34% increase in AUC for the active 14-OH-hydroxy metabolite have been seen when clarithromycin was used concomitantly with the CYP3A4 inducer efavirenz.
Interaction in eradication of H.pylori regimens
Although the plasma concentrations of clarithromycin and omeprazole may be increased when they are administered concurrently, no adjustment to the dosage is necessary. At the dosages recommended, there is no clinically significant interaction between clarithromycin and lansoprazole. Increased plasma concentrations of clarithromycin may also occur when it is co-administered with antacids or ranitidine. No adjustment to the dosage is necessary. There are no pharmacokinetic interactions with relevant antibiotics which are used in H. pylori eradication therapy.
4.6 Pregnancy And Lactation
Pregnancy
Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear evidence of teratogenic effects, or of adverse effects on the health of the neonate. Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of abortions. To date no other relevant epidemiological data are available.
Data from animal studies have shown reproductive toxicity (see section 5.3). The risk for humans is unknown. Clarithromycin should only be used during pregnancy after a careful benefit/risk assessment.
Lactation
Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhoea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be born in mind. The benefit of treatment of the mother should be weighed against the potential risk for the infant.
4.7 Effects On Ability To Drive And Use Machines
There are no data available on the effect of clarithromycin on the ability to drive or use machines. When performing these activities the possible occurrence of the adverse reactions dizziness, vertigo, confusion and disorientation should be taken into account.
4.8 Undesirable Effects
The most frequently reported events in adults taking clarithromycin tablets were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%).
In this section undesirable effects are defined as follows:
Very common (
Common (
Uncommon (
Rare (
Very rare (< 1/10,000), not known (cannot be estimated from the available data)
Infections and infestations
Common: Oral monilia
As with other antibiotics, prolonged use may result in the overgrowth of non-susceptible organisms.
Blood and the lymphatic system disorders
Uncommon: Decreased leucocyte levels
Very rare: Thrombocytopenia
Immune system disorders
Uncommon: Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis.
Psychiatric disorders
Very rare: Anxiety, insomnia, hallucinations, psychosis, disorientation, depersonalisation, bad dreams and confusion.
Nervous system disorders
Common: Headache, smell alteration,.
Very rare: Dizziness, vertigo, paraesthesia, convulsions.
Ear and labyrinth disorders
Rare: Tinnitus
Very rare: Reversible hearing loss
Cardiac disorders
Very rare: QT prolongation, ventricular tachycardia and Torsades de Pointes.
Gastrointestinal disorders
Common: Nausea, diarrhoea, vomiting, abdominal pain, dyspepsia, stomatitis, glossitis, reversible tooth and tongue discoloration, and taste perversion, i.e. metallic or bitter taste.
Very rare: Pancreatitis. Pseudomembranous colitis has been reported very rarely with clarithromycin, and may range in severity from mild to life threatening.
Hepato-biliary disorders
Uncommon: Hepatic dysfunction, which is usually transient and reversible, hepatitis and cholestasis with or without jaundice.
Very rare: Fatal hepatic failure has been reported particularly in patients with pre-existing liver disease or taking other hepatotoxic medicinal products.
Skin and subcutaneous tissue disorders
Very rare: Stevens-Johnson syndrome and toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders
Uncommon: Arthralgia, myalgia.
Renal and urinary disorders
Very rare: Interstitial nephritis, renal failure.
Investigations
Common: Elevated blood urea nitrogen
Uncommon: Prolongation of prothrombin time, elevated serum creatinine, altered liver function tests (increased transaminase levels).
Very rare: Hypoglycaemia has been observed especially after concomitant administration with antidiabetic medicinal products and insulin
4.9 Overdose
Symptoms of intoxication:
Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. Symptoms of overdose may largely correspond to the profile of adverse reactions. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokaliaemia and hypoxaemia.
Therapy of intoxication:
There is no specific antidote on overdose. Serum levels of clarithromycin can not be reduced by haemodialysis or peritoneal dialysis.
Adverse reactions accompanying overdose should be treated by gastric lavage and supportive measures. Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At first signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and the required measures should be initiated immediately.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
General properties
Pharmacological-therapeutical group:
Macrolides. ATC Code J01FA09.
Mechanism of action:
Clarithromycin exerts its anti-bacterial 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 clarithromycin are generally two-fold lower than the MICs of erythromycin.
The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for Haemophilus influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.
PK/PD relationship
For clarithromycin the AUC/ MIC is the major PK/ PD parameter correlating best with the efficacy of clarithromycin.
Mechanism of resistance:
The mechanisms of acquired resistance in macrolides are: efflux of active substance by an active pump mechanism, inducible or constitutive production of a methylase enzyme that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a 50s ribosomal protein.
Cross-resistance between clarithromycin and other macrolides and clindamycin and lincomycin may therefore occur. Methicillin-resistant and oxacillin-resistant staphylococci (MRSA) and penicillin-resistant Streptococcus pneumoniae are resistant to all currently available Beta-lactam antibiotics and macrolides such as clarithromycin.
Breakpoints
EUCAST (European Committee on Antimicrobial Susceptibility Testing)
|
|
|
Staphylococcus spp. |
|
|
Streptococcus spp.
|
|
|
Streptococcus pneumoniae |
|
|
Haemophilus influenzae |
|
|
Moraxella catarrhalis |
|
|
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 prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater than 10% in at least one country in the European Union
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
° No updated data were available at release of tables. Primary literature, scientific standard literature and therapeutic recommendations assume susceptibility.
$ Inherent susceptibility of most of the isolates shows intermediate resistance.
+ At least one region shows resistance rates higher than 50%.
1 The resistance rates are in some studies
2 The resistance rate is
Other information
Most available clinical experience from controlled randomised clinical trials indicate that clarithromycin 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-doudenal 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 medicinal product should be taken into the considerations for a new retreatment regimen.
5.2 Pharmacokinetic Properties
Absorption:
Clarithromycin 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 clarithromycin tablet is approximately 50%. The bioavailability of the suspension is identical to or slightly higher than the bioavailability of the tablets. The pharmacokinetic profile of the suspension in children corresponds to the pharmacokinetic profile of the suspension in adults. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, clarithromycin may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) clarithromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1 – 2 µg/ml clarithromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg clarithromycin twice daily the peak plasma level was 2,8 µg/ml. In children the following steady-state parameters were observed after the ninth dose in a dose regimen of 7,5 mg/kg twice daily on average for clarithromycin: Cmax 4,60 µg/ml, AUC 15,7 µg.hour/ml and Tmax 2,8 hours. The corresponding average values for the 14-OH metabolite were respectively: 1,64 µg/ml, 6,69 µg.hour/ml and 2,7 hours.
After administration of 250 mg clarithromycin 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:
Clarithromycin penetrates well into different compartments., with an estimated volume of distribution of 200-400 L Clarithromycin provides concentrations in some tissues that are several times higher than the circulating level of the active substance. Increased levels have been found in both tonsils and lung tissue. Clarithromycin also penetrates the gastric mucus.
Clarithromycin is approximately 80% bound to plasma proteins at therapeutic levels.
Biotransformation and elimination:
Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-dealkylation, oxidation and stereospecific hydroxylation at position C 14.
The pharmacokinetics of clarithromycin 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 clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin twice daily. With a 250 mg every 12 hours dosing, the half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours.
After oral administration of radioactive clarithromycin 70 - 80% of the radioactivity was found in the faeces. Approximately 20 -30% of clarithromycin appears as the unchanged active substance in the urine. This proportion is increased when the dose is increased. Renal insufficiency increases clarithromycin levels in plasma, if the dose is not decreased.
Total plasma clearance has been estimated to approximately 700 ml/min, with a renal clearance of approximately 170 ml/min.
Special populations
Renal impairment: Reduced renal insufficiency function results in increased plasma levels of clarithromycin and the active metabolite levels in plasma.
5.3 Preclinical Safety Data
In 4-week-studies in animals, toxicity of clarithromycin 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 (300 mg/kg/day) 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 massive dose of 400mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported
In vitro and in vivo studies showed that clarithromycin did not have genotoxic potential.
Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical dose in rabbit (iv) and x10 the clinical dose in monkey (po) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was generally noted in rat studies. However, cardiovascular malformations were observed in two studies 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%). Clarithromycin has been found in the milk of lactating animals.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Poloxamer 188
Povidone K 30
Hypromellose
Macrogol 6000
Titanium dioxide (E171)
Methacrylic acid – ethyl acrylate copolymer (1:1)
Triethyl citrate
Glycerol monostearate
Polysorbate 80
Sucrose
Maltodextrin
Potassium sorbate
Colloidal anhydrous silica
Xanthan gum
Fruit punch flavouring (natural and artificial flavouring substances including maltodextrin, modified starch and maltol).
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
After reconstitution 14 days.
6.4 Special Precautions For Storage
Do not store above 25°C.
After reconstitution: Do not store above 25°C.
6.5 Nature And Contents Of Container
60 ml, 120 ml and 240 ml HDPE bottles with child resistant PP-screw closures, an oral PE/PP-measuring syringe (5 ml) with filling marks at 2.5 ml, 3.75 ml and 5.0 ml and a PP-measuring spoon with filling marks at 1.25 ml, 2.5 ml and 5.0 ml.
Pack sizes:
Clarithromycin 125 mg/5ml granules for oral suspension
1 bottle contains 27.3 g granules for oral suspension for 40 ml ready-for-use suspension (required water amount: 23.6 g) or
34.1 g granules for oral suspension for 50 ml ready-for-use suspension (required water amount: 29.5 g) or
41.0 g granules for oral suspension for 60 ml ready-for-use suspension (required water amount: 35.4 g) or
47.8 g granules for oral suspension for 70 ml ready-for-use suspension (required water amount: 41.3 g) or
54.6 g granules for oral suspension for 80 ml ready-for-use suspension (required water amount: 47.2 g) or
68.3 g granules for oral suspension for 100 ml ready-for-use suspension (required water amount: 59.0 g) or
81.9 g granules for oral suspension for 120 ml ready-for-use suspension (required water amount: 70.8 g).
Double pack of 2 x 60 ml ready-for-use suspension: 2 x 41.0 g granules for oral suspension each for 2 x 60 ml ready-for-use suspension each (required water amount: 2 x 35.4 g each)
Clarithromycin 250 mg/5ml granules for oral suspension
1 bottle contains 34.1 g granules for oral suspension for 50 ml ready-for-use suspension (required water amount: 28.5 g) or
41.0 g granules for oral suspension for 60 ml ready-for-use suspension (required water amount: 34.2 g) or
47.8 g granules for oral suspension for 70 ml ready-for-use suspension (required water amount: 39.9 g) or
54.6 g granules for oral suspension for 80 ml ready-for-use suspension (required water amount: 45.6 g) or
68.3 g granules for oral suspension for 100 ml ready-for-use suspension (required water amount: 57.0 g).
Double pack of 2 x 60 ml ready-for-use-suspension: 2 x 41.0 g granules for oral suspension each for 2 x 60 ml ready-for-use suspension each (required water amount: 2 x 34.2 g each)
1, 2, 5, 10, 20, 30, 40, 50, 100 bottles.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The bottle should be filled with two-thirds of the overall required quantity of water, then thoroughly shaken and filled with water up to the mark and shaken again. The bottle should be shaken vigorously before each application.
After reconstitution with water the medicinal product results in a white to beige suspension.
If the dose is to be given using the oral dosing syringe, the syringe adaptor should be inserted into the bottle neck.
7. Marketing Authorisation Holder
Sandoz Ltd
200 Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
8. Marketing Authorisation Number(S)
PL 04416/0609 - Clarithromycin 125 mg/5ml granules for oral suspension
PL 04416/0610 - Clarithromycin 250 mg/5ml granules for oral suspension
9. Date Of First Authorisation/Renewal Of The Authorisation
2nd March 2005
10. Date Of Revision Of The Text
21st July 2010 (to be amended upon approval)
No comments:
Post a Comment