1. Name Of The Medicinal Product
Clarithromycin 250mg Film-coated Tablets
Clarithromycin 500mg film-coated Tablets
2. Qualitative And Quantitative Composition
Clarithromycin 250mg film-coated tablets
1 film-coated tablet contains 250mg Clarithromycin
Clarithromycin 500mg film-coated tablets
1 film-coated tablet contains 500mg Clarithromycin
For excipients. see 6.1
3. Pharmaceutical Form
Film-coated tablet
Clarithromycin 250mg film-coated tablets: dark yellow, capsule shaped film-coated tablets.
Clarithromycin 500mg film-coated tablets: light yellow, film-coated, oval shaped tablets.
4. Clinical Particulars
4.1 Therapeutic Indications
Clarithromycin film-coated tablets are indicated for the treatment of the following acute and chronic bacterial infections, when caused by susceptible bacteria.
Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia.
Upper respiratory tract infections for example, sinusitis and pharyngitis.
Clarithromycin is appropriate for initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens as listed in section 5.1.
Skin 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 H. pylori in 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 film-coated Tablets depends on the clinical condition of the patient and has to be defined in any case by the physician.
Children older than 12 years and adults:
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 can be used in a dose of 500 mg twice daily during the eradication therapy in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily*.
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.
Duration of therapy:
The duration of therapy with Clarithromycin film-coated Tablets 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 is 6 to 14 days.
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 (two 250 mg tablets or one 500 mg tablet) 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:
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 and formation of the 14-hydroxy metabolite.
4.3 Contraindications
• Clarithromycin film-coated Tablets should not be used in patients with known hypersensitivity to clarithromycin, to other macrolides or to any of the other tablet ingredients.
• Clarithromycin and ergot derivatives should not be co-administered.
• Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide and terfenadine. Elevated cisapride, pimozide and terfenadine levels have been reported in patients receiving either of these drugs 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.
• Clarithromycin should not be administered to hypokalaemic patients (prolongation of QT-time, see section 4.4).
4.4 Special Warnings And Precautions For Use
Due to a potential to increase QT, clarithromycin should be used with care in patients with a history of ventricular arrhythmias, severe cardiac insufficiency, uncorrected hypokalaemia and or hypomagnesaemia, bradycardia (<50 bpm), or during concomitant administration with other medicinal products with a QT-prolonging effect. Clarithromycin should not be used in patients with congenital or documented acquired QT prolongation.
Clarithromycin is principally excreted by the liver and kidney. Caution should be exercised in administering this antibiotic to patients with impaired hepatic or renal function.
Dosage of Clarithromycin should be suitably reduced depending on the degree of the renal impairment (see section 4.2). In elderly patients, the possibility of renal impairment should be considered.
H. pylori organisms may develop resistance to clarithromycin.
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 used of clarithromycin may result in an overgrowth of non-susceptible bacteria or fungi. If super-infection occurs, clarithromycin should be discontinued and appropriate therapy instituted.
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
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Medicines metabolised by cytochrome P450 enzyme system
As with other macrolide antibiotics the use of clarithromycin in patients concurrently taking drugs metabolised by the cytochrome P450 system (e.g. terfenadin, astemizol, alprazolam, triazolam, midazolam, carbamazepine, phenytoin, hexobarbital, pimozide, disopyramide, quinidine, ergot alkaloids, sildenafil, lovastatin, simvastatin, ciclosporin, tacrolimus, methylprednisolone, alfentanil, omeprazole, cisapride, warfarin, rifabutin, vinblastine) may be associated with elevations in serum levels of these other drugs.
Medicines that prolong QT interval
Macrolides have been reported to alter the metabolism of cisapride, terfenadine, astemizole and pimozide resulting in increased levels of these drugs. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes.
HMG Co-A reductase inhibitors
Rhabdomyolysis, co-incident with the co-administration of clarithromycin, and HMG-CoA reductase inhibitors, such as atorvastatin, cerivastatin, lovastatin, and simvastatin has been reported. Treatment should be stopped if muscle toxicity is suspected clinically (muscle pain, tenderness, or weakness) or if creatine phosphokinase is markedly raised or progressively rising.
Anticoagulants
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.
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.
Antivirals
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.
Ritonavir increases the area under the curve (AUC), Cmax and Cmin of clarithromycin when administered concurrently. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 ml/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30ml/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1g/day should not be co-administered with ritonavir.
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).
Ciclosporin, tacrolimus and sirolimus
Concomitant use of oral clarithromycin and ciclosporin or tacrolimus have resulted in more than a 2-fold increase of the Cmin-levels of both ciclosporin and tacrolimus. Similar effects are also expected for sirolimus. When initiating treatment with clarithromycin in patients already receiving any of these immunosuppressive agents, ciclosporin, 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 ciclosporin, tacrolimus or sirolimus, is again necessary to guide dose adjustment.
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.
Digoxin
The effects of digoxin may be potentiated with concomitant administration of clarithromycin. Monitoring of serum digoxin levels should be considered.
Carbamazepine
Clarithromycin may potentiate the effects of carbamazepine due to a reduction in the rate of excretion.
Rifabutin
Due to accelerated hepatic metabolism of clarithromycin, concomitant administration of rifabutin and clarithromycin resulted in an increase and decrease, respectively, in serum levels, followed by an increased risk of uveitis.
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
None has been reported so far.
4.8 Undesirable Effects
The most frequently reported events in adults taking clarithromycin were diarrhoea (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 (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.
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 leukocyte 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 Torsade 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 drugs.
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 drugs 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 side effects. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
General properties
Pharmacological-therapeutical group:
ATC Code J01FA09. Clarithromycin is a semi-synthetic derivative of erythromycin A.
Mechanism of action:
Clarithromycin 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 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 H influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Breakpoints
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* National Committee on Clinical Laboratory Standards, in 2001
** British Society for Antimicrobial Chemotherapy
Susceptibility
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an appropriate guidance on the probabilities whether micro-organisms will be susceptible to clarithromycin or not. As far as applicable the information on the European range of acquired resistance for the individual micro-organism is indicated in brackets.
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MRSA - methicillin resistant Staphylococcus aureus
1) Frequencies of resistance ranges calculated on NCCLS breakpoints
Other information
Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to clarithromycin can be predicted by testing erythromycin.
The mechanisms of acquired resistance in macrolides are: efflux of drug 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 50 S 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.
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 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 treatment regimen.
5.2 Pharmacokinetic Properties
Absorption:
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract – primarily in the jejunum - after oral administration. Due to its chemical structure (6-O-Methylerythromycin) clarithromycin is quite resistant to degradation by stomach acid. Serum 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 serum levels of 2,8 µg/ml were obtained.
After administration of 250 mg clarithromycin twice daily the pharmacological active 14-hydroxy metabolite attains peak plasma concentrations of 0,6 µg/ml.
Distribution:
Clarithromycin gives good penetration into different compartments. Therapeutic drug levels exceeding the minimum inhibitory levels for common pathogens can be rapidly achieved. Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin also penetrates the gastric mucus.
Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Serum half-life:
The serum half-life of the active 14-(R)-hydroxy metabolite ranges between 5 to 6 hours.
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.
After oral administration of radioactive clarithromycin 70 - 80% of the radioactivity was found in the faeces. Approximately 20 -30% of clarithromycin is collected as the unchanged parent molecule 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.
The pharmacokinetics of clarithromycin are non linear. This is an indication for a saturation of hepatic metabolism at high doses; however, steady state is attained within 2 days of dosing.
5.3 Preclinical Safety Data
In acute mouse and rat studies, the median lethal dose was greater than the highest feasible dose for administration (5g/kg).
In repeated dose studies, toxicity was related to dose, duration of treatment and species. Dogs were more sensitive than primates or rats. The major clinical signs at toxic doses included emesis, weakness, reduced food consumption and weight gain, salivation, dehydration and hyperactivity. In all species the liver was the primary target organ at toxic doses. Hepatotoxicity was detectable by early elevations of liver function tests. Discontinuation of the drug generally resulted in a return to or toward normal results. Other tissues less commonly affected included the stomach, thymus and other lymphoid tissues and 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.
Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Spraque-Dawley (p.o. and i.v.)), New Zealand White rabbits and cynomolgus monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate and embryonic loss was seen in monkeys but only at dose levels which were clearly toxic to the mothers.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Core: croscarmellose sodium, microcrystalline cellulose, povidone, magnesium stearate, colloidal anhydrous silica, talc.
Film-Coat: hypromellose, propylene glycol, titanium dioxide (E171), hydroxypropylcellulose, sorbitan monooleate, quinolin yellow (E104), vanillin.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
2 years.
6.4 Special Precautions For Storage
Store in the original package.
6.5 Nature And Contents Of Container
PVC/PVDC aluminium blister
Pack sizes:
Clarithromycin 250 mg film-coated Tablets: 8, 10, 12, 14, 15, 16, 20, 21, 24, 49, 50, 100, 100x1.
Clarithromycin 500mg film-coated tablets: 5, 6, 7, 8, 10, 12, 14, 15, 16, 20, 21, 30, 50, 60, 100, 100x1, 140.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
No Data Held
7. Marketing Authorisation Holder
Sandoz Limited
37 Woolmer Way
Bordon
Hampshire
GU35 9QE
United Kingdom
8. Marketing Authorisation Number(S)
PL 04416/0641 - 250mg Film-coated Tablets
PL 04416/0642 - 500mg film-coated Tablets
9. Date Of First Authorisation/Renewal Of The Authorisation
23rd December 2004
10. Date Of Revision Of The Text
18th November 2005
* according the publication in Gastroenterology. 1999 Feb; 116(2): 248-53
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