PATIENT INFORMATION LEAFLET
INTERNATIONAL NONPROPRIETARY NAME
Claractive 250 mg: oval, biconvex, yellow film-coated tablets with score line on one side.
Claractive 500 mg: oval, biconvex, yellow film-coated tablets with score line on one side.
Film-coated tablet contains
Active ingredient: clarithromycin 250 mg or 500 mg.
Excipients: povidone K30, polysorbate 80, silica colloidal anhydrous, talc, stearic acid, pregelatinised starch, magnesium stearate, croscarmellose sodium, microcrystalline cel- lulose.
Coating composition: Opadry® II yellow 85F32085 (polyvinyl alcohol partially hydro- lyzed, macrogol, titanium dioxide, talc, quinoline yellow aluminum lake, iron oxide yel- low, sunset yellow FCF aluminum lake).
АТC CODE J01FA09
PHARMACOLOGICAL PROPERTIES PHARMACODYNAMICS
Claractive is a second-generation semisynthetic broad-spectrum bacteriostatic anti- biotic of the macrolide group. The drug inhibits the protein synthesis by binding with the 50S ribosomal subunit of microbial cell membrane ribosomes susceptible microorga- nisms.
Clarithromycin is a high-potent substance against most aerobic and anaerobic gram- positive and gram-negative microorganisms, both in vitro and in vivo:
Production of β-lactamase does not influence on the activity of clarithromycin. Enterobacteriaceae, Pseudomonas spp. are resistant to Clarithromycin as well as other gram-negative bacteria that do not decompose lactose. Most strains of staphylococci that are resistant to methicillin and oxacillin are resistant to clarithromycin. Development of cross-resistance to clarithromycin and other macrolide antibiotics as well as to lincomycin and clindamycin is possible.
Microbiological activity of the main metabolite of clarithromycin in human body - 14 hydroxyclarithromycin against Haemophilus influenzae is 2 times higher than the microbiological activity of clarithromycin. Incoming substance and its major metabolite have either additive or synergistic effect regarding to the indicated microorganism. However, 14 hydroxyclarithromycin is 4-7 times less active to MAC than its intact compound. Clinical significance of this activity against MAC is unknown.
Clarithromycin is well absorbed from the gastrointestinal tract. When taken orally its bioavailability is 55%. Food delays absorption, but does not significantly influence on the bioavailability of clarithromycin. Binding with proteins is more than 90%. Appro- ximately 20% of clarithromycin is immediately metabolized in the liver by cytochrome ferments CYP3A4, CYP3A5 and CYP3A7 in the major metabolite - 14 hydroxycla- rithromycin, which have expressed activity related to Haemophilus influenzae. Maximum plasma concentration (Cmax) is achieved in less than 3 hours. When taken 250 mg of clarithromycin per day regularly the steady state concentration (Css) of parent drug is 0.62-0.84 µg/ml and the steady state concentration of its major metabolite is 0.4-0.7 µg/ml respectively; by increasing dose up to 500 mg of parent drug Css is 1.77-1.89 µg/ml and Css of its metabolite in plasma is 0.67-0.8 µg/ml. Clarithromycin can easily penetrate into tissues (lungs, palatine tonsil, saliva, sputum and middle ear, skin and soft tissues of the body) and the body fluid, where it reaches a concentration about 10 times higher than the concentration in serum. Half-life after administration of 250 mg dose is 3-4 hours; after administration of 500 mg dose is 5-7 hours. 20-30% of clari- thromycin are excreted unchanged by kidneys and the rest part as metabolites.
of peptic ulcer;
DOSAGE AND ADMINISTRATION
Claractive is administered orally without chewing or crushing, swallowed whole with small amount of water at any time (preferably in the same) of the day regardless of meals.
In case of missing the time of the drug administration the missed dose of the drug should be taken as soon as possible. However, when it is time of taking the next dose, do not double the dose of the drug in order to compensate the missed administration. The usual dose of medicine for adults and children older than 12 years is 250 mg every 12 hours. In case of severe infections the dose can be increased up to 500 mg every 12 hours. Usual length of treatment is 6-14 days.
To eradicate Helicobacter pylori the dose of 250-500 mg 2 times a day usually for 7-14 days is prescribed in combination with other drugs.
In patients with Mycobacterium avium infection the initial dose is 500 mg every 12 hours. If within 3-4 weeks on the basis of clinical or bacteriological data improvement isn't observed, the dose can be increased up to 1000 mg twice a day.
Treatment of disseminated infection caused by MAC in AIDS patients is recommended to continue as long as lasting clinical or microbiological efficacy of the drug. Clarithro- mycin should be used in complex with other antibacterial drugs.
In treatment of odontogenous infections the recommended dose is 250 mg every 12 hours for 5 days.
For elderly patients used the same dosage as for adults.
Administration of the drug in patients with hepatic insufficiency
There is no need to adjust the dose in patients with mild or moderate hepatic insuffi- ciency in patients with normal renal function.
Administration of the drug in patients with renal failure
For patients with impaired renal function with a creatinine clearance less than 30 ml/min the dose of clarithromycin should be reduced to 2 times i.e. to 250 mg once a day or 250 mg twice a day in more severe infections. The duration of the treatment should not be more than 14 days in such patients.
Digestive system: common – diarrhea, vomiting, abdominal pain, nausea; rare – glos- sitis, stomatitis, candidiasis of the oral mucosa, variation of the color of the tongue and teeth (reversible), liver function abnormalities, including transient increase in transa- minases and hepatocellular and/or cholestatic hepatitis, with or without jaundice (he- patic dysfunction may be severe and is usually reversible), acute pancreatitis, pseudo- membranous colitis (from moderate severity to life-threatening). Sporadic cases of death from liver failure were recorded, which is usually observed in the presence of severe comorbidities and/or concomitant use of other drugs.
Nervous system: uncommon – transient headache, dizziness, anxiety, insomnia, night- mares, tinnitus; rare – seizures; very rare – myalgia, paresthesia, confusion, disorienta- tion, hallucinations, psychosisand depersonalization.
Cardiovascular system: rare – ventricular tachycardia, ventricular arrhythmia type "pirouette", ventricular flutter and fibrillation, QT interval prolongation on the electro- cardiogram (as with other macrolides).
Sense organs: very rare – tinnitus, ringing of the ears, violation of smell, taste change (dysgeusia); in rare cases – hearing loss, passing after drug withdrawal.
Urinary system: very rare – the development of interstitial nephritis and renal failure. Allergic reactions: uncommon – skin rash, itching, urticaria, dermahemia; rare – anap- hylactic reactions, exudative erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis.
Laboratory values: uncommon – increased "liver" transaminases and bilirubin; very rare – leukopenia, thrombocytopenia, increased prothrombin time, hypercreatinine- mia, hypoglycemia (during simultaneous administration of hypoglycemic drugs).
Other: unusual bleeding, hemorrhage, myalgia, during prolonged or repeated use of the drug superinfectiondevelopmentis possible (developmentof microbialresistance).
Claractive should not be used during pregnancy except in cases of absence of alterna- tive therapy. In such cases and in the event of pregnancy during the drug administration a potential threat to the fetus should be considered.
During the administration of clarithromycin in patients with moderate and severe renal impairment, regardless of the functional state of the liver is necessary either to reduce
the single dose or increase the interval between doses of antibiotic. In clinical practice described colchicine toxicity when it is combined with clarithromycin, particularly in elderly. Some of them were observed in patients with renal insufficiency; several cases of death in these patients were reported.
Patients with creatinine clearance less than 25 ml/min and patients with a history of acute porphyria are not recommended for combination therapy of clarithromycin with ranitidine bismuth citrate.
Patients with impaired liver function and normal renal function, dose adjustment is not required. With caution the drug is prescribed in patients receiving drugs metabolized by the liver (recommended measure their concentration in blood serum).
In the case of concomitant prescription of Claractive with warfarin or other indirect anticoagulants it is necessary to control the prothrombin time.
When the prolonged and severe diarrhea occurs during or after the treatment a patient should be examined on having such diagnosis as pseudomembranous colitis. If the diagnosis is confirmed the drug should be immediate discontinued and the appropriate treatment should be prescribed.
During the therapy with clarithromycin myasthenia gravis symptoms and occurring of myasthenic syndrome symptoms have been registered.
During the unreasonable, prolonged or repeated administration of antibiotic the super- infection (insensitive growth of bacteria and fungi) may develop. With the development of the secondary infection the adequate therapy should be prescribed. The possibility of the development of cross-resistance between the drug Claractive and other macro- lide antibiotics, as well as lincomycin and clindamycin should be considered.
During the administration of clarithromycin for Helicobacter pylori eradication the control study on the presence of the pathogen should be performed not earlier than 4 weeks after discontinuation of the antibiotic.
INFLUENCE ON ABILITY TO DRIVE AND OTHER MECHANISMS
The studies of the effect of clarithromycin on the ability to drive and operate other mecha- nisms have not been performed.
However, it is necessary to exercise caution while driving or operating other mecha- nisms (during the treatment with clarithromycin such diagnosis as dizziness and/or disorientation may occur).
PREGNANCY AND LACTATION
The studies of the safe administration of clarithromycin in pregnant and lactating wo- men have not been performed. In the I trimester of pregnancy the use of clarithromycin is contraindicated. In the II and III trimester the prescription of clarithromycin is possible only if there is no alternative therapy and only if the potential positive effect to mother overweighs the potential risk to fetus.
Clarithromycin is excreted with breast milk. When the prescription of the drug during the period of lactation is necessary the breast-feeding should be stopped.
The drug is contraindicated in children under 12 years old.
During the simultaneous administration of clarithromycin with verapamil (the drug which blocks calcium channels) the decrease of blood pressure, bradyarrhythmia and lactic acidosis are observed.
In patients, receiving high doses of theophylline, the concentration of theophylline in blood serum, which can increase due to coadministration of clarithromycin, should be controlled.
Administration of 500 mg clarithromycin every 8 hours together with 40 mg omepra- zole daily resulted in increase of omeprazole Css (Cmax, AUC, T1/2 increased by 30%, 89% and 34% respectively) in healthy adult patients. The pH value of the gastric juice was
5.2 during the omeprazole monotherapy and 5.7 during the simultaneous administra- tion with clarithromycin.
Combined therapy of clarithromycin with ranitidine bismuth citrate resulted in increase of the concentration of ranitidine (57%), bismuth (48%) and 14 hydroxyclarithromycin (31%) in plasma. This effect does not have clinical significance.
Simultaneous administration of clarithromycin (tablets 250 mg) and zidovudine in adult HIV-infected patients may result in the decrease of the equilibrium level of zidovudine concentration. It is necessary to perform the adjustment of clarithromycin and zidovudine doses. The administration of the antibiotic does not have a statistically significant effect on the didanosine pharmacokinetics in adult HIV-infected patients.
During the simultaneous administration of 200 mg fluconazole daily with 1 g clarithro- mycin per day the equilibrium concentration of clarithromycin AUC may increase by 33% and 18% respectively. There is no need to adjust the dose of clarithromycin.
During the simultaneous administration of clarithromycin and ritonavir, atazanavir or other protease inhibitors AUC values of clarithromycin increase by 77% and AUC value of 14 hydroxyclarithromycin decreases by 100%. There is no need to adjust the dose in patients with the normal renal function, in patients with the creatinine clearance of 30-60 ml/min it is required to reduce the dose of clarithromycin by 50%, in patients with the creatinine clearance which is less than 30 ml/min the clarithromycin dose should be reduced by 75%.
It is reported about the increase of digoxin concentration in plasma of the patients who have administered digoxin and clarithromycin simultaneously. The content of digoxin in the serum should be constantly controlled to avoid digitalis intoxication and the development of potentially fatal arrhythmias.
Since the concomitant prescription of colchicine, which is a substrate for CYP3A and P- glycoprotein, and clarithromycin, as well as other macrolides - inhibitors of CYP3A and P-glycoprotein, the inhibition may result in exaggeration of colchicine action; the patients should be carefully controlled in order to identify the symptoms of the toxic action of colchicine. During the administration of clarithromycin with tolterodine in patients with a low CYP2D6 isoenzyme activity the reduction of tolterodine dose in the presence of clarithromycin may be required (an inhibitor of CYP3Aisozymes).
During the simultaneous administration of clarithromycin and the drugs, primarily me- tabolized by isoenzymes CYP3A, their concentrations may increase, which can en- hance or prolong both therapeutic and side effects.
Simultaneous administration with astemizole, cisapride, pimozide, terfenadine, ergota- mine and other ergot alkaloids, alprazolam, midazolam, triazolam is contraindicated.
The drug should be prescribed with caution with carbamazepine, cilostazol, cyclospo- rine, disopyramide, lovastatin, methylprednisolone, indirect anticoagulants (including warfarin), quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, vinblastine, pheny- toin, theophylline and valproic acid (they are metabolized by other cytochrome P450 isoenzymes). The dose adjustment of the drugs and the control of the concentration in
serum are necessary.
During the simultaneous administration with cisapride, pimozide, terfenadine and aste- mizole is possible increasing their concentration in the blood, QT prolongation and development of cardiac arrhythmias, including ventricular paroxysmal tachycardia, ventricular fibrillation or flutter, polymorphic ventricular tachycardia type "pirouette". Such a mechanism of interaction observed with the use of drugs metabolized by other cytochrome P450 isoenzyme - phenytoin, theophylline and valproic acid. ECG and blood serum level determinations are required for these drugs when administered concomitantly.
Clarithromycin may reduce triazolam clearance as a result enhancing its pharma- cological effects with the development of drowsiness and confused consciousness. For benzodiazepines, excretion of which is independent of the CYP3A isoenzymes (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithro- mycin is unlikely.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine (cytochrome P450 indu- cers) decrease the concentration of clarithromycin in plasma and weaken its thera- peutic effect, increasing the concentration of 14 hydroxyclarithromycin at the same time.
Simultaneous use of ergotamine and dihydroergotamine (ergot derivatives) may lead to acute ergot intoxication manifested severe peripheral vasospasm, ischemia of the limbs and other tissues, includingthe central nervous system, and pervertedsensitivity. During the simultaneous administration of clarithromycin with inhibitors of hydro- xymethylglutaryl-CoA reductase - lovastatin and simvastatin are described rare cases of rhabdomyolysis.
Attention should be paid to the possibility of cross resistance between clarithromycin and other macrolide antibiotics as well as lincomycin and clindamycin.
During the simultaneous administration of clarithromycin and itraconazole the con- centrations of both drugs in plasma may increase. The patients who administer itraconazole and clarithromycin simultaneously should be carefully controlled, since the enhancement or prolongation of both therapeutic and side effects of the drugs are possible.
During the simultaneous administration of clarithromycin (1 g daily) and saquinavir (soft gelatin capsules, 1200 mg 3 times daily) the increase of AUC and equilibrium concentration of saquinavir by 177% and 187%, respectively, and 40% of clarithro- mycin is possible. During the simultaneous administrations of the drugs for a short time in the doses/pharmaceutical forms, mentioned above, the dose adjustment is not necessary.
Symptoms: abdominal pain, nausea, vomiting, diarrhea, may cause headache, confu- sed consciousness.
Treatment: in case of overdose the immediate gastric lavage and symptomatic treat- ment are indicated.
Hemodialysis and peritoneal dialysis are not significantly reducing the concentration of clarithromycin in blood serum.
Claractive 250 mg
7 or 14 tablets in a blister.
2 blisters of 7 tablets or 1 blister of 14 tablets with the enclosed leaflet in a carton box.
Claractive 500 mg Film-coated tablets. 7 tablets in a blister.
Store in a protected from light place at temperature not exceeding 25°C. Keep out of reach of children!
Sold under prescription.
СLARACTIVE is a product and a trade mark of "Sanolife", Great Britain.
“WORLD MEDICINE İLAÇ SAN. VE TİC. А.Ş.”, TURKEY