Body weight* (kg)	Single dose when taking 2 times a day, ml
	125 mg/5 ml		250 mg /5 ml
	7.5 mg/kg 2 times a day	15 mg/kg 2 times a day	7.5 mg/kg 2 times a day	15 mg/kg 2 times a day
8-11	2,5 ml	5 ml	1,25 ml	2,5 ml
12-19	5 ml	10 ml	2,5 ml	5 ml
20-29	7,5 ml	15 ml	3,75 ml	7,5 ml
30-40	10 ml	20 ml	5 ml	10 ml

INTERNATIONAL NONPROPRIETARY NAME
Clarithromycin

PHARMACEUTICAL FORM
Granules for oral suspension.
Description: white or almost white coloured, homogeneous fluid granules.

COMPOSITION
5 ml of reconstituted suspension contain
Active ingredient: clarithromycin 125 mg or 250 mg.
Excipients: hypromellose, talc, simethicone emulsion, macrogol, methacrylic acid copolymer 30% dispersion, polysorbate 80, sodium hydroxide, sucrose, maltodextrin, potassium sorbate, silica colloidal anhydrous, xan- than gum, citric acid anhydrous, Tutti-Frutti flavour, titanium dioxide, magnesium stearate.

АТC CODE             J01FA09

PHARMACOTHERAPEUTIC GROUP
Antibiotic, macrolide.

PHARMACOLOGICAL PROPERTIESPHARMACODYNAMICS
Сlaractive is a second-generation semisynthetic broad-spectrum bacteriostatic antibiotic of the macrolide group. The drug inhibits the protein synthesis by binding with the 50S ribosomal subunit of microbial cell membrane ribosomes susceptible  microorganisms.
Clarithromycin is a high-potent substance against most aerobic and anaerobic gram-positive and gram- negative microorganisms, both in vitro and in vivo:

• aerobic gram-positive microorganisms: Staphylococcus spp. (including methicillin-sensitive Staphylococcusaureus), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viri- dans, Listeria monocytogenes;
• aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella(Branhamella) catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila, Bordetella pertussis, Helicobacterpylori, Campylobacter jejuni;
• mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium avium complex ((MAC), including Mycobacterium avium, Mycobacterium  intracellulare);

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. Clarithromycincan 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 clarithromycin (40% of clarithromycin when taken a suspension) are excretedunchangedby kidneysand the rest part as metabolites.

THERAPEUTIC  INDICATIONS

• upper respiratory tract infections: pharyngitis, laryngitis, tonsillitis, sinusitis;
• lower respiratory tract infections: bronchitis, pneumonia;
• acute otitis media;
• uncomplicated infections of the skin and subcutaneous tissue: folliculitis, furunculosis, erysipelas, impetigo, wound infection;
• treatment and prevention of common or localized mycobacterial infections caused by Mycobacterium avium,

Mycobacterium inlracellulare; localized infections caused by Mycobacterium fortuitum, Mycobacterium kansa- sii and Mycobacterium chelonae;

• peptic ulcer and/or duodenal ulcer (in combination therapy) – for the treatment of acute duodenal ulcer, Helico-

bacter pylori eradication and reduction of recurrence rate of peptic ulcer.

DOSAGE AND ADMINISTRATION
Сlaractive suspension is administered orally regardless of food.
The suspension is prepared immediately before the first use. To prepare the suspension water should be gra- dually added into the bottle with the granules and then the bottle should be shacked until the formation of a ho- mogeneous suspension. Before each use, the drug should be carefully stirred up.
The dosage should be determined individually depending on the age, body weight, renal function of the patient
and the severity of the infection.
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 recommended daily dose of Сlaractive suspension for children with non-mycobacterial infections   is
7.5 mg/kg 2 times a day. Maximum dose is 500 mg 2 times a day. Usual length of treatment is 5-10 days depen- ding on the activator and the severity of the patient's condition.
The table shows the dosing recommendations for children taking into account the body weight:

 

• For children weighing up to 8 kg the dose should be calculated per kilogram of the body weight (15-30 mg/kg per day)

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.
Administration of the drug in patients with hepatic insufficiency
There is no need to adjust the dose in patients with mild or moderate hepatic insufficiency or in patients with normal renal function.
Administration of the drug in patients with renal failure
For children with a creatinine clearance less than 30 ml/min the dose of clarithromycin should be reduced to 2 times. The duration of the treatment should not be more than 14 days in such patients.

CONTRAINDICATIONS

• hypersensitivity to clarithromycin or other components or macrolide antibiotics;
• porphyria;
• simultaneous administration of the following drugs: astemizole, cisapride, pimozide, terfenadine (since it can lead to QT interval prolongation and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and ventricular tachycardia type "pirouette");
• simultaneous administration of clarithromycin and ergotamine or dihydroergotamine (since it can lead to ergo- toxity);
• simultaneous administration of colchicine in patients with impaired hepatic or renal function;
• simultaneous administration of HMG-CoA reductase inhibitors (statins) that are significantly metabolized by isoenzyme CYP3A4 (lovastatin, simvastatin), because of the increased risk of myopathy, including rhabdo- myolysis;
• hypokalemia (risk of QT interval prolongation);
• QT interval prolongation or ventricular cardiac arrhythmias in past medical history, including ventricular tachy- cardia type "pirouette";
• severe liver failure, which run concurrently with renal failure;
• I trimester of pregnancy and lactation period.

SIDE EFFECTS
Parameters of the side effect frequency used below are determined in the following way: common (from
≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), unspecified frequency – the parameters of frequency can't be evaluated according to available data.
Digestive system: common – diarrhea, vomiting, abdominal pain, nausea, dyspepsia; uncommon – glossitis, stomatitis, gastritis, constipation, flatulence; unknown frequency – variation of the color of the tongue and teeth (reversible), pancreatitis.
Liver and bile passages: common – abnormalities in liver function tests; uncommon – increased levels of alanine aminotransferase and aspartate aminotransferase; unspecified frequency – hepatic failure, hepatocel- lular jaundice.
Nervoussystem: common– headache, insomnia, disturbanceof taste sensitivity; uncommon– dizziness, drow- siness, tremor; unspecified frequency – convulsions, loss of taste sensitivity, parosmia, anosmia, paresthesia, disorientation.
Cardiovascular system: uncommon – QT interval prolongation on the electrocardiogram, heart rate; unspe- cified frequency – ventricular tachycardia type "pirouette", ventricular tachycardia.
Organ of hearing: uncommon – hearing loss, acuphenes; unspecified frequency – deafness.
Kidneys: unspecified frequency – renal failure, interstitial nephritis.
Skin and subcutaneous tissues: common – rash, hyperhidrosis; uncommon – itching, rash, dermahemia; un- specified frequency – Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic manifestations, acne.
Hematopoietic system: uncommon – leukopenia, thrombocytopenia; unspecified frequency – agranulocytosis, thrombocytopenia.
Allergic reactions: uncommon – hypersensitivity; unspecified frequency - anaphylactic reaction.

PARTICULAR  INDICATIONS
During the administration of clarithromycin it has been reported about the compromised liver function, including increased level of liver enzymes, and hepatocellular and/or cholestatic hepatitis with biliousness or without it. This hepatic dysfunction may be severe and is usually reversible. The administration of clarithromycin should be immediately discontinued in the cases of such signs and symptoms of hepatitis as anorexia, biliousness, dark urine, itching and abdominal pain.
During the simultaneous administration of clarithromycin and colchicine the state of patients should be con- trolled by the doctor in order to detect the clinical signs of toxicity of colchicine. The dose of colchicine should be reduced for all the patients treated with colchicine and clarithromycin simultaneously. Simultaneous admini- stration of clarithromycin with colchicine in patients with renal or hepatic impairment is contraindicated.
Simultaneous oral administration of midazolam and clarithromycin should be avoided. When clarithromycin is administered together with intravenous form of midazolam, the patient's state should be carefully controlled for possible dose adjustment. The same precautionary measures should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam.
Clarithromycin should be administered with caution in combined therapy with statins. When simultaneous ad- ministration is necessary it is recommended to take the lowest dose of the statin. The statins that are indepen- dent from metabolism CYP3A(for example fluvastatin) should be administered.
Clarithromycin is preferably excreted by the liver. The drug should be prescribed with special care in patients with compromised liver function and in patients with moderate or severe renal impairment.
In case of concomitant prescription of Сlaractive with warfarin or other indirect anticoagulants it is necessary to control the prothrombin time.
When 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 imme- diate 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 superinfection (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 Сlarac- tive and other macrolide 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 OPERATE  MECHANISMS
The studies of the effect of clarithromycin on the ability to drive and operate other mechanisms have not been performed.
However, it is necessary to exercise caution while driving or operating other mechanisms (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 women have not been perfor- med. 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 foetus.
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.

PEDIATRIC USE
The safety and efficacy data of clarithromycin administration in children at the age of 6 months have not been detected. In children at the age of 12 years it is recommended to administer Сlaractive in the form of sus- pension.

DRUG INTERACTIONS
During the simultaneous administration of clarithromycin with verapamil (the drug which blocks calcium chan- nels) 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 omeprazole daily resulted in incre- ase 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 administration 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 (conventional release tablets) 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. 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 clarithromycin per day the equi- librium 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 CYP3Aand P- glycoprotein, and clari- thromycin, 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 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 metabolized by isoenzymes CYP3A, their concentrations may increase, which can enhance or prolong both therapeutic and side effects.
Simultaneous administration with astemizole, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids, lovastatin, simvastatin is contraindicated.

The drug should be prescribed with caution with carbamazepine, cilostazol, cyclosporine, disopyramide, methyl-prednisolone, indirect anticoagulants (including warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine, phenytoin and valproic acid (they are metabolized by other cytochrome P450 isoenzymes). The dose adjust-ment of the drugs and the control of the concentrationin serum are necessary.
Clarithromycin may reduce triazolam clearance as a result enhancing its pharmacological effects with the development of drowsiness and confused consciousness. For benzodiazepines, excretion of which is inde- pendent of the CYP3A isoenzymes (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine (cytochrome P450 inducers) decrease the concen- tration of clarithromycin in plasma and weaken its therapeutic effect, increasing the concentration of 14 hyd- roxyclarithromycin at the same time.
During the simultaneous administration of clarithromycin and itraconazole the concentrations 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 clarithromycin 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.

OVERDOSE
Symptoms: abdominal pain, nausea, vomiting, diarrhea, may cause headache, confused consciousness. Treatment: in case of overdose the immediate gastric lavage and symptomatic treatment are indicated. Hemodialysis and peritoneal dialysis are not significantly reducing the concentration of clarithromycin in blood serum.

PACKAGING
Сlaractive 125 mg/5 ml
Granules for oral suspension in amber glass bottle of 100 ml (70 ml of reconstituted suspension) with a scre- wing protective cap, equipped with safety ring.
1 bottle together with a measuring syringe with adaptor and a patient information leaflet in a carton box.
Сlaractive 250 mg/5 ml
Granules for oral suspension in amber glass bottle of 100 ml or 125 ml (50 ml or 100 ml of reconstituted sus- pension respectively) with a screwing protective cap, equipped with safety ring.

• bottle together with a measuring syringe with adaptor and the enclosed leaflet in a carton box.

STORAGE CONDITIONS
Store at temperature not exceeding 25°C. Keep out of reach of children!
Store reconstituted suspension not longer than 14 days.

SHELF LIFE

• years from the manufacturing date. Do not use after expiry date.

SALES TERMS
Sold under prescription.

MANUFACTURER
СLARACTIVE is a product and a trade mark of "Sanolife", Great Britain.
Manufactured by
“WORLD MEDICINE İLAÇ SAN. VE TİC. А.Ş.”, TURKEY