Friday, September 30, 2016

Kalcipos-D 500 mg / 800 IU chewable tablets





1. Name Of The Medicinal Product



Kalcipos-D 500 mg/ 800 IU chewable tablets


2. Qualitative And Quantitative Composition



Each chewable tablet contains calcium carbonate equivalent to 500 mg calcium, cholecalciferol (Vitamin D3) 800 IU (20 microgram).



Excipients: glucose 200 mg, sucrose 3.8 mg and hydrogenated soya-bean oil 0.8 mg.



For a full list of excipients, see section 6.1.



3. Pharmaceutical Form



Chewable tablet



White, round, engraved R152, diameter 17 mm.



4. Clinical Particulars



4.1 Therapeutic Indications



Prevention and treatment of calcium and vitamin D deficiency in the elderly. Vitamin D and calcium supplement in addition to specific osteoporosis treatment of patients who are at risk of vitamin D and calcium deficiency.



4.2 Posology And Method Of Administration



Adults and elderly



One chewable tablet (500 mg/800 IU) daily. To be chewed or slowly melted in the mouth.



The amount of calcium in Kalcipos-D is less than the usually recommended daily intake.



Kalcipos-D is therefore primarily to be used by patients with need of D-vitamin substitution but with a dietary intake of calcium of 500 mg-1000 mg per day. The patients dietary intake of calcium should be estimated by the prescriber.



Dosage in hepatic impairment



No dose adjustment is required



Dosage in renal impairment



Kalcipos-D should not be used in patients with severe renal impairment (see section 4.3).



There is no relevant indication for use of Kalcipos-D chewable tablets in children or adolescents.



4.3 Contraindications



• Diseases and/or conditions resulting in hypercalcaemia or hypercalciuria.



• Nephrolithiasis.



• Nephrocalcinosis



• Hypervitaminosis D.



• Renal failure.



• Hypersensitivity to calcium carbonate or cholecalciferol.



• Hypersensitivity to any of the excipients.



Kalcipos-D contains partially hydrogenated soya-bean oil and must not be used by persons allergic to peanuts or soya.



4.4 Special Warnings And Precautions For Use



Kalcipos-D chewable tablets should be prescribed with caution to patients suffering from sarcoidosis due to risk of increased metabolism of vitamin D into its active form. These patients should be monitored with regard to the calcium content in serum and urine.



During long-term treatment, serum calcium levels should be followed and renal function should be monitored through measurements of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics (see section 4.5) and in patients with a high tendency to calculus formation. In case of hypercalciuria (exceeding 300 mg (7.5 mmol)/24 hours) or signs of impaired renal function the dose should be reduced or the treatment discontinued.



Vitamin D should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of cholecalciferol is not metabolised normally and other forms of vitamin D should be used (see section 4.3, contraindications).



Kalcipos-D chewable tablets should be used cautiously in immobilised patients with osteoporosis due to increased risk of hypercalcaemia.



The content of vitamin D (800 IU) in Kalcipos-D chewable tablets should be considered when prescribing other medicinal products containing vitamin D. Additional doses of calcium or vitamin D should be taken under close medical supervision. In such cases it is necessary to monitor serum calcium levels and urinary calcium excretion frequently.



Co-administration with tetracyclines or quinolones is usually not recommended, or must be done with precaution (see section 4.5).



Kalcipos-D chewable tablets contains glucose and 3.8 mg sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.



The content of glucose may be harmful to the teeth.



Kalcipos-D chewable tablets are not intended for use in children.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcaemia, serum calcium should be regularly monitored during concomitant use of thiazide diuretics.



Concomitant use of phenytoin or barbiturates may reduce the effect of vitamin D3 since the metabolism increases.



Systemic corticosteroids reduce calcium absorption. During concomitant use, it may be necessary to increase the dose of Kalcipos-D.



Hypercalcaemia may increase the toxicity of cardiac glycosides during treatment with calcium and vitamin D. Patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.



The efficacy of levothyroxine can be reduced by the concurrent use of calcium, due to decreased levothyroxine absorption. Administration of calcium and levothyroxine should be separated by at least four hours.



If a bisphosphonate is used concomitantly, this preparation should be administered at least one hour before the intake of Kalcipos-D since gastrointestinal absorption may be reduced.



Calcium may also reduce absorption of sodium fluoride and iron salts, and such preparations should be administered at least three hours before the intake of Kalcipos-D.



Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.



Calcium carbonate may interfere with the absorption of concomitantly administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before or four to six hours after oral intake of calcium.



The absorption of quinolone antibiotics may be impaired if administered concomitantly with calcium. Quinolone antibiotics should be taken two hours before or six hours after intake of calcium.



Oxalic acid (found in spinach and rhubarb) and phytic acid (found in whole cereals) may inhibit calcium absorption through formation of insoluble compounds with calcium ions. The patient should not take calcium products within two hours of eating foods high in oxalic acid and phytic acid.



4.6 Pregnancy And Lactation



Pregnancy



During pregnancy the daily intake should not exceed 1500 mg calcium and 600 IU vitamin D. Kalcipos-D is not recommended during pregnancy. Studies in animals have shown reproductive toxicity of high doses of vitamin D (see 5.3). In pregnant women, overdoses of calcium and vitamin D should be avoided as permanent hypercalcaemia has been related to adverse effects on the developing foetus. Tablets can be used during pregnancy, in case of a calcium and vitamin D deficiency.



Breast-feeding



Kalcipos-D can be used during breast-feeding. Calcium and vitamin D3 pass into breast milk. This should be considered when giving additional vitamin D to the child.



4.7 Effects On Ability To Drive And Use Machines



There are no data about the effect of this product on driving capacity. An effect is, however, unlikely.



4.8 Undesirable Effects



Adverse reactions frequencies are defined as: uncommon (



Immune system disorders



Not known (cannot be estimated from the available data): Hypersensitivity reactions such as angioedema or laryngeal edema.



Metabolism and nutrition disorders



Uncommon: Hypercalcaemia and hypercalciuria.



Gastrointestinal disorders



Rare: Constipation, flatulence, nausea, abdominal pain, and diarrhoea.



Skin and subcutaneous disorders



Rare: Pruritus, rash and urticaria.



4.9 Overdose



Overdose can lead to hypervitaminosis and hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification.



Treatment of hypercalcaemia: The treatment with calcium and vitamin D must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D and cardiac glycosides must also be discontinued. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG and CVP should be followed.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: Mineral supplements



ATC-code: A12AX



Vitamin D increases the intestinal absorption of calcium.



Administration of calcium and vitamin D3 counteracts the increase of parathyroid hormone (PTH) which is caused by calcium deficiency and which cause increased bone resorption.



5.2 Pharmacokinetic Properties



Calcium



Absorption: The amount of calcium absorbed through the gastrointestinal tract is approximately 30% of the swallowed dose.



Distribution and metabolism: 99% of the calcium in the body is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood-calcium content is in the physiologically active ionised form with approximately 10% being complexed to citrate, phosphate or other anions, the remaining 40% being bound to proteins, principally albumin. The bioavailability of calcium can be slightly increased by concomitant intake of food.



Elimination: Calcium is eliminated through faeces, urine and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption.



Vitamin D



Absorption: Vitamin D is easily absorbed in the small intestine.



Distribution and metabolism: Cholecalciferol and its metabolites circulate in the blood bound to a specific globulin. Cholecalciferol is converted in the liver by hydroxylation to the active form 25-hydroxycholecalciferol. It is then further converted in the kidneys to 1,25- dihydroxycholecalciferol. 1,25-dihydroxycholecalciferol is the metabolite responsible for increasing calcium absorption. Vitamin D which is not metabolised is stored in adipose and muscle tissues.



Elimination: Vitamin D is excreted in faeces and urine.



5.3 Preclinical Safety Data



At doses far higher than the human therapeutic range teratogenicity has been observed in animal studies. There is further no information of relevance to the safety assessment in addition to what is stated in other parts of the SPC.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Liquid spray dried glucose



Magnesium stearate



Sodium citrate



Xylitol



all-rac-alfa-tocoferol



Acacia



Sodium laurilsulphate



Gelatine



Sucrose



Maize starch



Partially hydrogenated soya-bean oil



6.2 Incompatibilities



Not applicable.



6.3 Shelf Life



3 years



6.4 Special Precautions For Storage



Store in the original container, in order to protect from light. Keep container tightly closed in order to protect from moisture.



6.5 Nature And Contents Of Container



20, 30,40,50,60, 90 and 180 tablets in plastic containers of HDPE with screw caps made of HDPE.



Not all pack sizes may be marketed.



6.6 Special Precautions For Disposal And Other Handling



No special requirements.



7. Marketing Authorisation Holder



Meda Pharmaceuticals Ltd.,



Skyway House, Parsonage Road,



Takeley,



Bishop´s Stortford



United Kingdom



.



8. Marketing Authorisation Number(S)



PL 15142/0056



9. Date Of First Authorisation/Renewal Of The Authorisation



2009-12-22



10. Date Of Revision Of The Text



12 August 2010




Klaricid Paediatric Suspension 250mg / 5ml





1. Name Of The Medicinal Product



Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension


2. Qualitative And Quantitative Composition









 
 


Active




mg/5ml




Clarithromycin




250



3. Pharmaceutical Form



White to off - white granules for reconstitution.



4. Clinical Particulars



4.1 Therapeutic Indications



Consideration should be given to official guidance on the appropriate use of antibacterial agents.



Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is indicated in children 6 months to 12 years.



Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is indicated for the treatment of infections caused by susceptible organisms. Indications include:



Lower respiratory tract infections.



Upper respiratory tract infections.



Skin and skin structure infections.



Acute otitis media.



Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is usually active against the following organisms in vitro:



Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.



Gram-negative Bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae; Legionella pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejuni.



Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.



Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Chlamydia pneumoniae.



Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.



Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension has bactericidal activity against several bacterial strains. These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter species.



The activity of clarithromycin against H. pylori is greater at neutral pH than at acid pH.



4.2 Posology And Method Of Administration



Recommended doses and dosage schedules:



The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. The recommended daily dosage of Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension in children is given in the following table and is based on a 7.5mg/kg b.i.d. dosing regime. Doses up to 500mg b.i.d. have been used in the treatment of severe infections.



KLARICID PAEDIATRIC SUSPENSION 250MG/5ML OR CLARITHROMYCIN 250MG/5ML GRANULES FOR ORAL SUSPENSION



DOSAGE IN CHILDREN
































Dosage Based on Body Weight (kg)


   


Weight *



(kg)




Approx Age



(yrs)




Dosage



twice a day


 


(ml)




(mg)


  


8-11




1 - 2




1.25




62.50




12-19




3 - 6




2.5




125.00




20-29




7 - 9




3.75




187.50




30-40




10 - 12




5




250.00



* Children < 8 kg should be dosed on a per kg basis (approx. 7.5 mg/kg twice a day)



Preparation for use:



140 ml bottle: 74ml of water should be added to the granules in the bottle and shaken to yield 140ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.



100 ml bottle: 53ml of water should be added to the granules in the bottle and shaken to yield 100ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.



70 ml bottle: 37ml of water should be added to the granules in the bottle and shaken to yield 70ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.



50 ml bottle: 27ml of water should be added to the granules in the bottle and shaken to yield 50ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.



4.3 Contraindications



Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs or to any of its excipients.



Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.



Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointe (see section 4.5).



Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).



Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins), lovastatin or simvastatin, due to the risk of rhabdomyolysis. Treatment with these agents should be discontinued during clarithromycin treatment (see section 4.4).



Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time).



Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.



4.4 Special Warnings And Precautions For Use



The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see section 4.6).



Caution is advised in patients with severe renal insufficiency (see section 4.2).



Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering this antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.



Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.



Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile- associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.



Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy.



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). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity.



Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam (see section 4.5).



Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.



Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesaemia, bradycardia (<50 bpm), or when co-administered with other medicinal products associated with QT prolongation (see section 4.5). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).



Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.



Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta–lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.



In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.



Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).



HMG-CoA reductase inhibitors: Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (see section 4.5). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly. Patients should be monitored for signs and symptoms of myopathy. Rare reports of rhabdomyolysis have also been reported in patients taking atorvastatin or rosuvastatin concomitantly with clarithromycin. When used with clarithromycin, atorvastatin or rosuvastatin should be administered in the lowest possible doses. Adjustment of the statin dose or use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or pravastatin) should be considered.



Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycaemic agents and/or insulin can result in significant hypoglycaemia. With certain hypoglycaemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.



Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.



Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.



Long-term use may, as with other antibiotics, result in colonisation with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.



Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.



Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:



Cisapride, pimozide, astemizole and terfenadine:



Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see section 4.3).



Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.



Ergotamine/dihydroergotamine:



Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).



Effects of Other Medicinal Products on Clarithromycin



Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.



The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.



Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine



Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.



Fluconazole



Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.



Ritonavir



A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. 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 <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 gm/day should not be co-administered with ritonavir.



Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug interactions)



Effect of Clarithromycin on Other Medicinal Products



CYP3A-based interactions



Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolised by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolised by this enzyme.



Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.



The following drugs or drug classes are known or suspected to be metabolised by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, ciclosporin, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.



Antiarrhythmics



There have been post-marketed reports of torsade de points occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.



Omeprazole



Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.



Sildenafil, tadalafil and vardenafil



Each of these phosphodiesterase inhibitors is metabolised, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.



Theophylline, carbamazepine



Results of clinical studies indicate that there was a modest but statistically significant (p



Tolterodine



The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metaboliser population.



Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)



When midazolam was co-administered with clarithromycin tablets (500 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 CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.



There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.



Other drug interactions



Colchicine



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).



Digoxin



Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.



Zidovudine



Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudineto allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.



Phenytoin and Valproate



There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.



Bi-directional drug interactions



Atazanavir



Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.



Itraconazole



Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.



Saquinavir



Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin.



Verapamil



Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.



4.6 Pregnancy And Lactation



The safety of clarithromycin during pregnancy and breast feeding of infants has not been established. Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk. Clarithromycin is excreted into human breast milk.



4.7 Effects On Ability To Drive And Use Machines



There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.



4.8 Undesirable Effects



a. Summary of the safety profile



The most frequent and common adverse reactions related to clarithromycin therapy for both adult and peadiatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b of section 4.8).



There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without pre-existing mycobacterial infections.



b. Tabulated summary of adverse reactions



The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets.



The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (






























































































System Organ Class




Very common






Common






Uncommon






Not Known



(cannot be estimated from the available data)




Infections and infestations




 




 




Cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection




Pseudomembranous colitis, erysipelas, erythrasma




Blood and lymphatic system




 




 




Leukopenia, neutropenia4, thrombocythaemia3, eosinophilia4




Agranulocytosis, thrombocytopenia




Immune system disorders5




 




 




Anaphylactoid reaction1, hypersensitivity




Anaphylactic reaction




Metabolism and nutrition disorders




 




 




Anorexia, decreased appetite




Hypoglycaemia6




Psychiatric disorders




 




Insomnia




Anxiety, nervousness3, screaming3




Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams




Nervous system disorders




 




Dysgeusia, headache, taste perversion




Loss of consciousness1, dyskinesia1, dizziness, somnolence7, tremor




Convulsion, ageusia, parosmia, anosmia




Ear and labyrinth disorders




 




 




Vertigo, hearing impaired, tinnitus




Deafness




Cardiac disorders




 




 




Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged8, extrasystoles1, palpitations




Torsade de pointes8, ventricular tachycardia8




Vascular disorders




 




Vasodilation1




 




Haemorrhage9




Respiratory, thoracic and mediastinal disorder




 




 




Asthma1, epistaxis2, pulmonary embolism1




 




Gastrointestinal disorders




 




Diarrhoea10, vomiting, dyspepsia, nausea, abdominal pain




Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence,




Pancreatitis acute, tongue discolouration, tooth discolouration




Hepatobiliary disorders




 




Liver function test abnormal




Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4




Hepatic failure11, jaundice hepatocellular




Skin and subcutaneous tissue disorders




 




Rash, hyperhidrosis




Dermatitis bullous1, pruritus, urticaria, rash maculo-papular3




Stevens-Johnson syndrome5, toxic epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne




Musculoskeletal and connective tissue disorders




 




 




Muscle spasms3, musculoskeletal stiffness1, myalgia2




Rhabdomyolysis2,12, myopathy




Renal and urinary disorders




 




 




Blood creatinine increased1, blood urea increased1




Renal failure, nephritis interstitial




General disorders and administration site conditions




Injection site phlebitis1




Injection site pain1, injection site inflammation1




Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4




 




Investigations




 




 




Albumin globulin ratio abnormal1, blood alkaline phosphatase increased4, blood lactate dehydrogenase increased4




International normalised ratio increased9, prothrombin time prolonged9, urine color abnormal



1 ADRs reported only for the Powder for Solution for Injection formulation



2ADRs reported only for the Extended-Release Tablets formulation



3 ADRs reported only for the Granules for Oral Suspension formulation



4 ADRs reported only for the Immediate-Release Tablets formulation



5,8,10,11,12See section a)



6,7,9See section c)



c. Description of selected adverse reactions



Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.



In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications (see section 4.4).



A special attention to diarrhoea should be paid as Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. (see section 4.4)



In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).



As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section 4.4 and 4.5).



Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).



In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).



There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome. (see sections 4.4 and 4.5).



There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin (see section 4.4 and 4.5).



There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).



There is a risk of serious haemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see section 4.4 and 4.5).



There have been rare reports of clarithromycin ER tablets

Junior Parapaed Paracetamol Suspension 120mg / 5ml





1. Name Of The Medicinal Product



Junior Parapaed Paracetamol Suspension 120mg/5ml



Infant Paracetamol Suspension 120mg/5ml



Paracetamol Suspension 120mg/5ml



Asda Infant Paracetamol Oral Suspension 120mg/5ml



Enterprise Infant Paracetamol Suspension 120mg/5ml



Lexon Infant Paracetamol Oral Suspension 120mg/5ml



Tesco Children's Paracetamol Suspension 120 mg/5 ml



Paracetamol 120 mg/5 ml Oral Suspension


2. Qualitative And Quantitative Composition



Each 5ml spoonful contains Paracetamol BP 120mg



3. Pharmaceutical Form



Oral Suspension.



Pink suspension with cherry odour and taste.



4. Clinical Particulars



4.1 Therapeutic Indications



For the treatment of mild to moderate pain and as an anti-pyretic. Used for the relief of pain and feverishness associated with teething, toothache, headache, colds, flu and post-immunisation pyrexia.



4.2 Posology And Method Of Administration










Age




Dose




For post-vaccination fever for babies aged between 2 – 3 months




One 2.5 ml spoonful (small end)



If necessary, after 4-6 hours, give a second 2.5 ml dose




• Do not give to babies less than 2 months of age



• Do not give more than 2 doses



• Leave at least 4 hours between doses



• If further doses are needed, talk to your doctor or pharmacist


 


























Child's Age




How Much




How often



(in 24 hours)




3 – 6 months




One 2.5 ml spoonful (small end)




4 times




6 – 24 months




One 5 ml spoonful (large end)




4 times




2 – 4 years




One 5.0 ml spoonful (large end) and one 2.5 ml spoonful (small end)




4 times




4 – 8 years




Two 5 ml spoonfuls (large end)




4 times




8 – 10 years




Three 5 ml spoonfuls (large end)




4 times




10 – 12 years




Four 5 ml spoonfuls (large end)




4 times




• Do not give more than 4 doses in any 24 hour period



• Leave at least 4 hours between doses



• Do not give this medicine to your child for more than 3 days without speaking to your doctor or pharmacist


  


It is important to shake the bottle for at least 10 seconds before use.



4.3 Contraindications



Hypersensitivity to Paracetamol or any of the other constituents.



4.4 Special Warnings And Precautions For Use



Care is advised in the administration of Paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with (non-cirrhotic) alcoholic liver disease.



The label should contain the following statements:



• Contains paracetamol.



• Do not give this medicine with any other paracetamol-containing product.



• For oral use only.



• Never give more medicine than shown in the table.



• Do not overfill the spoon.



• Always use the spoon supplied with the pack.



• Do not give to babies less than 2 months of age.



• For infants 2-3 months no more than 2 doses should be given.



• Do not give more than 4 doses in any 24 hour period.



• Leave at least 4 hours between doses.



• Do not give this medicine to your child for more than 3 days without speaking to your doctor or pharmacist.



• As with all medicines, if your child is currently taking any medicine consult your doctor or pharmacist before taking this product.



• Do not store above 25°C. Store in the original package.



• Keep all medicines out of the reach and sight of children



• Immediate medical advice should be sought in the event of an overdose, even if the child seems well (label).



• Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage (leaflet).



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Drugs which induce hepatic microsomal enzymes such as alcohol. Concomitant barbiturates and tricyclic antidepressants may increase the hepatoxicity of Paracetamol particularly after overdose. Anti-convulsant or oral steroid contraceptives have the ability to reduce serum levels of Paracetamol by liver enzyme induction. The speed of absorption of Paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. The anti-coagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of Paracetamol with increased risk of bleeding; occasional doses have no significant effect.



4.6 Pregnancy And Lactation



Epidemiological studies in human pregnancy have shown no ill effects due to Paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.



Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data does not contraindicate breast-feeding.



4.7 Effects On Ability To Drive And Use Machines



None



4.8 Undesirable Effects



Adverse effects of Paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to Paracetamol. With prolonged use or overdosage, hepatic necrosis, acute pancreatitis and nephrotoxicity have been reported.



4.9 Overdose



Liver damage is possible in adults who have taken 10 g or more of Paracetamol. Ingestion of 5 g or more of Paracetamol may lead to liver damage if the patient has risk factors.



Risk Factors



If the patient:



a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St. John's Wort or other drugs that induce liver enzymes.



or



b, Regularly consumes ethanol in excess of recommended amounts.



or



c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.



Symptoms



Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.



Management



Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.



Treatment with activated charcoal should be considered if the overdose has been taken within one 1 hour. Plasma Paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of Paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 h from ingestion should be discussed with the NPIS or a liver unit.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependent on the inhibition of prostaglandin synthesis. This inhibition appears, however, to be on a selective basis.



5.2 Pharmacokinetic Properties



Paracetamol is rapidly and almost completely absorbed from the gastro-intestinal tract. The concentration in plasma reaches a peak in 30 to 60 minutes and the half-life in plasma is 1 to 4 hours after therapeutic doses. Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; 20 to 50 % may be bound at the concentrations encountered during acute intoxication. Following therapeutic doses 90 to 100% of the drug may be recovered in the urine within the first day. However, practically no Paracetamol is excreted unchanged, and the bulk is excreted after hepatic conjugation.



5.3 Preclinical Safety Data



There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Ethanol (96%)



Sorbitan Monooleate



Glycerol (E422)



Magnesium Aluminium Silicate



Hydrogenated Glucose Syrup (E965)



Saccharin Sodium (E954)



Xanthan Gum



Amaranth (E123)



Cherry Flavour



Sodium Benzoate (E211)



Citric Acid (monohydrate)



Polysorbate 80



Purified water



6.2 Incompatibilities



None known.



6.3 Shelf Life



Amber glass bottles – 3 years



High density polyethylene – 3 years.



6.4 Special Precautions For Storage



Do not store above 25°C. Store in the original container.



6.5 Nature And Contents Of Container



Pharmaceutical grade III amber glass bottles with pilfer proof screw caps.



Pack sizes: 70ml, 100ml, 150ml, 200ml, 500ml, 1 Litre and 2 Litre.



High density polyethylene bottles with tamper evident plastic cap.



Pack sizes: 500ml, 1 Litre and 2 Litre.



6.6 Special Precautions For Disposal And Other Handling



As for all medicines – no special requirements.



7. Marketing Authorisation Holder



Pinewood Laboratories Limited



Ballymacarbry



Clonmel



Co. Tipperary



Ireland



8. Marketing Authorisation Number(S)



PL 04917/0009



9. Date Of First Authorisation/Renewal Of The Authorisation



23/03/2007



10. Date Of Revision Of The Text



07/10/2011




Keppra 250,500,750 and 1000 mg film-coated Tablets, 100 mg / ml oral solution and 100 mg / ml concentrate for solution for infusion





1. Name Of The Medicinal Product



Keppra 250 mg film-coated tablets.



Keppra 500 mg film-coated tablets.



Keppra 750 mg film-coated tablets.



Keppra 1000 mg film-coated tablets.



Keppra 100 mg/ml, oral solution.



Keppra 100 mg/ml concentrate for solution for infusion


2. Qualitative And Quantitative Composition



Tablets:



Each film-coated tablet contains 250 mg levetiracetam, 500 mg levetiracetam, 750 mg levetiracetam or 1000 mg levetiracetam.



Excipient:



Keppra 750 mg film-coated Tablets:



Each film-coated tablet contains 0.19 mg of sunset yellow FCF (E110).



Oral solution:



Each ml contains 100 mg levetiracetam.



Excipients: methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and 300 mg maltitol liquid.



Solution for infusion:



Each ml contains 100 mg of levetiracetam.



Each 5 ml vial contains 500 mg of levetiracetam.



Excipients:



Each dose contains 57 mg of sodium.



For a full list of excipients, see section 6.1.



3. Pharmaceutical Form



Film-coated tablet:



Blue, oblong, scored and debossed with the code “ucb” and “250” on one side.



Yellow, oblong, scored and debossed with the code “ucb 500” on one side.



Orange, oblong, scored and debossed with the code “ucb 750” on one side.



White, oblong, scored and debossed with the code “ucb 1000” on one side.



Oral solution:



Clear liquid.



Concentrate for solution for infusion (sterile concentrate).



Clear, colourless, concentrate.



4. Clinical Particulars



4.1 Therapeutic Indications



Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.



Keppra is indicated as adjunctive therapy



• in the treatment of partial onset seizures with or without secondary generalisation in adults and children from 1 month of age with epilepsy.



• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.



• in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.



Keppra concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.



4.2 Posology And Method Of Administration



Posology



Monotherapy for adults and adolescents from 16 years of age



The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.



Add-on therapy for adults (



The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.



Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.



Duration of treatment



There is no experience with administration of intravenous levetiracetam for longer period than 4 days.



Special populations



Elderly (65 years and older)



Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below).



Renal impairment



The daily dose must be individualised according to renal function.



For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula:





Then CLcr is adjusted for body surface area (BSA) as follows:





Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal function:










Group




Creatinine clearance (ml/min/1.73m2)




Dose and frequency




Normal



Mild



Moderate



Severe



End-stage renal disease patients undergoing dialysis (1)




> 80



50-79



30-49



< 30



-




500 to 1,500 mg twice daily



500 to 1,000 mg twice daily



250 to 750 mg twice daily



250 to 500 mg twice daily



500 to 1,000 mg once daily (2)



(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.



(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.



For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.



The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination using, for young adolescents and children using the following formula (Schwartz formula):





ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male



Dosing adjustment for infants, children and adolescents patients weighing less than 50 kg with impaired renal function:
































Group




Creatinine clearance (ml/min/1.73 m2)




Dose and frequency (1)


 


Infants 1 to less than 6 months




Infants 6 to 23 months, children and adolescents weighing less than 50 kg


  


Normal




> 80




7 to 21 mg/kg (0.07 to 0.21 ml/kg) twice daily




10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily




Mild




50-79




7 to 14 mg/kg (0.07 to 0.14 ml/kg) twice daily




10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily




Moderate




30-49




3.5 to 10.5 mg/kg (0.035 to 0.105 ml/kg) twice daily




5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily




Severe




< 30




3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) twice daily




5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily




End-stage renal disease patients undergoing dialysis




--




7 to 14 mg/kg (0.07 to 0.14 ml/kg) once daily (2) (4)




10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (3) (5)



(1) Keppra oral solution should be used for doses under 250 mg and for patients unable to swallow tablets.



(2) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.



(3) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.



(4) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.



(5) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.



Hepatic impairment



No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73 m2.



Paediatric population



The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.



The tablet formulation is not adapted for use in infants and children under the age of 6 years. Keppra oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases Keppra oral solution should be used.



The safety and efficacy of Keppra concentrate for solution for infusion in infants and children less than 4 years have not been established.



Monotherapy



The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy treatment have not been established.



There are no data available.



Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg



Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 years.



The initial therapeutic dose is 10 mg/kg twice daily.



Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.



Dose in children 50 kg or greater is the same as in adults.



Dose recommendations for infants from 6 months of age, children and adolescents:

























Weight




Starting dose:



10 mg/kg twice daily




Maximum dose:



30 mg/kg twice daily




6 kg (1)




60 mg (0.6 ml) twice daily




180 mg (1.8 ml) twice daily




10 kg (1)




100 mg (1 ml) twice daily




300 mg (3 ml) twice daily




15 kg (1)




150 mg (1.5 ml) twice daily




450 mg (4.5 ml) twice daily




20 kg (1)




200 mg (2 ml) twice daily




600 mg (6 ml) twice daily




25 kg




250 mg twice daily




750 mg twice daily




From 50 kg (2)




500 mg twice daily




1,500 mg twice daily



(1) Children 25 kg or less should preferably start the treatment with Keppra 100 mg/ml oral solution.



(2) Dose in children and adolescents 50 kg or more is the same as in adults.



Add-on therapy for infants aged from 1 month to less than 6 month.



The oral solution is the formulation to use in infants.



The initial therapeutic dose is 7 mg/kg twice daily.



Depending upon the clinical response and tolerability, the dose can be increased up to 21 mg/kg twice daily. Dose changes should not exceed increases or decreases of 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.



Infants should start the treatment with Keppra 100 mg/ml oral solution.



Dose recommendations for infants aged from 1 month to less than 6 months:
















Weight




Starting dose:



7 mg/kg twice daily




Maximum dose:



21 mg/kg twice daily




4 kg




28 mg (0.3 ml) twice daily




84 mg (0.85 ml) twice daily




5 kg




35 mg (0.35 ml) twice daily




105 mg (1.05 ml) twice daily




7 kg




49 mg (0.5 ml)twice daily




147 mg (1.5 ml) twice daily



Three presentations are available:



- A 300 ml bottle with a 10 ml oral syringe (containing up to 1000 mg levetiracetam) graduated every 0.25 ml (corresponding to 25 mg).



This presentation should be prescribed for children aged 4 years and older, adolescents and adults.



- A 150 ml bottle with a 3 ml oral syringe (containing up to 300 mg levetiracetam) graduated every 0.1 ml (corresponding to 10 mg)



In order to ensure the accuracy of the dosing, this presentation should be prescribed for infants and young children aged from 6 months to less than 4 years.



- A 150 ml bottle with a 1 ml oral syringe (containing up to 100 mg levetiracetam) graduated every 0.05 ml (corresponding to 5 mg)



In order to ensure the accuracy of the dosing, this presentation should be prescribed for infants aged 1 month to less than 6 months.



Method of administration - tablets



The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.



Method of administration



The oral solution may be diluted in a glass of water or baby's bottle and may be taken with or without food. A graduated oral syringe, an adaptor for the syringe and instructions for use in the package leaflet are provided with Keppra.



The daily dose is administered in two equally divided doses.



Method of administration – solution for infusion



Keppra therapy can be initiated with either intravenous or oral administration.



Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained.



Keppra concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion (see section 6.6).



4.3 Contraindications



Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.



4.4 Special Warnings And Precautions For Use



Discontinuation



In accordance with current clinical practice, if Keppra has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).



Renal insufficiency



The administration of Keppra to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2).



Suicide



Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.



Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.



Paediatric population



The tablet formulation is not adapted for use in infants and children under the age of 6 years.



Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.



The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been exposed in clinical studies of which only 13 were aged < 6 months.



Excipients - tablets



Keppra 750 mg film-coated tablets contain E110 colouring agent which may cause allergic reactions.



Excipients – oral solution



Keppra 100 mg/ml oral solution includes methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).



It also includes maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.



Excipients – solution for infusion



This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose. To be taken into consideration by patients on a controlled sodium diet.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Antiepileptic medicinal products



Pre-marketing data from clinical studies conducted in adults indicate that Keppra did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of Keppra.



As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.



A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.



Probenecid



Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.



Oral contraceptives and other pharmacokinetics interactions



Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.



Antacids



No data on the influence of antacids on the absorption of levetiracetam are available.



Food and alcohol



The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.



No data on the interaction of levetiracetam with alcohol are available.



4.6 Pregnancy And Lactation



Pregnancy



There are no adequate data available from the use of levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown.



Keppra is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary.



As with other antiepileptic medicinal products, physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.



Breastfeeding



Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.



However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.



Fertility



No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.



4.7 Effects On Ability To Drive And Use Machines



No studies on the effects on the ability to drive and use machines have been performed.



Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.



4.8 Undesirable Effects



Summary of the safety profile



The adverse event profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.



Tabulated list of adverse reactions



Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. The frequency is defined as follows: very common (

























































































MedDRA SOC




Frequency category


   


Very common




Common




Uncommon




Rare


 


Infections and infestations




Nasopharyngitis




 




 




Infection




Blood and lymphatic system disorders




 




 




Thrombocytopenia, leukopenia(1)




Pancytopenia (1,2), neutropenia(1)




Metabolism and nutrition disorders




 




Anorexia




Weight decreased (1), weight increase




 




Psychiatric disorders




 




Depression, hostility/ aggression, anxiety(1), insomnia, nervousness/irritability




Suicide attempt(1), suicidal ideation(1), psychotic disorder(1), abnormal behaviour(1), hallucination(1), anger(1), confusional state (1), affect lability/mood swings, agitation




Completed suicide(1), personality disorder, thinking abnormal




Nervous system disorders




Somnolence, headache




Convulsion, balance disorder, dizziness, lethargy, tremor




Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia(1), disturbance in attention




Choreoathetosis(1), dyskinesia(1), hyperkinesia




Eye disorders




 




 




Diplopia, vision blurred




 




Ear and labyrinth disorders




 




Vertigo




 




 




Respiratory, thoracic and mediastinal disorders




 




Cough




 




 




Gastrointestinal disorders




 




Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea




 




Pancreatitis(1)




Hepatobiliary disorders




 




 




Liver function test abnormal(1)




Hepatic failure(1), hepatitis(1)




Skin and subcutaneous tissue disorders




 




Rash




Alopecia(1), eczema, pruitus,




Toxic epidermal necrolysis(1), Stevens-Johnson syndrome(1), erythema multiforme(1)




Musculoskeletal and connective tissue disorders




 




 




Muscular weakness, myalgia




 




General disorders and administration site conditions




 




Asthenia/fatigue




 




 




Injury, poisoning and procedural complications




 




 




Injury




 




(1) Adverse reactions added during post marketing experience.



(2) Bone marrow suppression identified in some of the cases.


    


Description of selected adverse reactions



The risk of anorexia is higher when topiramate is coadministered with levetiracetam.



In several cases of alopecia, recovery was observed when levetiracetam was discontinued.



Paediatric population



In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty (60) of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam.



The adverse event profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.



A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of Keppra in children 4 to 16 years of age with partial onset seizures. It was concluded that Keppra was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in Keppra treated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist). However subjects, who took Keppra in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.



4.9 Overdose



Symptoms



Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Keppra overdoses.



Management of overdose



After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.



The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.



Mechanism of action



The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.



In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.



Pharmacodynamic effects



Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.



In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam.



Clinical efficacy and safety



Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.



In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7 %, 31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6 % for patients on placebo.



Paediatric population



In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).



44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had a 50 % or greater reduction from baseline in the partial onset seizure frequency per week. With continued long-term treatment, 11.4 % of the patients were seizure-free for at least 6 months and 7.2 % were seizure-free for at least 1 year.



In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 116 patients and had a treatment duration of 5 days. In this study, patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral solution based on their age titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants one month to less than six months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and children 6 months to less than 4 years old, was use in this study. The total daily dose was administered b.i.d.



The primary measure of effectiveness was the responder rate (percent of patients with



Monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.



Efficacy of levetiracetam as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine controlled release (CR) in 576 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial seizures or with generalized tonic-clonic seizures only. The patients were randomized to carbamazepine CR 400 – 1200 mg/day or levetiracetam 1000 – 3000 mg/day, the duration of the treatment was up to 121 weeks depending on the response.



Six-month seizure freedom was achieved in 73.0 % of levetiracetam-treated patients and 72.8 % of carbamazepine-CR treated patients; the adjusted absolute difference between treatments was 0.2% (95 % CI: -7.8 8.2). More than half of the subjects remained seizure free for 12 months (56.6 % and 58.5 % of subjects on levetiracetam and on carbamazepine CR respectively).



In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to levetiracetam adjunctive therapy (36 adult patients out of 69).