Klaristell Iv 500 mg Powder for solution for injection

KLARISTELL IV is indicated in the treatment of infections due to susceptible organisms in the following conditions whenever parenteral therapy is required:

• Lower respiratory tract infections, e.g. bronchitis, pneumonia.
• Upper respiratory tract infections, e.g. pharyngitis and tonsillitis due to S.pyogenes, sinusitis.
• Skin and soft tissue infections due to S.aureus.

There is some evidence that disseminated and localised infections in HIV-positive adults, due to Mycobacterium avium or Mycobacterium intracellulare respond to clarithromycin. Based on bacteriological results, KLARISTELL IV should be used in conjunction with other antimycobacterials. To a lesser extent localised infections due to Mycobacterium kansasii have responded to clarithromycin.

Posology

Adults

The recommended dosage of KLARISTELL IV is 1,0 gram daily, divided into 2 equal doses, each infused, following further dilution with an appropriate I.V. diluent, over a 60 minute period. Clarithromycin should not be given as a bolus or an intra-muscular injection. Intravenous therapy may be limited for up to 2 to 5 days in the very ill patient and should be changed to oral therapy whenever possible as determined by the physician.

Special populations

Renal impairment

If the patient has creatinine clearance of less than 30 mL/min, the dosage of KLARISTELL IV should be reduced to one-half of the normal recommended dose.

Dosage in HIV patients with atypical mycobacterial infections

There is currently no data regarding use of KLARISTELL IV in immunocompromised patients. However, data is available regarding the use of oral clarithromycin in HIV-infected patients. In disseminated or localised mycobacterium infections (M.avium, M.intracellulare, M.chelonae, M. Kansasii) an oral dosage of 1000 mg/day in two divided doses has been used. Treatment of disseminated Mycobacterium avium complex infections in AIDS patients should continue as long as clinical and microbiological benefit is demonstrated. In patients on treatment exceeding 12 weeks, a decrease in efficacy has been noted. KLARISTELL IV should be used in conjunction with other antimycobacterial medicines. Treatment of other nontuberculous mycobacterial infections should continue at the discretion of the physician.

Paediatric population

Children older than 12 years: As for adults.

Children under 12 years: The safety of KLARISTELL IV for use in children has not been established.

Method of administration

KLARISTELL IV is for intravenous administration. Preparation for use: The final solution for infusion is prepared as follows: Prepare the initial solution of KLARISTELL IV by adding 10 mL of sterile water for injection to the 500 mg vial and shake vigorously until the entire contents are dissolved.

• Hypersensitivity to clarithromycin, macrolide antibiotic medicines or any of the excipients listed in section 6.1.
• Concomitant administration with ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see sections 4.4 and 4.5).
• Concomitant administration with oral midazolam is contraindicated (see section 4.5).
• Concomitant administration with lomitapide is contraindicated (see section 4.5).
• Concomitant administration with any of the following medicines is contraindicated: certain antihistamines (e.g. astemizole and terfenadine), domperidone, cisapride and pimozide as this may result in QT prolongation and cardiac dysrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see sections 4.4 and 4.5).
• Patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac dysrhythmia, including torsades de pointes (see sections 4.4 and 4.5).
• Concomitant administration with ticagrelor or ranolazine is contraindicated.
• Concomitant administration with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).
• Patients taking colchicine (see section 4.4 and 4.5).
• Patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of QT time).
• Patients who suffer from severe hepatic failure in combination with renal impairment.

Pregnancy

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

Hepatic impairment

KLARISTELL IV is extensively metabolised in the liver and caution should be exercised in administration to patients with impaired hepatic function.

Renal impairment

Caution should also be exercised when administering to patients with moderate to severe renal impairment (see section 4.2).

Fatal hepatic failure

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. 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 medicines. If signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen, treatment with KLARISTELL IV must be stopped.

Pseudomembranous colitis

Pseudomembranous colitis has been reported with nearly all antibacterial medicines, including macrolides, such as KLARISTELL IV and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial medicines including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial medicines 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 medicines. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Medicines inhibiting peristalsis should be avoided.

Colchicine toxicity

Colchicine toxicity with concomitant use of KLARISTELL IV, a strong CYP3A4 inhibitor, 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). Concomitant administration of KLARISTELL IV, and colchicine is contraindicated (see section 4.3).

Triazolobenzodiazepines

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see section 4.5). Concomitant administration of oral midazolam and KLARISTELL IV is contraindicated (see section 4.3).

Cardiovascular Events

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac dysrhythmia and torsades de pointes, have been seen in treatment with macrolides including clarithromycin (see section 4.8). Carefully consider the balance of benefits and risks before prescribing clarithromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see section 4.5). Therefore, as the following situations may lead to an increased risk for ventricular dysrhythmias (including torsades de pointes), KLARISTELL IV should be used with caution in the following patients:

• Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia.
• Patients with electrolyte disturbances such as hypomagnesaemia. KLARISTELL IV must not be given to patients with hypokalaemia (see section 4.3).
• Patients concomitantly taking other medicines associated with QT prolongation (see section 4.5).
• Concomitant administration of KLARISTELL IV with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section 4.3).
• KLARISTELL IV must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular dysrhythmia (see section 4.3).

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short-term risk of dysrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing KLARISTELL IV.

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, KLARISTELL IV should be used in combination with additional appropriate antibiotics.

Skin and soft tissue conditions

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, such as KLARISTELL IV. 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 medicine 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, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

Severe acute hypersensitivity reactions

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS)), KLARISTELL IV therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Cytochrome CYP3A4 inducers

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

HMG-CoA reductase inhibitors (statins)

Concomitant use of KLARISTELL IV with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of KLARISTELL IV with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see section 4.5).

Oral hypoglycaemic medicines/Insulin

The concomitant use of KLARISTELL IV and oral hypoglycaemic medicines (such as sulphonylureas e.g. gliclazide or glimepiride) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended (see section 4.5).

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

• Astemizole, cisapride, domperidone, pimozide, and terfenadine: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac dysrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes.
• Macrolides, such as KLARISTELL IV, have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac dysrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes.
• Co-administration of KLARISTELL IV with ergotamine or dihydroergotamine may be associated with acute ergot toxicity characterised by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Permanent tissue damage may occur.
• Oral midazolam: When midazolam was co-administered with KLARISTELL IV tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and KLARISTELL IV is contraindicated.
• HMG-CoA reductase inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated as these statins are extensively metabolised by CYP3A4 and concomitant treatment with KLARISTELL IV increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with KLARISTELL IV cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Effects of other medicines on KLARISTELL IV: Medicines 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.

Pregnancy

Safety of KLARISTELL IV during pregnancy and lactation has not been established. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal development cannot be excluded. Some observational studies evaluating exposure to KLARISTELL IV during the first and second trimester have reported an increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major congenital malformations with use of macrolides including KLARISTELL IV during pregnancy provide conflicting results. Therefore, use during pregnancy is not advised without carefully weighing the benefit against risks (see section 5.3).

Breastfeeding

The safety of clarithromycin for using during breast-feeding of infants has not been established. Clarithromycin is excreted into human breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive about 1.7% of the maternal weight-adjusted dose of KLARISTELL IV.

Fertility

In the rat, fertility studies have not shown any evidence of harmful effects (see section 5.3).

There are no data available 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 KLARISTELL IV, should be taken into account before patients drive or use machines.

a) Summary of the safety profile

The most frequent and common adverse reactions related to KLARISTELL IV therapy for both adult and paediatric 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.

b) Tabulated list of adverse reactions

The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with clarithromycin.

Signs and symptoms

Ingestion of large amounts of KLARISTELL IV have been reported to produce gastrointestinal symptoms. A patient with a history of bipolar disorder who ingested 8 g of KLARISTELL IV tablets showed altered mental status, paranoic behaviour, hypokalaemia and hypoxaemia.

Treatment

In the case of over-dosage, KLARISTELL IV should be discontinued and all other appropriate supportive measures should be instituted. Allergic reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed medicine and supportive measures. Like other macrolides, haemodialysis or peritoneal dialysis are not expected to appreciably affect clarithromycin serum levels.