Primaxin IV Injection

Transcription

1 Seite 1 von 20 Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU Telephone: +44 (0) Fax: +44 (0) Medical Information medicalinformationuk@merck.com Need to contact this company? Summary of Product Characteristics last updated on the emc: 05/03/2009 Primaxin IV Injection 1. NAME OF THE MEDICINAL PRODUCT 'Primaxin' IV 500 mg Injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 'Primaxin' IV 500 mg Injection contains 500 mg imipenem (as the monohydrate) with 500 mg cilastatin (as the sodium salt). 3. PHARMACEUTICAL FORM Powder for concentrate for solution for infusion. 'Primaxin' IV is available as vials containing sterile white to light yellow powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Broad spectrum beta lactam antibiotic. 'Primaxin' contains: imipenem, a member of a class of beta lactam antibiotics thienamycins the cilastatin sodium, a specific enzyme inhibitor, that blocks the metabolism of imipenem in the kidney and substantially increases the concentration of unchanged imipenem in the urinary tract. 'Primaxin' is bactericidal against an unusually wide spectrum of Gram positive, Gram negative, aerobic and anaerobic pathogens. 'Primaxin' is useful for treating single and polymicrobic infections, and initiating therapy prior to identification of the causative organisms. 'Primaxin' is indicated for the treatment of the following infections due to susceptible organisms: 'Primaxin' IV

2 Seite 2 von 20 Lower respiratory tract infections Intra abdominal infections Genito urinary infections Gynaecological infections Septicaemia Bone and joint infections Skin and soft tissue infections Note: 'Primaxin' is not indicated against central nervous system infections. 'Primaxin' is indicated against mixed infections caused by susceptible aerobic and anaerobic bacteria. The majority of these infections are associated with contamination by faecal flora, or flora originating from the vagina, skin, and mouth. In these mixed infections, 'Primaxin' is usually effective against Bacteroides fragilis sp., the most commonly encountered anaerobic pathogen, which is usually resistant to the aminoglycosides, cephalosporins and penicillins. Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of bacterial agents. Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available. Prophylaxis: 'Primaxin' IV is also indicated for the prevention of certain post operative infections in patients undergoing contaminated or potentially contaminated surgical procedures or where the occurrence of post operative infection could be especially serious. 4.2 Posology and method of administration The total daily dosage and route of administration of 'Primaxin' should be based on the type or severity of infection, consideration of degree of susceptibility of the pathogen(s), renal function and bodyweight. Doses cited are based on a bodyweight of >70 kg. The total daily requirement should be given in equally divided doses. The dosage recommendations that follow specify the amounts of

3 Seite 3 von 20 imipenem to be given. An equivalent amount of cilastatin is provided with this. One vial of 'Primaxin' IV 500 mg provides the equivalent of 500 mg anhydrous imipenem and 500 mg cilastatin. Use in the elderly Age does not usually affect the tolerability and efficacy of 'Primaxin'. The dosage should be determined by the severity of the infection, the susceptibility of the causative organism(s), the patient's clinical condition, and renal function. INTRAVENOUS ADMINISTRATION This formulation should not be used intramuscularly. The dosage of 'Primaxin' IV should be determined by the severity of the infection, the antibiotic susceptibility of the causative organism(s) and the condition of the patient. Note: All recommended doses refer to the imipenem fraction of 'Primaxin'. Adults (based on 70 kg bodyweight): The usual adult daily dosage is 1 2 g administered in 3 4 equally divided doses (see chart below). In infections due to less sensitive organisms, the daily dose may be increased to a maximum dose of 50 mg/kg/day (not exceeding 4 g daily). Usual adult intravenous dosage Each dose of 250 mg or 500 mg should be given by intravenous infusion over minutes. Each dose of 1000 mg should be infused over minutes. In patients who develop nausea during infusion, the infusion rate may be slowed. IV administration Severity of infection Dose Dosage interval Total daily dose Mild 250 mg 6 hours 1.0 g Moderate 500 mg 8 hours 1.5 g Severe fully susceptible Severe and/or lifethreatening infections due to less sensitive organisms (primarily some 500 mg 6 hours 2.0 g 1000 mg 1000 mg 8 hours 6 hours 3.0 g 4.0 g

4 Seite 4 von 20 strains of P.aeruginosa ) Primaxin' has been used successfully as monotherapy in immunocompromised cancer patients for confirmed or suspected infections such as sepsis. Prophylactic use For prophylaxis against post surgical infections in adults, 1 g 'Primaxin' IV should be given intravenously on induction of anaesthesia and 1 g three hours later. For high risk (i.e. colorectal) surgery, two additional 0.5 g doses can be given at 8 and 16 hours after induction. In patients with renal insufficiency As in patients with normal renal function, dosing is based on the severity of the infection. The maximum dosage for patients with various degrees of renal functional impairment is shown in the following table. Doses cited are based on a bodyweight of 70 kg. Proportionate reduction in dose administered should be made for patients with lower bodyweight. Maximum dosage in relation to renal function Renal function Mild impairment Moderate impairment Severe** impairment Creatinine clearance (ml/min) Dose (mg) Dosage interval (hrs) Maximum total daily dose* (g) * The higher dose should be reserved for infections caused by less susceptible organisms. ** Patients with creatinine clearance of 6 20 ml/min should be treated with 250 mg (or 3.5 mg/kg, whichever is lower) every 12 hours for most pathogens. When the 500 mg dose is used in these patients there may be an increased risk of convulsions. Patients with a creatinine clearance of <5 ml/min should not receive 'Primaxin' IV unless haemodialysis is started within 48 hours.

5 Seite 5 von 20 'Primaxin' is cleared by haemodialysis. The patient should receive 'Primaxin' IV immediately after haemodialysis and at 12 hourly intervals thereafter. Dialysis patients, especially those with background CNS disease, should be carefully monitored; patients on haemodialysis should receive 'Primaxin' IV only when the benefit outweighs the potential risk of convulsions (see 4.4 'Special warnings and special precautions for use'). There are currently inadequate data to recommend the use of 'Primaxin' IV for patients on peritoneal dialysis. Paediatric dosage Age Dose Dosage interval 3 months of age and older (less than 40 kg bodyweight) The maximum daily dose should not exceed 2 g. Children over 40 kg bodyweight should receive adult doses. Clinical data are insufficient to recommend an optimal dose for children under 3 months of age or infants and children with impaired renal function. 'Primaxin' IV is not recommended for the therapy of meningitis. If meningitis is suspected an appropriate antibiotic should be used. 'Primaxin' IV may be used in children with sepsis as long as they are not suspected of having meningitis. 4.3 Contraindications Hypersensitivity to this product. 4.4 Special warnings and precautions for use Warning Total daily dose 15 mg/kg 6 hours 60 mg/kg There is some clinical and laboratory evidence of partial cross allergenicity between 'Primaxin' and the other beta lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta lactam antibiotics. Before initiating therapy with 'Primaxin', careful inquiry should be made concerning previous hypersensitivity reactions to beta

6 Seite 6 von 20 lactam antibiotics. If an allergic reaction to 'Primaxin' occurs, the drug should be discontinued and appropriate measures undertaken. Pseudomembranous colitis, reported with virtually all antibiotics, can range from mild to life threatening in severity. 'Primaxin' should be prescribed with caution in patients with a history of gastro intestinal disease, particularly colitis. Treatment related diarrhoea should always be considered as a pointer to this diagnosis. While studies indicate that a toxin of Clostridium difficile is one of the primary causes of antibiotic associated colitis, other causes should be considered. Paediatric use 'Primaxin' IV: Efficacy and tolerability in infants under 3 months of age have yet to be established; therefore, 'Primaxin' IV is not recommended for use below this age. Central nervous system: Patients with CNS disorders and/or compromised renal function (accumulation of 'Primaxin' may occur) have shown CNS side effects, especially when recommended dosages based on bodyweight and renal function were exceeded. Hence it is recommended that the dosage schedules of 'Primaxin' should be strictly adhered to, and established anticonvulsant therapy continued. If focal tremors, myoclonus or convulsions occur, the patient should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If these symptoms continue, the dosage should be reduced, or 'Primaxin' withdrawn completely. Use in patients with renal insufficiency Patients with creatinine clearances of <5 ml/min should not receive 'Primaxin' IV unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, 'Primaxin' IV is recommended only when the benefit outweighs the potential risk of convulsions. 4.5 Interaction with other medicinal products and other forms of interaction General seizures have been reported in patients who received ganciclovir and 'Primaxin' IV. These drugs should not be used concomitantly unless the potential benefit outweighs the risk. Decreased serum levels of valproic acid with co-administration of carbapenem antibiotics have been reported during post-marketing and in some cases breakthrough seizures have occurred. Careful monitoring of serum levels of valproic acid should be considered if imipenem is to be co-administered with valproic acid (e.g. sodium

7 Seite 7 von 20 valproate). Concomitant probenecid has been shown to double the plasma level and half life of cilastatin, but with no effect on its urinary recovery. Concomitant probenecid showed only minimal increases in plasma level and half life of imipenem, with urinary recovery of active imipenem decreased to approximately 60% of the administered dose. 4.6 Pregnancy and lactation Pregnant monkeys showed evidence of maternal and foetal toxicity with bolus injections at doses equivalent to twice the human dose. The use of 'Primaxin' in pregnant women has not been studied and 'Primaxin' should therefore not be given in pregnancy unless the anticipated benefit to the mother outweighs the possible risk to the foetus. 'Primaxin' has been detected in human milk. If the use of 'Primaxin' is deemed essential, the mother should stop breastfeeding. 4.7 Effects on ability to drive and use machines There are no specific data; however, some of the CNS side-effects, such as dizziness, psychic disturbances, confusion and seizures, may affect the ability to drive or operate machinery. 4.8 Undesirable effects Side effects 'Primaxin' is generally well tolerated. Side effects rarely require cessation of therapy and are generally mild and transient; serious side effects are rare. Local reactions: erythema, local pain and induration, thrombophlebitis. Allergic: rash, pruritus, urticaria, erythema multiforme, Stevens- Johnson syndrome, angioedema, toxic epidermal necrolysis (rarely), exfoliative dermatitis, (rarely) candidiasis, fever including drug fever, anaphylactic reactions. Gastro intestinal: nausea, vomiting, diarrhoea, staining of teeth and/or tongue. Pseudomembranous colitis has been reported. Blood: eosinophilia, leucopenia, neutropenia including agranulocytosis, thrombocytopenia, thrombocytosis, decreased

8 Seite 8 von 20 haemoglobin and prolonged prothrombin time. A positive direct Coombs test may develop. Liver function: mild increases in serum transaminases, bilirubin and/or serum alkaline phosphatase, hepatitis rarely have been reported. Renal function: oliguria/anuria, polyuria, acute renal failure (rarely). The role of 'Primaxin' in changes in renal function is difficult to assess, since factors predisposing to pre renal uraemia or to impaired renal function usually have been present. Elevated serum creatinine and blood urea have been seen. A harmless urine discoloration, not to be confused with haematuria, has been seen in children. Central nervous system: myoclonic activity, psychic disturbances including hallucinations, paraesthesia, confusional states or convulsions have been reported. Granulocytopenic patients: drug-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with 'Primaxin'. Special senses: hearing loss, taste perversion. Other reported reactions with an unknown causal relationship Gastro intestinal: haemorrhagic colitis, gastro enteritis, abdominal pain, glossitis, tongue papillar hypertrophy, heartburn, pharyngeal pain, increased salivation. Central nervous system: dizziness, somnolence, encephalopathy, vertigo, headache. Special senses: tinnitus. Respiratory: chest discomfort, dyspnoea, hyperventilation, thoracic spine pain. Cardiovascular: hypotension, palpitations, tachycardia. Skin: flushing, cyanosis, hyperhidrosis, skin texture changes, pruritus vulvae. Body as a whole: polyarthralgia, asthenia/weakness. Blood: haemolytic anaemia, pancytopenia, bone marrow depression. 4.9 Overdose

9 Seite 9 von 20 No specific information is available on the treatment of overdosage with 'Primaxin'. Imipenem-cilastatin sodium is haemodialysable. However, usefulness of this procedure in the overdosage setting is unknown. 5. PHARMACOLOGICAL PROPERTIES Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01D H Pharmacodynamic properties Mechanism of Action Imipenem is a potent inhibitor of bacterial cell wall synthesis and is highly reactive towards penicillin binding protein. Imipenem is more potent in its bactericidal effect than other antibiotics studied. Imipenem also provides excellent stability to degradative bacterial beta lactamases. Imipenem is therefore active against a high percentage of organisms resistant to other beta lactam antibiotics. Cilastatin sodium is a competitive, reversible, and specific inhibitor of dehydropeptidase I, the renal enzyme which metabolises and inactivates imipenem. Cilastatin sodium is devoid of intrinsic antibacterial activity itself and does not affect the antibacterial activity of imipenem. Bacteriology 'Primaxin' has a unique anti bacterial spectrum. Against Gram negative species, 'Primaxin' shares the spectrum of the newer cephalosporins and penicillins; against Gram positive species 'Primaxin' exerts the high bacterial potency previously associated only with narrow spectrum beta lactam antibiotics and the first generation cephalosporins. The antibiotic spectrum of 'Primaxin' is broader than that of other antibiotics studied and includes virtually all clinically significant pathogenic genera. In vitro tests show that imipenem acts synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. Breakpoints (NCCLS) The general MIC susceptibility test breakpoints to separate sensitive (S) pathogens from resistant (R) pathogens are: S 4

10 Seite 10 von 20 mcg/ml, R 16 mcg/ml. For Haemophilus spp. S defined. 4 mcg/ml, R MIC breakpoint not For Neisseria gonorrhoeae MIC breakpoints not defined. For Streptococcus pneumoniae S 0.12 mcg/ml, R 1 mcg/ml For streptococci other than S. pneumoniae MIC breakpoints not defined. Susceptibility The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. The information below gives only approximate guidance on the probability as to whether the microorganism will be susceptible to 'Primaxin' or not. Organism SUSCEPTIBLE Prevalence of Resistance (Range) [European Union] Gram-positive aerobes: Bacillus spp Enterococcus faecalis 0 to 7% Erysipelothrix rhusiopathiae Listeria monocytogenes Nocardia spp

11 Seite 11 von 20 Pediococcus spp Staphylococcus aureus (methicillin susceptible, including penicillinaseproducing strains Staphylococcus epidermidis (methicillin susceptible, including penicillinaseproducing strains) 0% 0 to 7% Staphylococcus saprophyticus 0% Streptococcus agalactiae* Streptococcus Group C Streptococcus Group G Streptococcus pneumoniae 0% Streptococcus pneumoniae, PRSP 0 to 83% Streptococcus pyogenes* Viridans group streptococci* (including alpha and gamma hemolytic strains) Gram-negative aerobes: Achromobacter spp. Acinetobacter baumannii 0 to 67% Aeromonas hydrophila 0 to 50% Alcaligenes spp Bordetella bronchicanis

12 Seite 12 von 20 Bordetella bronchiseptica Bordetella pertussis Brucella melitensis Burkholderia pseudomallei (formerly pseudomonas pseudomallei) Burkholderia stutzeri (formerly pseudomonas stutzeri) Campylobacter spp. Capnocytophaga spp. Citrobacter freundii 0% Citrobacter koseri (formerly Citrobacter diversus 0% Eikenella corrodens Enterobacter aerogenes 0% Enterobacter agglomerans Enterobacter cloacae 0 to 13% Eschericia coli 0% Gardnerella vaginalis Haemophilus ducreyi Haemophilus influenzae (including betalactamase-producing strains)*

13 Seite 13 von 20 Haemophilus parainfluenzae* Hafnia alvei 0% Klebsiella oxytoca 0% Klebsiella ozaenae Klebsiella pneumoniae 0% Moraxella catarrhalis 0% Morganella morganii (formerly Proteus morganii) 0 to 7% Neisseria gonorrhoeae (including penicillinase-producing strains)* Neisseria meningitidis Pasteurella spp 0% Pasteurella multocida Plesiomonas shigelloides Proteus mirabilis 0% Proteus vulgaris 0 to 8% Providencia alcalifaciens Providencia rettgeri (formerly Proteus rettgeri) 0 to 20% Providencia stuartii 0% Pseudomonas aeruginosa 0 to 20% Pseudomonas fluorescens Pseudomonas putida

14 Seite 14 von 20 Salmonella spp 0% Salmonella typhi Serratia spp Serratia proteamaculans (formerly Serratia liquefaciens) Serratia marcescens 0% Shigella spp. 0% Yersinia spp (formerly Pasteurella) Yersinia enterocolitica Yersinia pseudotuberculosis Gram-positive Anaerobes: Actinomyces spp Bifidobacterium spp. Clostridium spp 0% Clostridium pefringens Eubacterium spp. Lactobacillus spp.

15 Seite 15 von 20 Mobiluncus spp. Microaerophilic streptococci Peptococcus spp. Peptostreptococcus spp. 0% Propionibacterium spp (including P. acnes) Gram-negative Anaerobes: Bacteroides spp. 6% Bacteroides distasonis Bacteroides fragilis 0 to 7% Bacteroides ovatus Bacteroides thetaitaomicron 0% Bacteroides uniformis Bacteroides vulgatus Bilophila wadsworthia Fusobacterium spp. Fusobacterium necrophorum Fusobacterium nucleatum

16 Seite 16 von 20 Porphyromonas asaccharolytica (formerly Bacteroides asaccharolytica bivius) Prevotella bivia (formerly Bacteroides bivius) Prevotella disiens (formerly Bacteroides disiens) Prevotella intermedia (formerly Bacteroides intermedius) Prevotella melaninogenica (formerly Bacteroides melaninogenicus) Veillonella spp Others: Mycobacterium fortuitum Myobacterium smegmatis RESISTANT Gram-positive Aerobes: Enterococcus faecium methicillin-resistant staphylococci Gram-negative Aerobes:

17 Seite 17 von 20 Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia) (Some strains of Burkholderia cepacia (formerly Pseudomonas cepacia) *Resistant breakpoint not defined. Mechanism/s of Resistance For species considered susceptible to imipenem, resistance was uncommon in surveillance studies in Europe. In resistant isolates, resistance to other antibacterial agents of the carbapenem class was seen in some, but not all isolates. Imipenem is effectively stable to hydrolysis by most classes of beta-lactamases, including penicillinases, cephalosporinases and extended spectrum betalactamases, but not metallo-beta-lactamases. Although effectively stable to beta-lactamase activity, resistance, when seen, is generally due to a combination of decreased permeability and lowlevel beta-lactamase hydrolysis. The mechanism of action of imipenem differs from that of other classes of antibiotics, such as quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based crossresistance between imipenem and these substances. However, micro-organisms may exhibit resistance to more than one class of antibacterial agents when the mechanism is, or includes, impermeability to some compounds. 5.2 Pharmacokinetic properties 'Primaxin' IV The product is administered intravenously, therefore bioavailability data are not relevant. Imipenem: Peak plasma levels of 36.4 mcg/ml after 500 mg, halflife 62.0 (±3.9) mins; plasma clearance (±15.9) ml/min. Co-administration of cilastatin sodium increases plasma concentrations of imipenem and increases the AUC by about 20%. There is also a decrease in plasma clearance (194.9 ml/min) and an increase in renal clearance, urinary recovery and urinary concentration. 5.3 Preclinical safety data No relevant data.

18 Seite 18 von PHARMACEUTICAL PARTICULARS 6.1 List of excipients The only inactive ingredient in 'Primaxin' IV is sodium bicarbonate. 6.2 Incompatibilities 'Primaxin' is chemically incompatible with lactate and should not be reconstituted with diluents containing lactate. 'Primaxin' IV can, however, be administered into an IV tubing through which a lactate solution is being infused. 'Primaxin' should not be mixed or physically added to other antibiotics. 6.3 Shelf life 24 months. 6.4 Special precautions for storage Vials of dry 'Primaxin' should be stored below 25 C. The container should be kept in the outer carton until immediately before use. After reconstitution 'Primaxin' IV can be kept at room temperature (below 25 C) for up to three hours or under refrigeration (below 4 C) for up to 24 hours. 6.5 Nature and contents of container 'Primaxin' IV 500 mg strength is available in Type I (20ml) clear glass vials with grey butyl rubber stoppers (West Formula 1816) and aluminium collar seals with plastic flip-off tops. The vial size for 'Primaxin' IV 500 mg strength is 20ml 6.6 Special precautions for disposal and other handling Preparation of intravenous solution The following table is provided for convenience in reconstituting 'Primaxin' IV for intravenous infusion. Strength 'Primaxin' IV 500 mg Volume of diluent added (ml) Approximate concentration of imipenem (mg/ml) Reconstitution of 20 ml vial Contents of the vials must be suspended and transferred to 100 ml of an appropriate infusion solution. A suggested procedure is to add approximately 10 ml from the appropriate infusion solution (see 'Compatibility and Stability')) to the vial. Shake well and

19 Seite 19 von 20 transfer the resulting suspension to the infusion solution container. CAUTION: THE SUSPENSION IS NOT FOR DIRECT INFUSION. Repeat with an additional 10 ml of infusion solution to ensure complete transfer of vial contents to the infusion solution. The resulting mixture should be agitated until clear. Compatibility and stability In keeping with good clinical and pharmaceutical practice, 'Primaxin' IV should be administered as a freshly prepared solution. On the few occasions where changing circumstances make this impracticable, reconstituted 'Primaxin' IV retains satisfactory potency for three hours at room temperature (up to 25 C) or 24 hours in a refrigerator (below 4 C) when prepared in any of the following diluents: 0.9% Sodium Chloride Injection; 5% Dextrose and 0.9% Sodium Chloride; 5% Dextrose and 0.225% Sodium Chloride; 5% Mannitol. 'Primaxin' IV is chemically incompatible with lactate and should not be reconstituted with diluents containing lactate. 'Primaxin' IV can, however, be administered into an IV tubing through which a lactate solution is being infused. 'Primaxin' should not be mixed with, or physically added to, other antibiotics. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Hertfordshire EN11 9BU 8. MARKETING AUTHORISATION NUMBER(S) PL 0025/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Licence first granted 30 June 1988 Licence last renewed 07 October DATE OF REVISION OF THE TEXT February 2009 LEGAL CATEGORY: P.O.M. denotes registered trademark of Merck & Co., Inc., Whitehouse

20 Seite 20 von 20 Station, NJ, USA. Merck Sharp & Dohme Limited All rights reserved. SPC.TENIV.08.UK.2942