Mesporin Ceftriaxone Disodium Salt and Lidocaine Hydrochloride Injection

Mesporin™

Mesporin™ 250 mg powder and solvent for solution for IM injection

Mesporin™ 500 mg powder and solvent for solution for IM injection

Mesporin™ 1000 mg powder and solvent for solution for IM injection

 

QUALITATIVE AND QUANTITATIVE COMPOSITION

Mesporin 250 mg powder and solvent for solution for IM injection

Each vial contains 250 mg of ceftriaxone (as 298.3 mg ceftriaxone disodium salt). Each vial contains approximately 3.6 mmol (or 83 mg) of sodium per gram of ceftriaxone.

Each ampoule contains: 20 mg lidocaine hydrochloride and water for injection q.s. 2 ml.

 

Mesporin 500 mg powder and solvent for solution for IM injection

Each vial contains: 500 mg of ceftriaxone (in the form of 596.5 mg ceftriaxone disodium salt). Each vial contains approximately 3.6 mmol (or 83 mg) of sodium per gram of ceftriaxone.

Each ampoule contains: 20 mg lidocaine hydrochloride and water for injection q.s. 2 ml.

 

Mesporin 1000 mg powder and solvent for solution for IM injection

Each vial contains 1000 mg of ceftriaxone (as 1193 mg ceftriaxone disodium salt). Each vial contains approximately 3.6 mmol (or 83 mg) of sodium per gram of ceftriaxone.

Each ampoule contains: 35 mg lidocaine hydrochloride and water for injection q.s. 3.5 ml.

 

PHARMACEUTICAL FORM

Powder and solvent for solution for IM injection.

Almost white or yellowish, crystalline powder.

 

CLINICAL PARTICULARS

Therapeutic indications

Mesporin is indicated for the treatment of the following infections when caused by micro-organisms that are susceptible to ceftriaxone and if parenteral treatment is necessary (see section “Pharmacodynamic properties”):

– Sepsis;

– Bacterial meningitis;

– Infections of bones or joints;

– Infections of skin or soft tissues;

– Pneumonia.

Mesporin is indicated for perioperative prophylaxis in patients with a certain risk of severe postoperative infections (see section “Special warnings and precautions for use”).

Depending on the mode of surgery and the expected spectrum of pathogens ceftriaxone may be used in combination with an appropriate antimicrobial agent with additional anaerobic coverage.

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

 

Posology and method of administration

Route and method of administration

Mesporin may be administered by intramuscular (IM) injection after reconstitution of the solution according to the directions given below (see section “Instructions for use and handling”).

Dosage and mode of administration should be determined by the severity and site of infection, susceptibility of the causative micro-organism and the patient’s age and condition.

The intramuscular route of administration should only be used in exceptional clinical situations (see section “Contraindications”) and must undergo a risk-benefit assessment.

For IM injections the special recommendation described below and in section “Instructions for use and handling” must be followed.

For intramuscular administration Mesporin is injected deep into the gluteus maximus muscle. Not more than 1 g of ceftriaxone should be injected on either side of the body.

The maximum daily dose by intramuscular administration should not exceed 2 g.

 

Normal dosage

Adults and adolescents aged over 12 years with a body weight ≥50kg

The usual dose is 1 to 2 g of ceftriaxone, administered once a day (every 24 hours).

 

Children aged between 2 years and 12 years and body weight <50kg

The recommended daily dose is 20-80 mg per kg of body weight every 24 hours. In severe infections the daily dose of 80 mg/kg of body weight must not be exceeded, except in meningitis (see section “Posology and method of administration”: “Special dosage recommendations”).

Children with a body weight of 50 kg or more receive the usual adult dosage once daily (see above).

 

Elderly

For elderly patients the dosage recommendations are the same as for adults without modification.

Age group Normal dosage Frequency
Children 2 years-12 years of age <50kg 20-80 mg/kg Once a day
Adolescents over 12-17 years ≥50kg 1-2 g Once a day
Adults ≥17 years 1-2 g Once a day
Elderly 1-2 g Once a day

 

Special dosage recommendations

Meningitis

Treatment is initiated with 100 mg per kg body weight once daily – not exceeding 4g daily. After determining the sensitivity of the pathogen the dose may be reduced accordingly.

 

Perioperative prophylaxis

The normal daily dose of ceftriaxone should be administered 30-90 minutes prior to surgery. One single administration is usually sufficient.

 

Renal insufficiency

In patients with impaired renal function, adjustment of the ceftriaxone dose is not necessary if the hepatic function is normal. In renal insufficiency with a reduced creatinine clearance <10 ml/min the daily dose of ceftriaxone should not exceed 2 g in adult patients.

 

Hepatic insufficiency

The dose does not need to be altered in patients with a liver disease provided that the renal function is normal (see section “Undesirable effects”).

In simultaneous severe renal and hepatic insufficiency the serum ceftriaxone concentrations should be monitored regularly and the dosage adjusted appropriately for children and adults (see sections “Special warnings and precautions for use” and “Pharmacokinetic properties”).

 

Haemodialysis or peritoneal dialysis

As ceftriaxone is dialysable only to a very minor extent there is no need for an additional dose of ceftriaxone after the dialysis.

Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.

In patients on continuous ambulatory peritoneal dialysis (CAPD), ceftriaxone may be administered either intravenously or in case of CAPD associated infections may be added directly to the dialysis solution (e .g. 1-2 g ceftriaxone in the first dialysis fluid of the respective day of treatment) (see section “Instructions for use and handling”).

 

Duration of therapy

The normal duration of therapy depends on te characteristics of the infection. Generally the administration of ceftriaxone should be continued for at least 48-72 hours beyond the normalisation of body temperature and evidence of bacterial eradication has been obtained. Dosage recommendations for special indications should be taken into account.

 

Contraindications

Hypersensitivity to the active substance or to any of the excipients. Mesporin is contraindicated in patients with known hypersensitivity to beta-lactam antibiotics.

In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be borne in mind.

Hyperbilirubinaemic newborns and preterm newborns should not be treated with ceftriaxone. In vitro studies have shown that ceftriaxone can displace bilirubin from it binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.

Ceftriaxone is contra-indicated in:

– Premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life),

– Full-term newborns (up to 28 days of age)

• With jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired.

Contraindications of lidocaine must be excluded before IM injection of ceftriaxone when lidocaine is use as solvent.

IM injections of this product are contraindicated in:

– Children aged <2 years;

– During pregnancy and lactation.

 

Special warnings and precautions for use

In suspected or proven infections with Pseudomonas aeruginosa, high resistance rates (> 60%) for ceftriaxone in at least some European countries should be taken into consideration (see section “Pharmacodynamic properties”).

In infections caused by Pseudomonas aeruginosa with proven sensitivity to ceftriaxone a combination with amino-glycosides is warranted to avoid secondary resistance.

In infections caused by other bacteria in patients with neutropenic fever interventional treatment with ceftriaxone should be combined with an aminoglycoside.

Special caution is required to determine previous hypersensitivity reactions to penicillin or to other beta-lactam medicinal products because patients hypersensitive to these medicines may be hypersensitive to ceftriaxone as well (cross-allergy).

Hypersensitivity reactions against ceftriaxone are more likely in patients with any other type of hypersensitivity or asthma bronchiale.

Injections with ceftriaxone should be used with special caution in patients with allergic diathesis, because hypersensitivity reactions emerge faster and proceed more severely after intravenous injection (see section “Undesirable effects”).

As with other cephalosporins, the possibility of anaphylactic shock cannot be ruled out even if the patient history is well known.

Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including Mesporin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

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.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficie may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

It is indicated to monitor renal and liver function and haematological parameters at regular intervals during prolonged treatment (see section “Undesirable effects”). In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined in section “Posology and method of administration”.

In case of simultaneous impairment of renal and liver function, serum-level of ceftriaxone should be monitored in regular intervals.

Each administration of antibiotics can lead to multiplication of pathogens resistant to the active substance used. Signs of consecutive secondary infections with such pathogens (including Candida and fungi) are to be heeded. Secondary infections are to be treated accordingly.

Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.

Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder, usually following doses higher than the standard recommended dose.

These shadows are, however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of Mesporin therapy. Rarely have these findings been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended.

Discontinuation of Mesporin treatment in symptomatic cases should be at the discretion of the physician.

Ceftriaxone may precipitate in the kidneys when given at high doses and in the presence of other risk factors (see section “Undesirable effects”). This can lead to renal failure and anuria, and is reversible upon discontinuation of therapy.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of ceftriaxone related biliary precipitation cannot be ruled out.

In severe renal and hepatic insufficiency, dosage should be reduced according to given recommendations (see section “Posology and method of administration”).

Safety and effectiveness of Mesporin in neonates, infants and children have been established for the dosages described in section “Posology and method of administration”. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

Mesporin should not be used in neonates (especially prematures) at risk of developing bilirubin encephalopathy.

During prolonged treatment complete blood count should be performed at regular intervals.

Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the drug to produce a positive Coombs’ test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.

In case lidocaine is used as a solvent Ceftriaxone solutions should only be used for IM injection.

Each gram of Mesporin contains approximately 83 mg (3.6 mmol) sodium. To be taken into consideration by patients on a controlled sodium diet.

 

Interaction with other medicinal products and other forms of interaction

No impairment of renal function has so far been observed after concurrent administration of large doses of Mesporin and potent diuretics (e.g. furosemide). There is no evidence that Mesporin increases renal toxicity of aminoglycosides.

In a pharmacokinetic drug interaction study conducted in healthy volunteers, no interaction between ceftriaxone and azithromycin was observed.

In comparative studies of ceftriaxone (associated with other drugs) and ertapenem, ceftriaxone did not significantly alter the adverse event profile of ertapenem.

No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Mesporin. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins.

The elimination of Mesporin is not altered by probenecid.

In an in-vitro study, antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.

Based on literature reports, ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

In patients treated with ceftriaxone, the Coombs’ test may rarely become false-positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia.

Likewise, non-enzymatic methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically.

As with many other classes of antibiotics, cephalosporins suppress the intestinal flora with consequent reduction in enterohepatic circulation of oestrogen metabolites. Thus, ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives.

Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment.

 

Pregnancy and lactation

Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, foetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed.

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman.

IM injections of this drug are contraindicated during pregnancy and lactation (see section “Contraindications”).

 

Effects on ability to drive and use machines

Since Mesporin sometimes induces dizziness, the ability to drive and use machines can be impaired.

 

Undesirable effects

The undesirable effects are usually mild and transient.

 

Infections and Infestations

Rare: Mycosis of the genital tract.

Superinfection caused by micro-organisms non-susceptible to ceftriaxone (Candida, fungi or other resistant microorganisms) may develop. Pseudomembraneous colitis is a rare undesirable effect caused by infection with Clostridium difficile during treatment with ceftriaxone. Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use.

 

Blood and lymphatic system disorders (about 2 %)

Eosinophilia, leukopenia, neutropenia, granulocytopenia, hemolytic anemia and thrombocytopenia.

Unknown frequency: cases of agranulocytosis (< 500/mm3) have been reported, most of them after 10 days of treatment and following total doses of 20 g or more.

Coagulation disorders have been reported as very rare side effects.

 

Immune system disorders (rare)

Anaphylactic and anaphylactoid reactions, e.g. bronchospasm.

 

Nervous system disorders (rare)

Headache, dizziness and shivering.

 

Ear and labyrinth disorders (rare)

Vertigo.

 

Gastrointestinal disorders (about 2 % of the cases)

Loose stools or diarrhoea, nausea vomiting, stomatitis, glossitis. There were isolated reports of pancreatitis.

 

Hepatobiliary disorders

Rare: Increase in serum liver enzymes and symptomatic precipitation of ceftriaxone calcium salt in the gallbladder. Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, mostly in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application, in some studies to above 30 %.

The incidence seems to be lower with slow infusion (20-30 minutes). This effect is usually asymptomatic, but in rare cases, the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone.

 

Skin and subcutaneous tissue disorders (about 1 %)

Exanthema, allergic dermatitis, pruritus, urticarial, edema.

Unknown frequency: cases of severe cutaneous adverse reactions (erythema multiforme, Steven-Johnson syndrome or Lyell’s Syndrome/toxic epidermal necrolysis) have been reported.

 

Renal and urinary disorders (rare)

Increase in serum creatinine, glycosuria, haematuria and oliguria. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.

Very rare cases of renal precipitation have been reported, mostly in children older than 3 years and who have been treated with either high daily doses (e.g. ≥ 80 mg/kg/day) or total doses exceeding 10 grams and presenting other risk factors (e.g. fluid restrictions, confinement to bed, etc) The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon discontinuation of ceftriaxone.

 

General disorders and administration site conditions

Rare: fever.

There were rare cases of phlebitis reactions after intravenous administration. These events can be minimized by a slow injection of the drug (over 2 to 4 minutes).

An IM injection without lidocaine is painful.

 

Investigations

In patients treated with ceftriaxone the Coombs’ test may rarely become false-positive.

Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosemia.

Likewise, non-enzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically.

 

Overdose

In the case of overdose nausea, vomiting, diarrhoea, can occur. Ceftriaxone concentration cannot be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group:

1.1.2.3 — Anti-infective drugs. Antibacterials.

Cephalosporins. 3rd generation cephalosporins.

ATC code: J01DD04

 

Mechanism of action

Ceftriaxone has bactericidal activity that results from the inhibition of bacterial cell wall synthesis. Ceftriaxone has a high degree of stability in the presence of beta-lactamases produced by Gram-negative and Gram-positive bacteria.

Synergistic effects of ceftriaxone and aminoglycosides on certain Gram-negative bacteria have been noted in vitro.

 

Mechanism of resistance

Ceftriaxone is active against organisms producing some types of beta-Iactamase, for example TEM-1. However, it is inactivated by beta-lactamases that can efficiently hydrolyse cephalosporins, such as many of the extended-spectrum beta-lactamases and chromosomal cephalosporinases (e.g. AmpC type enzymes). Ceftriaxone cannot be expected to be active against the majority of bacteria with penicillin-binding proteins that have reduced affinity for beta-lactam medicinal products. Resistance may also be mediated by bacterial impermeability or by bacterial drug efflux pumps. More than one of these four means of resistance may be present in the same organism.

 

Breakpoints

The minimum inhibitory concentration (MIC, according to the German Institute for Standardisation DIN 58940) is 4 mg/l (sensitive) and 32 mg/l (resistant).

The MIC breakpoints according to the Clinical and Laboratory Standards Institute (formerly National Committee for Clinical Laboratory Standards are 8 µg/ml (sensitive), 16-32 µg/ml (intermediate) and 64 µg/ml (resistant) for Enterobacteriaceae and Staphylococcus spp.

The respective values for Streptococcus pneumoniae are 0.5 µg/ ml (sensitive), 1 µg/ml (intermediate) and 2 µg/ml (resistant).

The breakpoints for sensitivity are 2 µg/ml for Haemophilus spp. and 0.25 µg/ml for Neisseria gonorrhoea.

The respective values for anaerobes are 16 µg/ml (sensitive), 32 µg/ml (intermediate) and 64 µg/ml (resistant).

 

Microbiology

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such, that the utility of the agent in at least some types of infections is questionable.

 

Commonly susceptible species

Gram-positive aerobes

Staphylococcus aureus1 (MSSA)

Streptococcus agalactiae

Streptococcus bovis

Streptococcus pyogenes1

Streptococcus pneumoniae1

 

Gram-positive anaerobes

Peptococcus niger

Peptostreptococcus spp.

 

Gram-negative aerobes

Citrobacter koseri2

Escherichia coli1

Haemophilus influenzae1

Haemophilus parainfluenzae1

Klebsiella pneumoniae1

Klebsiella oxytoca1

Moraxella catarrhalis1

Morganella morganii2

Neisseria meningitidis1

Proteus mirabilis1,2

Proteus vulgaris2

Providencia spp.2

Salmonella spp.2

Serratia spp.2

Shigella spp.2

 

Species for which acquired resistance may be a problem

Gram-positive aerobes

Staphylococcus epidermidis1,3 (MSSE)

 

Gram-negative aerobes

Citrobacter freundii2

Enterobacter spp.2,4

Pseudomonas aeruginosa3,5

 

Inherently resistant species

Gram-positive aerobes

Enterococcus faecalis

Enterococcus faecium

Listeria monocytogenes

Staphylococcus aureus MRSA

Staphylococcus epidermidis MRSE

 

Gram-positive anaerobes

Clostridium difficile

 

Gram-negative aerobes

Acinetobacter spp.

Achromobacter spp.

Aeromonas spp.

Alcaligenes spp.

Flavobacterium spp.

Legionella gormanii

 

Gram-negative anaerobes

Bacteroides spp.

 

Others

Chlamydia spp.

Chlamydophila spp.

Mycobacterium spp.

Mycoplasma spp.

Rickettsia spp.

Ureaplasma urealyticum

1) Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

2) Some strains produce inducible or stably derepressed chromosomally-encoded cephalosporinases and extended spectrum beta-lactamases and thus are clinically resistant to cephalosporins.

3) Species with natural intermediate susceptibility.

4) Clinical efficacy has been demonstrated for susceptible isolates of Enterobacter cloacae and Enterobacter aerogenes in approved Clinical indications.

5) In suspected or proven Pseudomonas infection combination with an aminoglycoside is necessary.

 

Pharmacokinetic properties

Ceftriaxone is a cephalosporin for parenteral administration. Ceftriaxone is not absorbed after oral administration.

After a dose of 1-2 g, concentrations have been shown to remain above the MIC values for most infection-causing pathogens for over 24 hours in over 60 different tissues (including lungs, heart, bile ducts, liver, tonsils, middle ear, nasal mucosa, bones) and in many tissue fluids (including cerebrospinal fluid, pleural fluid as well as prostatic and synovial fluid).

 

Absorption

Ceftriaxone is completely absorbed following intramuscular administration with peak plasma concentrations (about 80 mg/l) occurring between 2 and 3 hours after dosing.

 

Distribution

Ceftriaxone distributes well in various compartments and also passes the placental barrier. The mean volume of distribution in healthy adults is 0.131/kg.

Ceftriaxone is reversibly bound to albumin. The binding is 95 % at plasma concentrations less than 100 mg/I with the binding percentage decreasing as the concentration increases (to 85 % at ceftriaxone plasma concentrations of 300 µg/ml).

 

Serum levels

Following an intravenous infusion of 1 g of ceftriaxone for 30 minutes, serum levels immediately after cessation of the infusion process were at 123.2 µg/ml, and at 94.81, 57.8, 20.2 and 4.6 µg/ml, respectively, 1.5, 4, 12 and 24 hours after the onset of infusion.

Subsequent to an IM injection of 1 g of ceftriaxone the serum concentration amounted to 79.2 µg/ml after 1.5 hours, and afterwards 58.2, 35.5 and 7.8 µg/ml at the respective time-points 4, 12 and 24 hours after injection.

Ceftriaxone penetrates the inflamed meninges of newborn, infants and children. In CSF the peak concentrations of 18 mg/I are achieved, after a 50-100 mg/kg intravenous dose, in about four hours. In adult patients with meningitis, therapeutic concentrations are achieved within 2-24 hours with the dose of 50 mg/kg.

Ceftriaxone crosses the placenta and is excreted in human milk at low concentrations.

 

Biotransformation

Ceftriaxone does not undergo systemic metabolism but it is broken down in the small intestine by bacterial action.

 

Elimination

Over a 0.15 to 3 g dose range, the values of elimination half-life range from 6 to 9 hours, total plasma clearance from 0.6-1.4 I/h and renal clearance from 0.3-0.7 I/h. 50-60 % of ceftriaxone is eliminated as an unchanged active substance in the urine whilst the remainder is excreted via the bile into the faeces as microbiologically inactive metabolites. Ceftriaxone concentrates in the urine. The urine concentrations are 5-10 times higher than those found in the plasma. Ceftriaxone cannot be removed by dialysis.

This applies to both haemodialysis and peritoneal dialysis.

Urinary excretion is via glomerular filtration. No tubular secretion takes place. For this reason, no increase in the serum levels is to be expected in coincident administration of probenecid and actually, even at higher dosage (e. g. with 1-2 g probenecid), not found.

 

Non-Linearity

The pharmacokinetics of ceftriaxone is non-linear with respect to the dose. This non-linearity is explained by a concentration dependent decrease of binding to plasma proteins which leads to a respective increase in distribution and elimination. With the exception of elimination half-life, all pharmacokinetic parameters are dose-dependent. Repeat dosing of 0.5 g to 2 g results in 15%-36% accumulation above single dose values.

 

Special patient groups

Elderly above 75 years

The plasma elimination half-life of ceftriaxone is 2 to 3 times increased compared to young adults.

 

Newborns

In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in the adults. In infants aged less than 8 days the average elimination half-life is usually 2 to 3 times increased compared to young adults.

 

Patients with impaired renal and/or liver function

Patients with an impaired renal function have an increased excretion of ceftriaxone into the bile.

Patients with an impaired liver function have an increased renal excretion of ceftriaxone. The plasma elimination half-life of ceftriaxone is almost not increased in these patient groups. Patients with an impaired renal function, as well as an impaired liver function, may have an increased ceftriaxone plasma elimination half-life.

In case of terminal renal insufficiency, the half-life is distinctively higher and reaches approximately 14 hours.

 

Preclinical safety data

Repeated administration in animals confirmed the known reversible side effects of 3rd generation cephalosporins administered parenterally at high doses (e. g. change in laboratory parameters, intestinal disorders and some degree of nephrotoxicity). One particular side effect of ceftriaxone is the formation of gallstones in the gallbladder of the dog and also, but to a lesser extent, of the monkeys.

Reproductive studies in animals have shown no evidence of embryotoxicity, foetotoxicity, teratogenicity or adverse effects in male or female fertility, in birth or in perinatal and postnatal development.

In primates, no embryotoxicity or teratogenicity has been observed. Ceftriaxone neither has mutagenic nor antigenic activity.

 

PHARMACEUTICAL PARTICULARS

List of excipients

1 % lidocaine hydrochloride and water for injections.

 

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section “Instructions for use and handling”.

Based on studies, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

 

Special precautions for storage

Keep out of the reach and sight of children.

Mesporin 250 IM

Store dry below 30 °C.

Mesporin 500/1000 IM

Climatic zone I and II: Do not store above 25 °C.

Climatic zone III and IV: Do not store above 30 °C.

Do not use this medication after the expiry date which is stated on the carton after “EXP”.

The expiry date refers to the last day of that month.

It is recommended to use each reconstituted solution freshly.

Its effectiveness remains for up to 6 hours at room temperature (15-25 °C) and up to 24 hours under refrigeration (2-8 °C).

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

 

Nature and contents of container

Mesporin consists of a transparent glass vial of hydrolytic class I with 15 ml volume – containing the active substance (ceftriaxone sodium powder) – and a butyric rubber stopper as well as an amber glass ampoule of hydrolytic class I with 2.0 or 3.5 ml volume – containing the solvent (1% lidocaine HCI).

 

Instructions for use and handling

Ceftriaxone is usually administered by deep IM injection.

Mesporin should be dissolved in 2 ml (Mesporin dosed at 250 mg or 500 mg) or 3.5 ml (Mesporin dosed at 1000 mg) of 1 % w/v lidocaine hydrochloride solvent for injection solution.

The resulting solution should be administered by deep IM injection. Doses higher than 1 g should be divided and injected into more than one location.

Not more than 1 g of ceftriaxone should be administered in the same body place (see section “Posology and method of administration”).

Solutions in lidocaine should not be administered intravenously (see section “Special warning and precautions for use).

Ceftriaxone should not be mixed in the same syringe with any other drug than 1% w/v lidocaine hydrochloride solution (for IM injection only).

The reconstituted solution should be stirred for about 60 seconds to ensure complete dissolution of ceftriaxone.

 

Presentation

Vials and ampoules are packed inside plastic trays used for protection during transportation. The plastic trays are packed into a cardboard box with the package leaflet.

Packs of 1 unit.

 

DATE OF REVISION OF THE TEXT

09.02.2010

 

Manufactured by

Labesfal – Laboratbrios Almiro, S.A., Zona Industrial do Lagedo,
Santiago de Besteiros, 3465-157, Portugal

 

Manufactured for

Acino AG, Miesbach, Germany.

To report a safety issue or for queries in relation to drug safety – please send an e-mail to: pv@acino-oharma.com