Rocephin 1g powder and solvent for IM injection only.

Each 1g vial of powder contains 1g ceftriaxone as 1.19g ceftriaxone sodium.

Excipients:

Contains approximately 85 mg of sodium per dose.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for IM injection.

Powder: White to yellowish-orange crystalline powder.

Solvent: a clear colourless solution.

Ceftriaxone is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible micro-organisms (see section 5.1) and when parenteral therapy is required:

Respiratory tract infections including pneumonia, acute and chronic bronchitis and ear, nose and throat infections.

Renal and urinary tract infections.

Septicaemia. Meningitis.

Abdominal infections including peritonitis and infections of the biliary tract.

Soft tissue infections including cellulitis and wound infections.

Gonorrhoea.

Peri-operative prophylaxis of infections associated with surgery. Infections in patients with impaired defence mechanisms.

Treatment may be started before the results of susceptibility tests are known.

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

Rocephin may be administered by deep intramuscular injection only after reconstitution of the solution according to the directions given below. For instructions on reconstitution of the product before administration, see section 6.6.

Dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient's condition. Under most circumstances a once-daily dose - or, in the specified indications, a single dose - will give satisfactory therapeutic results.

Adults and children 12 years and over

Standard therapeutic dosage: 1g once daily.

Severe infections: 2 - 4g daily, normally as a single dose every 24 hours.

The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Rocephin should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

Acute, uncomplicated gonorrhoea: A single dose of 250mg intramuscularly should be administered. Simultaneous administration of probenecid is not indicated.

Peri-operative prophylaxis: Usually 1g as a single intramuscular dose 30-90 minutes prior to surgery. In colorectal surgery, 2g should be given intramuscularly, in conjunction with a suitable agent against anaerobic bacteria.

Elderly

These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory (see below).

Children under 12 years

Standard therapeutic dosage: 20 - 50mg/kg body-weight once daily.

Up to 80mg/kg body-weight daily may be given in severe infections, except in neonates where a daily dosage of 50mg/kg should not be exceeded. For children with body weights of 50 kg or more, the usual adult dosage should be used.

Renal and hepatic impairment

In patients with impaired renal function, there is no need to reduce the dosage of Rocephin provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance < 10ml per minute) should the daily dosage be limited to 2g or less.

In patients with liver damage there is no need for the dosage to be reduced provided renal function is intact.

In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of Rocephin should be determined at regular intervals in order to ensure that the plasma level is in excess of the minimum inhibitory concentration of the causative organism(s), assuming this is sensitive, and dosage adjusted so that accumulation of Rocephin does not occur.

In patients undergoing dialysis, no additional supplementary dosing is required following 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.

Rocephin 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 its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.

Ceftriaxone is contraindicated 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

     • if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see sections 4.4, 4.8 and 6.2).

Contraindications of lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine is used as a solvent.

The stated dosage should not be exceeded.

As with other cephalosporins, anaphylactic reactions with fatal outcome were also reported, even if a patient is not known to be allergic or previously exposed.

Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, any other cephalosporin, or to any penicillin or other beta-lactam drug. Ceftriaxone is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta lactam drug. Ceftriaxone should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug.

Ceftriaxone should be given with caution to patients who have other allergic diatheses.

In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under section 4.2.

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Rocephin. Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Rocephin, 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. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical eva luation should be instituted as clinically indicated.

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftriaxone. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to administration of antibacterial agents (see section 4.8).

As with other cephalosporins, prolonged use of ceftriaxone may result in the overgrowth of non-susceptible organisms, such as enterococci and Candida spp.

Interaction with Calcium-Containing Products

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term newborns aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that newborns have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used, or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions. (See sections 4.3, 4.8, 5.2 and 6.2).

Shadows which have been mistaken for gallstones have been detected by 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 Rocephin therapy. Rarely, have these findings been associated with symptoms. In symptomatic cases, conservative non-surgical management is recommended. Discontinuation of Rocephin treatment in symptomatic cases should be at the discretion of the clinician (see section 4.8).

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with Rocephin. 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 Rocephin-related biliary precipitation cannot be ruled out.

Safety and effectiveness of Rocephin in neonates, infants and children have been established for the dosages in section 4.2.

During prolonged treatment, the blood cell count should be checked regularly.

Each gram of Rocephin contains approximately 3.6mmol sodium. To be taken into consideration by patients on a controlled sodium diet.

For intramuscular injection, only the lidocaine solvent provided should be used.

No impairment of renal function has so far been observed after concurrent administration of large doses of Rocephin and potent diuretics (e.g. furosemide).

No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with Rocephin.

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

Simultaneous administration of probenecid does not reduce the elimination of Rocephin and its use with Rocephin is not indicated.

In vitro, chloramphenicol has been shown to be antagonistic with respect to ceftriaxone and other cephalosporins. The clinical relevance of this finding is unknown, but caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.

Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides (see section 6.2).

In patients treated with Rocephin, the Coombs' test may rarely become false-positive. Rocephin, 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 Rocephin should be done enzymatically.

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

For ceftriaxone limited clinical data on exposed pregnancies are available. Ceftriaxone crosses the placental barrier. 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. Since safety in human pregnancy is not established ceftriaxone should not be used unless absolutely indicated.

Lactation

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

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

Rarely severe adverse reactions have been reported in preterm and full-term newborns (aged <28 days). These reactions have caused death in some cases. These newborns had been treated with intravenous ceftriaxone and calcium. Some of them had received ceftriaxone and calcium at different times and on different intravenous lines. Precipitations of ceftriaxone – calcium salt have been observed in lungs and kidneys of these dead preterm newborns. The high risk of precipitation is due to the low blood volume of the newborns. Moreover the half life is longer than in adults (see sections 4.3, 4.4 and 5.2).

The most frequently reported adverse events for ceftriaxone are diarrhoea, nausea and vomiting. Other reported adverse events include hypersensitivity reactions such as allergic skin reactions and anaphylactic reactions, secondary infections with yeast, fungi or resistant organisms as well as changes in blood cell counts.

Infections and infestations

Rare ( 0.01 % - < 0.1 %): Mycosis of the genital tract.

Superinfections of various sites with yeasts, fungi or other resistant microorganisms are possible.

Pseudomembraneous colitis is a rare undesirable effect caused by infection with Clostridium difficile during treatment with Rocephin. Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use (see section 4.4).

Blood and lymphatic system disorders

Rare ( 0.01 % - < 0.1 %): Neutropenia, leucopenia, eosinophilia, thrombocytopenia, anaemia (including haemolytic anaemia), slight prolongation of prothrombin time.

Very rare (< 0.01 %) including isolated reports: Positive Coombs' test, coagulation disorders, agranulocytosis (< 500/m³), mostly after 10 days of treatment and following total doses of 20g ceftriaxone and more.

Immune system disorders

Rare ( 0.01 % - < 0.1 %): Anaphylactic (e.g. bronchospasm) and anaphylactoid reactions (see section 4.4).

Nervous system disorders

Rare ( 0.01 % - < 0.1 %): Headache, dizziness.

Gastrointestinal disorders

Common ( 1% - < 10%): Loose stools or diarrhoea, nausea, vomiting.

Rare ( 0.01 % - < 0.1 %): Stomatitis, glossitis. These side effects are usually mild and commonly disappear during treatment or after discontinuation of treatment.

Very rare (< 0.01 %) including isolated reports: Pseudomembranous colitis (mostly caused by Clostridium difficile), pancreatitis (possibly caused by obstruction of bile ducts).

Hepato-biliary disorders

Rare ( 0.01 % - < 0.1 %): Increase in serum liver enzymes (AST, ALT, alkaline phosphatase), jaundice.

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed (see section 4.4), 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

Uncommon ( 0.1 % - < 1 %): Allergic skin reactions such as maculopapular rash or exanthema, urticaria, dermatitis, pruritis, oedema.

Very rare (< 0.01 %) including isolated reports: Erythema multiforme, Stevens Johnson Syndrome, Lyell's Syndrome/toxic epidermal necrolysis.

Renal and urinary disorders

Rare ( 0.01 % - < 0.1 %): Increase in serum creatinine, oliguria, glycosuria, haematuria.

Very rare (< 0.01 %) including isolated reports: Renal precipitation, mostly in children older than 3 years who have been treated with either high daily doses (e.g. 80 mg/kg/day) or total doses exceeding 10g and with other risk factors such as dehydration or immobilisation. Renal precipitation is reversible upon discontinuation of ceftriaxone. Anuria and renal impairment have been reported in association.

General disorders and administration site conditions

Rare ( 0.01 % - < 0.1 %): Phlebitis and injection site pain following intravenous administration. This can be minimised by slow injection over at least 2-4 minutes. Rigors, pyrexia.

An intramuscular injection without lidocaine solution is painful.

In the case of overdosage, nausea, vomiting, diarrhoea can occur. Ceftriaxone concentrations would not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment should be symptomatic.

Ceftriaxone is a long-acting, broad spectrum cephalosporin antibiotic for parenteral use.

The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone exerts in vitro activity against a wide range of Gram-negative and Gram-positive organisms including both aerobic and anaerobic species. Ceftriaxone is highly stable to most beta-lactamases, both penicillinases and cephalosporinases, of Gram-positive and Gram-negative bacteria.

The outstanding feature of Rocephin is its relatively long plasma elimination half-life of approximately 8 hours, which makes single or once-daily dosage of the drug appropriate for most patients.

Microbiology

Ceftriaxone is usually active against the following micro-organisms in vitro and in clinical infections (see section 4.1). The list is not exhaustive and focuses on those organisms of particular clinical interest.

Gram-positive aerobes

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus group A (Streptococcus pyogenes)

Streptococcus group B (Streptococcus agalactiae)

Streptococcus viridans

Streptococcus bovis

Note

Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. In general, Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are resistant.

Gram-negative aerobes

Aeromonas spp.

Alcaligenes spp.

Moraxella catarrhalis (beta-lactamase negative and positive)

Citrobacter spp.

Enterobacter spp. (some strains are resistant)

Escherichia coli

Haemophilus ducreyi

Haemophilus influenzae (including penicillinase-producing strains)

Haemophilus parainfluenzae

Klebsiella spp. (including K. pneumoniae)

Moraxella spp.

Morganella morganii (= Proteus morganii)

Neisseria gonorrhoeae (including penicillinase-producing strains)

Neisseria meningitidis

Plesiomonas shigelloides

Proteus mirabilis

Proteus vulgaris

Providencia spp.

Pseudomonas spp. (some strains are resistant)

Salmonella spp. (including S. typhi)

Serratia spp. (including S. marcescens)

Shigella spp.

Vibrio spp. (including V. cholerae)

Yersinia spp. (including Y. enterocolitica)

Note

Many strains of the above organisms that are multiply resistant to other antibiotics, e.g. penicillins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone. Treponema pallidum is sensitive in vitro and in animal experiments. Clinical investigations indicate that primary and secondary syphilis respond well to ceftriaxone therapy. With a few exceptions clinical P. aeruginosa isolates are resistant to ceftriaxone.

Synergy between Rocephin and aminoglycosides has been demonstrated with many Gram-negative bacilli under experimental conditions. Although enhanced activity of such combinations is not always predictable, it should be considered in severe, life-threatening infections due to organisms such as Pseudomonas aeruginosa. Because of physical incompatibility the two drugs must be administered separately at the recommended dosages.

Anaerobic organisms

Bacteroides spp. (many strains notably B. fragilis are resistant)

Clostridium spp. (except C. difficile)

Fusobacterium spp. (except F. mortiferum and F. varium)

Gaffkia anaerobica (formerly peptococcus)

Peptostreptococcus spp.

Susceptibility to ceftriaxone can be determined by the disc diffusion test or by the agar or broth dilution test using standardised techniques for susceptibility testing such as those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The NCCLS issued the following interpretative breakpoints for ceftriaxone:

Dilution susceptibility testing: Susceptible 8mg/litre; moderately susceptible 16 - 32mg/litre; resistant 64mg/litre.

Diffusion susceptibility testing using a 30 microgram ceftriaxone disc: Susceptible 21mm; moderately susceptible 20 - 14mm; resistant 13mm.

Organisms should be tested with the ceftriaxone disc since it has been shown by in vitro tests to be active against certain strains resistant to cephalosporin class discs.

Where NCCLS recommendations are not in daily use, alternative, well standardised, susceptibility interpretative guidelines such as those issued by DIN, ICS and others may be substituted.

The pharmacokinetics of Rocephin are largely determined by its concentration-dependent binding to serum albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

Plasma concentrations: Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of 500mg Rocephin in 1.06% Lidocaine produces mean peak plasma concentrations of 40 - 70mg/l within 1 hour. Bioavailability after intramuscular injection is 100%.

Excretion: Rocephin is eliminated mainly as unchanged ceftriaxone, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10 - 22ml/min. The renal clearance is 5 - 12ml/min. The elimination half-life in adults is about 8 hours. The half-life is not significantly affected by the dose, the route of administration or by repeated administration. Due to its high protein binding, ceftriaxone is not dialysable.

Pharmacokinetics in special clinical situations:

Children

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 adults. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.

Elderly

In elderly persons aged over 75 years, the average elimination half-life is usually 2 to 3 times longer than in the young adult group. Dosage in the elderly need not be altered except as indicated under renal dysfunction.

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.

Cerebrospinal fluid: Rocephin crosses non-inflamed and inflamed meninges, attaining concentrations 4 - 17% of the simultaneous plasma concentration.

Not applicable.

Rocephin should not be mixed in the same syringe with any drug other than 1.06% Lidocaine Injection (for intramuscular injection only).

Solutions containing ceftriaxone should not be mixed with or added to other agents. In particular, Rocephin is not compatible with calcium-containing solutions such as Hartmann's solution and Ringer's solution. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions (see section 4.3, 4.4 and 4.8).

Based on literature reports ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole or aminoglycosides (see section 4.5).

Powder =Three years.

Solvent = Five years.

Reconstituted product: Chemical and physical in-use stability has been demonstrated for 6 hours at or below 25°C or 24 hours at 2-8°C. The product must be protected from light. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Do not store above 25°C. Keep vial in the outer carton to protect from light.

For storage of reconstituted product see section 6.3.

Powder = Type I Ph. Eur. clear glass vials with teflonised rubber stopper and aluminium cap containing a sterile, white to yellowish orange crystalline powder.

Solvent = Type I Ph. Eur. clear glass ampoule containing 3.5ml of solvent.

Rocephin 1g vials, in packs of 1.

Preparation of solutions for injection

The use of freshly prepared solutions is recommended.

For single use only. Discard any unused content.

When reconstituted for intramuscular injection, the white to yellowish-orange crystalline powder gives a pale yellow to amber solution. The displacement value of 250 mg of Rocephin is 0.18 ml.

Each gram of Rocephin contains approximately 3.6 mmol sodium.

Intramuscular injection: 1g Rocephin should be dissolved in 3.5ml of 1.06% Lidocaine Injection, provided in the package. The solution should be administered by deep intramuscular injection. Dosages greater than 1g should be divided and injected at more than one site.

Solutions in Lidocaine should not be administered intravenously.

Any unused product or waste material should be disposed of in accordance with local requirements.

Roche Products Limited,

6 Falcon Way,

Shire Park,

Welwyn Garden City,

AL7 1TW,

United Kingdom.

PA 50/62/8

Date of first authorisation: 6^th May 2005

Date of renewal: 6^th May 2010

February 2011

Rocephin is a registered trade mark