Wockhardt UK Ltd





Section 4.3

Text added/amended as follows:

Known or suspected allergy to cephalosporins.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta‑lactam drug.

Ceftriaxone 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 constituted with Lidocaine Injection BP must never be used:

- by the intravenous route

- in infants under 30 months

- in subjects with a previous history of hypersensitivity to Lidocaine Injection BP

- in patients who have an unpaced heart block

- in patients with severe heart failure.

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

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

o   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.

Section 4.4

Text added/amended as follows:

....

If lidocaine is used as a solvent ceftriaxone solutions should only be used for intramuscular injection.

As with other cephalosporins, anaphylactic shock cannot be ruled out even if a thorough patient history is taken.

...

Safety and effectiveness of ceftriaxone in neonates, infants and children have been established for the dosages described under Dosage and administration. In vivo and in vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.  Clinical data obtained in neonates have confirmed this finding.  Ceftriaxone should therefore not be used in neonates (especially prematures) at risk of developing bilirubin encephalopathy.  jaundiced new-borns or in babies who are hypoalbuminaemic, acidotic or born prematurely, in whom bilirubin binding is likely to be impaired. 

Ceftriaxone may precipitate in the gall bladder and then be detectable as shadows on ultrasound Shadows which have been mistaken for gallstones, have been detected on sonograms of the gallbladder, usually following doses of higher than the standard recommended dose (see section 4.8).  These shadows are, however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of ceftriaxone therapy. Rarely have these findings been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended. Discontinuation of ceftriaxone treatment in symptomatic cases should be at the discretion of the physician. This These shadows can happen appear in patients of any age, but is are more likely in infants and small children who are usually given a larger dose of ceftriaxone on a body weight basis.  In children, doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.  There is no clear evidence of gallstones or of acute cholecystitis developing in children or infants treated with ceftriaxone.  As the condition appears to be transient and reversible upon discontinuation, therapeutic procedures are normally not indicated.

....

Cephalosporins may cause bleeding due to hypoprothrombinaemia and should be used with caution in patients with renal or hepatic impairment, malnourished patients or those with low vitamin K levels and also in patients receiving prolonged cephalosporin therapy who are at increased risk of developing hypoprothrombinaemia.

...

Superinfections with non-susceptible micro-organisms (such as yeasts, fungi) may occur as with or other resistant organisms anti-bacterial agents may occur.  A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone.  Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea 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 diarrhea 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 evaluation should be instituted as clinically indicated.

Section 4.5

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Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone  must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially, of one another, if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium.

The elimination of ceftriaxone is not altered by probenecid.

...

Aminoglycoside antibiotics and diuretics:  No impairment of renal function has so far been observed in man after simultaneous concurrent administration of large doses of ceftriaxone with and potent diuretics (e.g.furosemide).  No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with ceftriaxone. There is no evidence that ceftriaxone increases renal toxicity of aminoglycosides.

Alcohol: The ceftriaxone molecule does not contain the N-methylthio-tetrazole substituent, which has been associated with a disulfiram-like effect, when alcohol is taken during therapy with certain cephalosporins.  No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration  of ceftriaxone. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins.

...

Anticoagulants: As ceftriaxone has an N-methylthiotriazine side-chain, it might have the potential to cause hypoprothrombinaemia. (Refer to section 4.8, Undesirable effects) resulting in an increased risk of bleeding in patients treated with anticoagulants.

Oral Contraceptives: 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.

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

Section 4.6

Text added/amended as follows:

Pregnancy:  It is known that ceftriaxone crosses the placental barrier.  Ceftriaxone has not been associated with adverse events on foetal development in laboratory animals but its safety in human pregnancy has not been established. Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed. Therefore it ceftriaxone should not be used in pregnancy unless absolutely indicated.

Lactation:  Ceftriaxone is Low concentrations of ceftriaxone are excreted in the human milk. in small amounts and is usually compatible with breast feeding,but careful monitoring of the infant is recommended.   Only minimal amounts of ceftriaxone are excreted in breast milk. However, caution is advised in nursing mothers Caution should be exercised when ceftriaxone is administered to a nursing woman.

Section 4.8

Text added/amended as follows:

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.

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stomatitis and glossitis.

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Infections

Superinfections caused by microorganisms non-susceptible to ceftriaxone such as  with yeasts, fungi (mycosis of the genital tract) or other resistant microorganisms may occur develop.  A rare side-effect is pPseudomembranous colitis which has resulted from is a rare undesirable effect caused by infection with Clostridium difficile during treatment with ceftriaxone.  It is important to consider this diagnosis Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use. subsequent to the administration of antibacterial agents.

Hypersensitivity

Uncommon (≥ 0.1% - < 1%): Maculopapular rash or exanthema, pruritus, urticaria, oedema, shivering and anaphylactic or anaphylactoid reactions (e.g. bronchospasm) and allergic dermatitis have occurred. 

...

Blood and lymphatic system disorders

Rare (≥ 0.01% - < 0.1%) Common (≥1% - ≤10%):

Haematological reactions have included anaemia (all grades), haemolytic anaemia, granulocytopenia, leucopenia, neutropenia, thrombocytopenia, and eosinophilia, and agranulocytosis.  Coagulation disorders have been reported as very rare side effects.

Unknown frequency of agranulocytosis (<500/mm3) has been reported, mostly after 10 days of treatment and following total doses of 20g or more. 

There have been rare reports of fatal haemolysis in association with ceftriaxone. Ceftriaxone has rarely been associated with prolongation of prothrombin time, however, bleeding and bruising due to hypoprothrombinaemia may be more prevalent in patients with renal or hepatic impairment, malnourished patients or those with low vitamin K levels and patients receiving prolonged ceftriaxone therapy.

Central Nervous system

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

Administration of high doses of cephalosporins, particularly in patients with renal insufficiency, may result in convulsions.

Renal and Urinary

Rare (≥ 0.01% - < 0.1%): Glycosuria, oliguria, haematuria, increase in serum creatinine. 

Very rare  (< 0.01%):  reversible symptomatic urinary precipitates of calcium ceftriaxone have occurred after ceftriaxone administration.  Patients who are very young, immobilised or who are dehydrated are at increased risk.  There have been a few reports of anuria and renal impairment following this reaction. 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.≥ 80mg/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.

Acute renal tubular necrosis may occur rarely with ceftriaxone.

Genital 

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

Hepatobiliary system

Rare (≥ 0.01% - < 0.1%):  Hepatitis and/or cholestatic jaundice, increase in liver enzymes. Transient elevations in liver function tests have been reported in a few cases.

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Local effects 

Rare (≥ 0.01% - < 0.1%):  Pain or discomfort may be experienced at the site of intramuscular injection immediately after administration but is usually well tolerated and transient.  Intramuscular injection without lidocaine solution is painful. Local phlebitis has occurred rarely following intravenous administration but can be minimised by slow injection over at least 2-4 minutes.

Influence on diagnostic tests

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

Likewise, nonenzymatic 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.

Section 4.9

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

Section 6.2

Text added/amended as follows:

Addition of clindamycin phosphate

 Section 4.2, 4.3, 4.4, 4.8, 5.2, 6.2, amended - To update SmPC warnings regarding incompatibilities between ceftriaxone and calcium and contraindication in premature infants in line with European agreements. 

Solutions in lignocaine should not be administered intravenously.

Ceftriaxone should not be given to patients with a history of hypersensitivity to cephalosporin antibiotics.

Known or suspected allergy to cephalosporins.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta‑lactam drug.

Ceftriaxone constituted with lidocaine must never be used:

- by the intravenous route

- in infants under 30 months

- in subjects with a previous history of hypersensitivity to lidocaine

- in patients who have an unpaced heart block

- in patients with severe heart failure.

Ceftriaxone should not be given to neonates with jaundice or those who are hypoalbuminaemic or acidotic or have other conditions, such as prematurity, in which bilirubin binding is likely to be impaired.

The stated dosage should not be exceeded.

Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, cephalosporins, penicillins, or other beta‑lactam drugs. 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 (see section 4.3, Contra-indications). 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.  Care is required when administering ceftriaxone to patients who have previously shown hypersensitivity (especially anaphylactic reaction) to penicillins or other non-cephalosporin b-lactam antibiotics, as occasional instances of cross allergenicity between cephalosporins and these antibiotics have been recorded. Anaphylactic shock requires immediate counter measures.

In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under Posology and method of administration.

In vivo and in vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.  Clinical data obtained in neonates have confirmed this finding.  Ceftriaxone should therefore not be used in jaundiced new-borns or in babies who are hypoalbuminaemic, acidotic or born prematurely, in whom bilirubin binding is likely to be impaired. 

Ceftriaxone may precipitate in the gall bladder and then be detectable as shadows on ultrasound (see section 4.8 Undesirable effects).  This can happen in patients of any age, but is more likely in infants and small children who are usually given a larger dose of ceftriaxone on a body weight basis.  In children, doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.  There is no clear evidence of gallstones or of acute cholecystitis developing in children or infants treated with ceftriaxone.  As the condition appears to be transient and reversible upon discontinuation, therapeutic procedures are normally not indicated, , and conservative management of ceftriaxone precipitate in the gallbladder is recommended.

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.

Regular blood counts (haemoglobin, erythrocyte, leucocyte and platelet counts and screening for prolongation of prothrombin time) should be carried out during treatmen

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 can not be ruled out.

Superinfections with yeasts, fungi or other resistant organisms may occur.  A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone.  Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Pregnancy:  It is known that ceftriaxone crosses the placental barrier. 

Ceftriaxone has not been associated with adverse events on foetal development in laboratory animals but its safety in human pregnancy has not been established.  Therefore, it should not be used in pregnancy unless absolutely indicated.

None.

Ceftriaxone has been associated with dizziness, which may affect the ability to drive or operate machinery.

Ceftriaxone has been generally well tolerated.  Adverse reactions are usually  mild and transient.

The most common side-effects are

GGastrointestinal:,

Common (≥ 1% - <10%):  consisting mainly of lLoose stools and diarrhoea (diarrhoea may sometimes be a symptom of pseudomembranous colitis, see 4.4 Special warnings and precautions for use) or, occasionally, nausea and vomiting.,

Rare (≥ 0.01% - < 0.1%):  sStomatitis, and glossitis and abdominal pain. 

Superinfections with yeasts, fungi or other resistant organisms may occur.  A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone.  Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Cutaneous reactions Hypersensitivity:

including

Uncommon (≥ 0.1% - < 1%): mMaculopapular rash or exanthema, pruritus, urticaria, oedema and allergic dermatitis have occurred. 

Rare  (≥ 0.01% - < 0.1%): Drug fever, shivering.  Anaphylactic-type reactions such as bronchospasm are rare.

Very rare (< 0.01%):  Isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens Johnson Syndrome and Lyell’s Syndrome/toxic epidermal necrolysis) have been reported.

Blood and lymphatic system disorders:

Rare (≥ 0.01% - < 0.1%):

Haematological reactions have included anaemia (all grades), haemolytic anaemia, leucopenia, neutropenia, thrombocytopenia, eosinophilia, and agranulocytosis and positive Coombs’ test.  Regular blood counts should be carried out during treatment.  Ceftriaxone has rarely been associated with prolongation of prothrombin time.

Central Nervous system:

Rare (≥ 0.01% - < 0.1%):  Headache and dizziness, drug fever, shivering. and transient elevations in liver function tests have been reported in a few cases.

Renal and urinary:

Rare (≥ 0.01% - < 0.1%): Other rarely observed adverse reactions include gGlycosuria, oliguria, haematuria, increase in serum creatinine. 

Very rare  (< 0.01%):  reversible symptomatic urinary precipitates of calcium ceftriaxone have occurred after ceftriaxone administration.  Patients who are very young, immobilised or who are dehydrated are at increased risk.  There have been a few reports of anuria and renal impairment following this reaction.

Genital:  

Rare (≥ 0.01% - < 0.1%):  mMycosis of the genital tract.and anaphylactic-type reactions such as bronchospasm.

Hepatobiliary system:

Rare (≥ 0.01% - < 0.1%):  Transient elevations in liver function tests have been reported in a few cases.

Very rarely, reversible symptomatic urinary precipitates of calcium ceftriaxone have occurred after ceftriaxone administration.  Patients who are very young, immobilised or who are dehydrated are at increased risk.  There have been a few reports of anuria and renal impairment following this reaction.

Shadows which have been mistaken for gallstones, but which are precipitates of calcium ceftriaxone, have been detected by sonograms.  These abnormalities are commonly observed after an adult daily dose of two grams per day or more, or its equivalent in children; these abnormalities were particularly observed in children with an incidence of above 30% in isolated reports.. At doses of two grams a day or above these biliary precipitates may occasionally cause symptoms.  Should patients develop symptoms, non-surgical management is recommended and discontinuation of ceftriaxone should be considered.  The evidence suggests biliary precipitates usually disappear once ceftriaxone has been stopped.  The risk of biliary precipitates may be increased by treatment duration greater than 14 days, renal failure, dehydration or total parenteral nutrition. 

Pancreas:  

Very rare (< 0.01%):  There have been isolated reports of pancreatitis although a causal relationship to ceftriaxone has not been established.

Superinfections with yeasts, fungi or other resistant organisms may occur.  A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone.  Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Local effects: