BIOPHIN Powder for solution for injection or infusion Ref.[115703] Active ingredients: Ceftriaxone

Hypersensitivity reactions

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8).

Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). In case of severe hypersensitivity reactions, treatment with Biophin must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to Biophin, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if Biophin is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Severe cutaneous adverse reactions (Stevens Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS)) which can be life-threatening or fatal, have been reported in association with Biophin treatment; however, the frequency of these events is not known (see section 4.8).

Jarisch-Herxheimer reaction (JHR)

Some patients with spirochete infections may experience a Jarisch- Herxheimer reaction (JHR) shortly after Biophin treatment is started. JHR is usually a self-limiting condition or can be managed by symptomatic treatment. The antibiotic treatment should not be discontinued if such reaction occurs.'

Interaction with calcium containing products

Cases of fatal reactions with calcium-Biophin precipitates in lungs and kidneys in premature and full-term neonates aged less than 1 month have been described. At least one of them had received Biophin 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 neonates, treated with Biophin and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that neonates have an increased risk of precipitation of Biophin-calcium compared to other age groups.

In patients of any age Biophin must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age Biophin 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 total parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of Biophin is considered necessary in patients requiring continuous nutrition, TPN solutions and Biophin can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of Biophin infusion and the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2).

Paediatric population

Safety and effectiveness of Biophin in neonates, infants and children have been established for the dosages described under Posology and Method of Administration (see section 4.2). Studies have shown that Biophin, like some other cephalosporins, can displace bilirubin from serum albumin.

Biophin is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section 4.3).

Immune mediated haemolytic anaemia

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Biophin (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during Biophin treatment in both adults and children. If a patient develops anaemia while on Biophin, the diagnosis of a cephalosporin-associated anaemia should be considered and Biophin discontinued until the aetiology is determined.

Long term treatment

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

Colitis/Overgrowth of non-susceptible microorganisms

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including Biophin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of Biophin (see section 4.8). Discontinuation of therapy with Biophin and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

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

Severe renal and hepatic insufficiency

In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see section 4.2).

Interference with serological testing

Interference with Coombs tests may occur, as Biophin may lead to false- positive test results. Biophin can also lead to false-positive test results for galactosaemia (see section 4.8).

Non-enzymatic methods for the glucose determination in urine may give false-positive results. Urine glucose determination during therapy with Biophin should be done enzymatically (see section 4.8).

The presence of Biophin may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.

Sodium

This medicinal product contains 82mg sodium per 1g vial, equivalent to 4.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Antibacterial spectrum

Biophin has a limited spectrum of antibacterial activity and may not be suitable for use as a single agent for the treatment of some types of infections unless the pathogen has already been confirmed (see section 4.2). In polymicrobial infections, where suspected pathogens include organisms resistant to Biophin, administration of an additional antibiotic should be considered.

Use of lidocaine

In case a lidocaine solution is used as a solvent, Biophin solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use (see section 4.3). The lidocaine solution should never be administered intravenously.

Biliary lithiasis

When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium Biophin. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at Biophin doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of Biophin therapy. Rarely precipitates of calcium Biophin have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of Biophin treatment should be considered by the physician based on specific benefit risk assessment (see section 4.8).

Biliary stasis

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with Biophin (see section 4.8). 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 of Biophin-related biliary precipitation cannot be ruled out.

Renal lithiasis

Cases of renal lithiasis have been reported, which is reversible upon discontinuation of Biophin (see section 4.8). In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the physician based on specific benefit risk assessment.

Encephalopathy

Encephalopathy has been reported with the use of Biophin (see section 4.8), particularly in elderly patients with severe renal impairment (see section 4.2) or central nervous system disorders. If Biophin-associated encephalopathy is suspected (e.g. decreased level of consciousness, altered mental state, myoclonus, convulsions), discontinuation of Biophin should be considered.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute Biophin vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form.

Precipitation of Biophin-calcium can also occur when Biophin is mixed with calcium-containing solutions in the same intravenous administration line.

Biophin must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Biophin 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 Biophin-calcium (see sections 4.2, 4.3, 4.4, 4.8 and 6.2).

Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently and the posology of the anti-vitamin K drug adjusted accordingly, both during and after treatment with Biophin (see section 4.8).

There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (and renal function) in clinical practice should be closely adhered to in such cases.

In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and Biophin. The clinical relevance of this finding is unknown.

There have been no reports of an interaction between Biophin and oral calcium-containing products or interaction between intramuscular Biophin and calcium-containing products (intravenous or oral).

In patients treated with Biophin, the Coombs' test may lead to false-positive test results. Biophin, like other antibiotics, may result in false-positive tests for galactosaemia.

Likewise, non-enzymatic methods for glucose determination in urine may yield false-positive results. For this reason, glucose level determination in urine during therapy with Biophin should be carried out enzymatically.

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

Simultaneous administration of probenecid does not reduce the elimination of Biophin.

Pregnancy

Biophin crosses the placental barrier. There are limited amounts of data from the use of Biophin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development (see section 5.3). Biophin should only be administered during pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs the risk.

Breastfeeding

Biophin is excreted into human milk in low concentrations but at therapeutic doses of Biophin no effects on the breastfed infants are anticipated. However, a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded. The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Biophin therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Reproductive studies have shown no evidence of adverse effects on male or female fertility.

During treatment with Biophin, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8). Patients should be cautious when driving or operating machinery.

The most frequently reported adverse reactions for Biophin are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.

Data to determine the frequency of Biophin ADRs was derived from clinical trials.

The following convention has been used for the classification of frequency: Very common (≥1/10), Common (≥1/100 - <1/10), Uncommon (≥1/1000 - <1/100), Rare (≥1/10000 - <1/1000), Not known (cannot be estimated from the available data).

^a Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
^b See section 4.4
^c Usually reversible upon discontinuation of Biophin

Description of selected adverse reactions

Infections and infestations

Reports of diarrhoea following the use of Biophin may be associated with Clostridium difficile. Appropriate fluid and electrolyte management should be instituted (see section 4.4).

Biophin-calcium salt precipitation

Rarely, severe, and in some cases, fatal, adverse reactions have been reported in pre-term and full-term neonates (aged <28 days) who had been treated with intravenous Biophin and calcium. Precipitations of Biophin-calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in neonates is a result of their low blood volume and the longer half-life of Biophin compared with adults (see sections 4.3, 4.4, and 5.2).

Cases of Biophin precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. ≥80 mg/kg/day or total doses exceeding 10 grams) and who have other risk factors (e.g. dehydration, confinement to bed). This event may be asymptomatic or symptomatic, and may lead to ureteric obstruction and postrenal acute renal failure, but is usually reversible upon discontinuation of Biophin (see section 4.4).

Precipitation of Biophin calcium salt in the gallbladder has been observed, primarily 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 - above 30% in some studies. The incidence appears to be lower with slow infusion (20-30 minutes). This effect is usually asymptomatic, but the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting in rare cases. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of Biophin (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Based on literature reports, Biophin is not compatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

Solutions containing Biophin should not be mixed with or added to other agents except those mentioned in section 6.6

In particular, diluents containing calcium, (e.g. Ringer's solution, Hartmann's solution) should not be used to reconstitute Biophin vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Biophin must not be mixed or administered simultaneously with calcium containing solutions including total parenteral nutrition (see section 4.2, 4.3, 4.4 and 4.8).

If treatment with a combination of another antibiotic with Biophin is intended, administration should not occur in the same syringe or in the same infusion solution.