CIFOBAN

Cifoban must be prescribed only by a physician competent in the application of RCA in the specific treatment mode of CVVHD, CVVHDF, SLEDD and/or TPE. For the paediatric population, Cifoban must be prescribed and monitored by physicians competent in the aforementioned treatment modes in children.

Posology Adults The pre-filter infusion rate of Cifoban is to be titrated proportional to the blood flow of the extracorporeal circuit to achieve a sufficient suppression of ionised calcium of the blood within the filter as per applied RCA protocol.

35 mmol/l is to be targeted, which is usually achieved with dosing of 4-5 mmol citrate per litre of treated blood. , the citrate concentration of Cifoban). The patient’s systemic ionised calcium concentration is to be maintained in the normal physiologic range, which commonly requires calcium supplementation.

4 litre/day. The extracorporeal blood flow must be sufficient to reach the therapy targets but be kept low enough to avoid unnecessary citrate infusion and promote clearance of citrate within the applied filter. 4). Higher blood flows in combination with a lower dosing of Cifoban may unnecessarily reduce filter patency.

Regarding the composition of the dialysis and substitution fluids within the indicated treatment protocol, calcium-free, low sodium and low-bicarbonate solutions are preferably to be considered. These are recommended to be selected in view of Cifoban- associated sodium and buffer supply per applied protocol.

A calcium-free dialysis solution must be considered particularly for continuously applied therapies. A calcium-containing dialysis solution can be considered for SLEDD when a suitable calcium-free solution is not available. In this case, a higher post-filter ionised calcium concentration may be accepted in view of the relatively short duration of treatment or alternatively Cifoban may be dosed to a higher concentration per litre of treated blood.

4). Cifoban must then be dosed to a lower concentration per litre of treated blood. 5 mmol/l blood during CVVHDF treatment modes, respectively. Similar dosing guidance may be applicable with other treatment protocols. g. shock with severe lactic acidosis, severe liver failure).

Treatment is to be initiated with a sufficiently low citrate dose. When treated with CVVHD or CVVHDF at a blood flow not exceeding 100-120 ml/min, the citrate load generally is kept sufficiently low. 4). When treated with SLEDD at a blood flow not exceeding appr.

150-200 ml/min, an at least equal dialysate flow, and a treatment duration not extending beyond 12 hours, the patient citrate load generally is kept sufficiently low. 4). In TPE, filter citrate clearance is generally limited, and comparatively lower, due to maximum acceptable filtration fractions.

Citrate exposure may be further increased by using fresh frozen plasma (FFP) for the exchange. A blood flow not exceeding 100-120 ml/min is recommended when exchanging with FFP. 4). 4) is recommended. Geriatric population Elderly patients may be at risk of impaired citrate metabolism.

No dose reduction is required. 4) is recommended. Paediatric population The safety and efficacy of Cifoban in preterm newborn infants has not yet been established. 4). Cifoban can be applied in children of all age groups (term neonates up to adolescents), when the patient citrate load remains sufficiently low.

Of note, for the smallest patients, only scarce data is available. The used equipment must support paediatric application for the given weight, including the required low blood flows. Blood flow and citrate dose guidance per age category • Neonates up to toddlers (0 to 23 months): if a blood flow of 7-8 ml/kg/min (or higher) is required per used equipment, the citrate dosing is to be initiated at appr.

3 mmol/l blood. • Children (2 to 11 years): the blood flow must not exceed 5-6 ml/kg/min; the citrate dosing can be initiated at appr. 4 mmol/l blood, as per protocol. • Adolescents (12 to 17 years): the blood flow must be sufficient to reach the therapy targets, and generally not exceed blood flows in adults of similar weight.

The citrate dosing can be initiated at appr. 4 mmol/l blood, as per […]

Undesirable effects can result from the Cifoban solution or the dialysis treatment. g. hypocalcaemia, hypernatraemia, hypomagnesaemia) or metabolic alkalosis # Potentially life-threatening Undesirable events may also result from the equipment and other solutions used in the therapy.

Please refer to the applicable product leaflet / instructions for use. 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.

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4 Special warnings and precautions for use Warnings Monitoring frequencies of impacted patient serum values The indicated therapies call for the close monitoring of the patient’s haemodynamic status, fluid balance, glucose level, electrolyte and acid-base balance before and during treatment.

, TPE can invoke these changes more rapidly than CVVHD. The treatment- and RCA protocol must reflect this. When using Cifoban, these may include the following monitoring frequencies and particulars: - The patient ionised calcium, pH and bicarbonate, sodium, and lactate according to clinical need, must be measured at baseline or at least within 1 hour upon start of the therapy.

Further exemplary measurement frequencies are 1-hourly for TPE, 3-4 hourly for SLEDD, up to 6-8-hourly for CVVHD and CVVHDF. - When balanced solutions are used, pre- and post-treatment measurements (TPE, SLEDD) or daily measurements (CVVHD, CVVHDF) of magnesium and total calcium may suffice.

- More intensified monitoring generally calls for a frequency that is 2-4 times higher. - A blood gas analyzer shall directly be accessible. - A separate arterial access is preferred as the sampling location. A sampling port in the access line is often available, however, its use can result in false measurement results in the case of recirculation at the catheter tip.

If circuit ionised calcium monitoring is part of the applied RCA protocol, a respective sampling port is required. The RCA protocol can request a first measurement within 20-30 minutes after treatment initiation to confirm the correct circuit set-up and subsequent measurements after each adaptation of the Cifoban dose (wait > 5 minutes after adjustment before taking the sample for the establishment of the new ionised calcium concentration).

Citrate accumulation due to impaired metabolism In children and in adult patients with reduced citrate metabolism; as for example in patients with reduced hepatic function, hypoxia (hypoxemia) or a disturbed oxygen metabolism, RCA can lead to citrate accumulation.

25 and/or metabolic acidosis. Early signs may include decreased lactate clearance during therapy. It may then become necessary to increase the dialysate flow, reduce the blood flow, reduce the citrate dosing, or stop using Cifoban for anticoagulation.

Intensified monitoring is recommended. Citrate overload Cifoban is hypernatraemic and, once metabolised, a source of bicarbonate. 2 Posology and method of administration). Iatrogenic metabolic alkalosis and hypernatraemia may nevertheless develop and can be managed by reducing blood flow or, when covered by the applied RCA protocol, by increasing dialysate flow.

These interventions reduce the patient sodium citrate load. g. 9% sodium chloride can be considered. g. 5% glucose can be considered. In both cases, the additional volume load shall be considered by the treating physician. e. reduced filter permeability) can result in a citrate overload.

Filter clogging could reduce removal of calcium, citrate, sodium, and other substances, and result in hypercalcaemia, metabolic alkalosis, hypernatraemia, and other deviations from the expected therapy effect. In such a situation, it is likely no longer possible to correct the abnormalities via the interventions mentioned above.

The filter then needs to be changed. 9. Insufficient citrate load If the other solutions used in the RCA protocol overcompensate for the sodium and bicarbonate buffer provision of Cifoban, iatrogenic metabolic acidosis and hyponatraemia may develop.

These serum imbalances can be managed by increasing blood flow or, when covered by RCA protocol, by decreasing dialysate flow. These interventions increase the patient sodium citrate load. Further, persisting metabolic acidosis and hyponatraemia can be managed by the controlled infusion of a sodium hydrogen carbonate solution.

Prolonged patient immobilisation Under RCA, the early sign of an ionised hypercalcaemia may be masked by a decrease in the calcium infusion rate. Especially patients in a prolonged immobilised position may undergo bone remodelling/demineralisation, resulting in the release of calcium from the bones.

This can ultimately lead to bone fractures. In patients under RCA for longer than 2 weeks continuously, or in whom the calcium infusion rate is progressively decreasing, bone turnover markers must be closely monitored. , heparin induced thrombocytopenia type II).

An appropriately chosen systemic anticoagulant may then be required. RCA may be used in addition to further improve filter patency. g. 4 above). 2 must be observed. Pre-existing hypocalcaemia Critically ill patients may have hypocalcaemia.

With RCA, there may be a drop in the systemic ionised […]

1 - Known severely impaired citrate metabolism (see section