Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Fresenius Medical Care Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg v.d.H., Germany
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. The exact frequency depends on the status of the patient and how rapidly the treatment can invoke changes to the blood volume and composition of the patient: e.g., 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:
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).
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. Signs are ionised hypocalcaemia, an increased need for calcium substitution, a ratio of total over ionised calcium above 2.25 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.
Cifoban is hypernatraemic and, once metabolised, a source of bicarbonate. When deciding on the composition of other fluids within the RCA protocol, low-sodium and low-bicarbonate concentrations are preferable (please refer to section 4.2 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. Further, for metabolic alkalosis, the controlled infusion of e.g. 0.9% sodium chloride can be considered. Similarly, for hypernatraemia the controlled infusion of e.g. 5% glucose can be considered. In both cases, the additional volume load shall be considered by the treating physician.
Alternatively, filter clogging (i.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 exchanged.
For an inadvertent overdose of the medicinal product, please refer to section 4.9.
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.
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 should be closely monitored.
Early clotting can occur despite adequate RCA in patients that are in a (suspected) hypercoagulant state (e.g., 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.
Patients with a known severe mitochondrial dysfunction (e.g. paracetamol and metformin intoxications) may be preferably treated with an alternative anticoagulant protocol to mitigate the risk of citrate accumulation (see in this section 4.4 above). If treatment with Cifoban is initiated, the posology for special populations in section 4.2 should be observed.
Critically ill patients may have hypocalcaemia. With RCA, there may be a drop in the systemic ionised calcium concentration during the first hours of treatment, which recovers subsequently. Therefore, a pre-existing hypocalcaemia preferably is treated before initiating the procedure to reduce the risk of suffering from any clinically relevant hypocalcaemia after treatment initiation.
Citrate chelates calcium and magnesium ions which, via subsequent elimination within the filter, could cause hypocalcaemia (see sections 4.8 and 4.9) and/or hypomagnesaemia (see section 4.8). Infusion of calcium for compensation of losses is often standard practice and supplementation with magnesium might as well be necessary. The need for compensation must be part of the RCA protocol.
Blood plasma products containing citrate, e.g. fresh frozen plasma, are regularly part of the exchange protocol for TPE in critically ill patients. In addition to providing a citrate load, blood products may also be hypernatraemic. Hence, the risk of both citrate accumulation and citrate overload is increased (see above). Management must be part of the RCA protocol.
No pharmacodynamic drug interactions among the constituents of Cifoban are to be expected. Interactions could only be expected by inadequate or incorrect therapeutic use of the solution (see sections 4.4 and 4.9).
Interaction or compatibility studies with other medicinal products have not been performed. Thus, no other substance or solution must be added to Cifoban (see also section 6.2).
Calcium containing solutions applied at the level of the filter (i.e. dialysis fluid) or upstream of the filter may reduce the effect of Cifoban.
Interactions are conceivable with sodium-enriched products, which may increase the risk of hypernatraemia (see section 4.8). Analogously, products containing hydrogen carbonate (or precursors metabolised yielding hydrogen carbonate, e.g. acetate) may increase the risk of a high concentration of hydrogen carbonate in the blood (metabolic alkalosis, see section 4.8). Analogously, blood products containing citrate may increase the risk of a higher citrate concentration in the blood (hypocalcaemia, metabolic acidosis, see section 4.8) and increase the risk of a high concentration of hydrogen carbonate in the blood (metabolic alkalosis, see section 4.8).
There are no data from the use of Cifoban in pregnant or breast-feeding women.
Animal studies are insufficient with respect to reproductive toxicity.
Cifoban should not be used during pregnancy and breast-feeding unless the clinical condition of the woman requires treatment with RCA.
No human data on the effect of sodium and citrate on fertility are available.
Not relevant.
Undesirable effects can result from the Cifoban solution or the dialysis treatment.
| System Organ Class (SOC) | Frequency | Undesirable effects (Preferred Term) |
|---|---|---|
| Immune system disorders | Not known | Hypersensitivity |
| Metabolism and nutrition disorders | Very common (≥1/10) | Hypocalcaemia (<1.1 mmol/l) (see section 4.4) |
| Hypernatraemia (>145 mmol/l) (see section 4.4) | ||
| Metabolic alkalosis (pH >7.45) (see citrate overload in section 4.4) | ||
| Common (≥1/100 to <1/10) | Severe hypocalcaemia (<0.9 mmol/l) (see sections 4.4 and 4.9) | |
| Hypomagnesaemia (<0.7 mmol/l) (see citrate chelation in section 4.4) | ||
| Severe hypernatraemia (>155 mmol/l) (see sections 4.4 and 4.9) | ||
| Severe metabolic alkalosis (pH >7.55) (see citrate overload in section 4.4) | ||
| Severe metabolic acidosis (pH <7.2) (see citrate accumulation in section 4.4) | ||
| Not known | Fluid overload (see method of administration in section 4.2) | |
| Nervous system disorders | Not known | Headache* |
| Seizure* | ||
| Coma*# | ||
| Cardiac disorders | Not known | Arrhythmia* |
| Cardiac arrest*# | ||
| Pulmonary oedema (due to severe metabolic acidosis) | ||
| Vascular disorders | Not known | Hypotension* |
| Respiratory, thoracic and mediastinal disorders | Not known | Bronchospasm* |
| Respiratory arrest*# | ||
| Tachypnoea (Kussmaul breathing, due to severe metabolic acidosis) | ||
| Gastrointestinal disorders | Not known | Vomiting* |
| Musculoskeletal and connective tissue disorders | Not known | Muscle spasms/cramps* |
* Due to (severe) electrolyte imbalance (e.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 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 HPRA Pharmacovigilance, Website: www.hpra.ie.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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