CIFOBAN Solution for infusion Ref.[50948] Active ingredients: Sodium citrate

Cifoban should 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 should be prescribed and monitored by physicians competent in the aforementioned treatment modes in children.

Posology

Adults

The pre-filter infusion rate of Cifoban should 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. Generally, a post-filter ionised calcium concentration below 0.3-0.35 mmol/l should be targeted, which is usually achieved with dosing of 4-5 mmol citrate per litre treated blood. The required Cifoban flow (in ml/min) can be calculated by multiplying this intended citrate dosing with the blood flow (in ml/min) and dividing by 136 mmol/l (i.e., the citrate concentration of Cifoban). The patient’s systemic ionised calcium concentration should be maintained in the normal physiologic range, which commonly requires calcium supplementation.

The application volume of Cifoban in adult patients should not exceed 10.4 litre/day. The extracorporeal blood flow should 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. This mitigates the risk of citrate overload and citrate accumulation (see section 4.4). 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 should be considered. These should be selected in view of Cifoban-associated sodium and buffer supply per applied protocol.

A calcium-free dialysis solution should particularly be considered 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 treated blood. Accepting higher post-filter ionised calcium concentrations can likewise be appropriate in TPE, especially when the substitution fluid contains citrate (see section 4.4). Cifoban should then be dosed to a lower concentration per litre treated blood.

When used in combination with a calcium-free dialysis solution for CVVHD or CVVHDF having a sodium content of 133 mmol/l and bicarbonate content of 20 mmol/l, the citrate amount added to the blood before entering the dialysis filter should be targeted to 3 to 5 mmol/l blood during CVVHD and to 3 to 5.5 mmol/l blood during CVVHDF treatment modes, respectively. Similar dosing guidance may be applicable with other treatment protocols.

Special populations

Patients with impaired citrate metabolism

Cifoban can be applied in patients with a risk of having impaired citrate metabolism (e.g. shock with severe lactic acidosis, severe liver failure).

Treatment should 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. The citrate dosing can be initiated at 4-5 mmol/l blood, as per protocol, and may only have to be reduced upon clear signs of citrate accumulation (please refer to section 4.4). 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. When calcium-containing dialysate is applied, the citrate dosing can be initiated at up to 6-7 mmol/l blood, as per protocol, and may only have to be reduced upon clear signs of citrate accumulation (please refer to section 4.4).

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. The citrate dosing can be initiated at 3-4 mmol/l blood, as per protocol, and may only have to be reduced upon clear signs of citrate accumulation (please refer to section 4.4).

In all these therapies, intensified monitoring to prevent the development of citrate accumulation (see section 4.4) is recommended.

Geriatric population

Elderly patients may be at risk of impaired citrate metabolism. No dose reduction is required. Frequent monitoring to detect citrate accumulation (see section 4.4) is recommended.

Paediatric population

The safety and efficacy of Cifoban in preterm newborn infants has not yet been established. There are insufficient data available (see section 4.4).

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

• Children (2 to 11 years): the blood flow should 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 should 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 protocol.
• 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 should be initiated at appr. 3 mmol/l blood.

The citrate dosing may have to be reduced upon clear signs of citrate accumulation (please refer to section 4.4). When treated with CVVHD or CVVHDF a post-filter ionised calcium concentration below 0.3-0.35 mmol/l is preferably targeted, but this target depends on the feasible citrate dose.

Intensified monitoring to prevent the development of citrate overload and citrate accumulation (see section 4.4) is required in neonates up to toddlers and recommended in children and adolescents. Further, please refer to the posology considerations as given above for patients with impaired citrate metabolism. To limit the patient citrate load, a modest exchange rate is required when exchange with fresh frozen plasma is indicated, along with parallel calcium substitution recommended to maintain a normal systemic ionised calcium concentration.

Maximum infusion volumes for exemplary term neonatal up to adolescent weights are given in the table below. Of note, typical daily application volumes remain clearly below these limits consequent to the use of moderate blood flows as described above.

Method of administration

Extracorporeal use. To be infused into the extracorporeal blood circuit only.

Infusion only by an integrated pump within the extracorporeal blood purification device, which is intended by its manufacturer for the infusion of a concentrated citrate solution in the pre-pump segment of the access tubing system (“blood access line”), to mitigate the risk of any inadvertent overdose (see section 4.9). The device should also remove the volume provided by Cifoban into the effluent, to prevent fluid overload (see section 4.8).

The special warnings and precautions in section 4.4 must be considered, especially those concerning monitoring and the need for additional substitutions.

Additionally:

• Cifoban must only be used in accordance with an appropriate protocol for RCA. It shall only be used by, or under the direction of, a physician competent in the application of RCA and by health care professionals who are sufficiently trained in the indicated therapies and in the application of the involved products.
• Handling instructions of the used extracorporeal blood purification device and the tubing system provided by the manufacturer must be adhered to.
• Cifoban can be used for RCA in an intensive care unit or under similar conditions, where it must be used under close medical supervision and continuous monitoring.

For instructions on handling of the medicinal product before administration, see section 6.6.

Inadvertent administration of too high volumes of Cifoban may lead to an overdose, which can cause a life-threatening situation for the patient.

Inappropriate infusion of too large amounts of citrate causes acute hypocalcaemia (and metabolic alkalosis, hypernatraemia) and may expose the patient to neurological and cardiac complications. This derangement needs to be corrected by immediately stopping/lowering the amount of Cifoban solution and by the intravenous administration of calcium.

2 years.

Shelf life after opening: From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Do not refrigerate or freeze.

Keep the bags in the outer carton in order to protect from light.

The medicinal product is provided pairwise as two identical solution bags which can be separated by a tear seam in the protective bag.

The solution bag is made of polypropylene-elastomer-blends. Each bag is equipped with a connective tubing made of polypropylene-elastomer-blends, a connector made of polycarbonate and is covered by a polyolefine-based protective multilayer bag.

Pack sizes:

SecuNect connector system: 8 bags of 1500 ml.

SafeLock connector system: 8 bags of 1500 ml.

Not all pack sizes may be marketed.

Disposal

The solution is for single use only. Any unused solution and damaged container should be discarded.

Handling

The solution bags are equipped either with a SecuNect connector or with a SafeLock connector.

The following points prior to the use of the solution bag have to be considered:

Aseptic technique should be used throughout administration to the patient. The solution should be used immediately after opening to avoid microbiological contamination.

Extracorporeal use. To be infused into the extracorporeal blood circuit only.

For solution bags equipped with a SecuNect connector (transparent with a green ring):

1. Separate the two bags at the tear seam without damaging the integrity of the overwrap.

2. Remove the overwrap only immediately before using the solution. Check the solution bag (label, expiry date, clearness of the solution, bag and overwrap not damaged).

Plastic containers may occasionally be damaged during transport from the manufacturer to the dialysis clinic or hospital clinic or within the clinic itself. This can lead to contamination and the growth of bacteria or fungi in the solution. Therefore, careful inspection of the bag and the solution before use is essential. Particular attention should be paid to even the slightest damage to the closure of the bag, the welding seams and the corners of the bag. The solution should only be used if coloruless and clear and if the bag and connector are undamaged and intact.

3. Put the bag on the dedicated attachment by its hanger hole.

4. Remove the protection cap from the SecuNect connector with its green ring and attach the connector only to its corresponding counterpart with same colour to prevent misconnection. Do not touch any inner parts especially do not touch on top of the connector. The inner part of the connector is delivered sterile and is not intended to be further treated with chemical disinfectants. Connect the bag connector with a twisting motion to the tubing line connector by hand, overcoming a guarding force until a “click” is audible and connection is established.

5. Before start of treatment and in case of bag changes break the frangible pin of the bag connector and make sure that the pin is completely broken.

6. Proceed with the further steps as indicated in the treatment applied RCA protocol.

For solution bags equipped with a SafeLock connector (transparent):

1. Separate the two bags at the tear seam without damaging the integrity of the overwrap.

2. Remove the overwrap only immediately before using the solution. Check the solution bag (label, expiry date, clearness of the solution, bag and overwrap not damaged).

Plastic containers may occasionally be damaged during transport from the manufacturer to the dialysis clinic or hospital clinic or within the clinic itself. This can lead to contamination and the growth of bacteria or fungi in the solution. Therefore, careful inspection of the bag and the solution before use is essential. Particular attention should be paid to even the slightest damage to the closure of the bag, the welding seams and the corners of the bag. The solution should only be used if colourless and clear and if the bag and connector are undamaged and intact.

3. Put the bag on the dedicated attachment by its hanger hole.

4. Remove the protection cap from the transparent SafeLock connector and attach the connector only to its corresponding counterpart to prevent misconnection. Do not touch any inner parts especially do not touch on top of the connector. The inner part of the connector is delivered sterile and is not intended to be further treated with chemical disinfectants. Connect the bag connector with the appropriate counterpart and twist together.

5. Before start of treatment and in case of bag changes break the frangible pin of the bag connector and make sure that the pin is completely broken.

6. Proceed with the further steps as indicated in the treatment applied RCA protocol.

The solution is not intended to be used for the addition of any drugs.