CRESEMBA Powder for concentrate for solution for infusion Ref.[9617] Active ingredients: Isavuconazole

Posology

Early targeted therapy (pre-emptive or diagnostic-driven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly.

Detailed information on dosage recommendations is provided in the following table:

Table 1. Dosage recommendation:

¹ Six administrations in total.
² Maintenance dose: Starting 12 to 24 hours after the last loading dose.
³ After reconstitution and dilution.

The maximum of any individual loading or daily maintenance dose to be administered to any paediatric patient is 200 mg isavuconazole.

Duration of therapy should be determined by the clinical response (see section 5.1).

For long-term treatment beyond 6 months, the benefit-risk balance should be carefully considered (see sections 5.1 and 5.3).

Switch to oral isavuconazole

CRESEMBA is available as 100 mg and 40 mg hard capsules. On the basis of the high oral bioavailability (98%, see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated. For detailed dosing recommendations, please see section 4.2 of the Summary of Product Characteristics for CRESEMBA 40 mg and 100 mg hard capsules.

Elderly

No dose adjustment is necessary for elderly patients; however, the clinical experience in elderly patients is limited.

Renal impairment

No dose adjustment is necessary in adult patients with renal impairment, including patients with end-stage renal disease (see section 5.2).

No dose recommendation can be made for paediatric patients with renal impairment, as no relevant data are available.

Hepatic impairment

No dose adjustment is necessary in adult patients with mild or moderate hepatic impairment (Child-Pugh Classes A and B) (see sections 4.4 and 5.2).

Isavuconazole has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks (see sections 4.4, 4.8 and 5.2).

No dose recommendation can be made for paediatric patients with hepatic impairment, as no relevant data are available.

Paediatric population

The safety and efficacy of isavuconazole in paediatric patients aged less than 1 year has not been established.

Method of administration

Intravenous use.

Precautions to be taken before handling or administering the medicinal product

CRESEMBA must be reconstituted and then further diluted to a concentration corresponding to a range of 0.4 to 0.8 mg/mL isavuconazole prior to administration by intravenous infusion over a minimum of 1 hour to reduce the risk of infusion-related reactions. Higher concentrations should be avoided as these may cause local irritation at the site of infusion. The infusion must be administered via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) and with a pore size of 0.2 μm to 1.2 μm. CRESEMBA must only be given as an intravenous infusion.

For detailed instructions on the reconstitution and dilution of CRESEMBA before administration, see section 6.6.

Symptoms

Symptoms reported more frequently at supratherapeutic doses of CRESEMBA (equivalent to isavuconazole 600 mg/day) evaluated in a QT study than in the therapeutic dose group (equivalent to isavuconazole 200 mg/day dose) included: headache, dizziness, paraesthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhoea, oral hypoaesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia

Management of overdose

Isavuconazole is not removed by haemodialysis. There is no specific antidote for isavuconazole. In the event of an overdose, supportive treatment should be instituted.

4 years.

Chemical and physical in-use stability after reconstitution and dilution has been demonstrated for 24 hours at 2°C to 8°C, or 6 hours at room temperature.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C to 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

One 10 mL Type I glass vial with rubber stopper and an aluminum cap with plastic seal.

Reconstitution

One vial of the powder for concentrate for solution for infusion should be reconstituted by addition of 5 mL water for injections to the vial. The reconstituted concentrate contains 40 mg isavuconazole per mL. The vial should be shaken to dissolve the powder completely. The reconstituted solution should be inspected visually for particulate matter and discoloration. Reconstituted concentrate should be clear and free of visible particulate. It must be further diluted prior to administration.

Dilution and administration

Adults and paediatric patients with bodyweight from 37 kg

After reconstitution, the entire content of the reconstituted concentrate should be removed from the vial and added to an infusion bag containing 250 mL of either sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) dextrose solution. The infusion solution contains approximately 0.8 mg isavuconazole per mL.

Paediatric patients with bodyweight below 37 kg

The final concentration of the infusion solution should be in the range of 0.4 to 0.8 mg isavuconazole per mL. Higher concentrations should be avoided as these may cause local irritation at the site of infusion.

To obtain the final concentration, the appropriate volume of the reconstituted concentrate based on paediatric dosing recommendations (see section 4.2) should be removed from the vial and added to an infusion bag containing the appropriate amount of diluent.

The appropriate volume of the infusion bag is calculated as follows:

[Required dose (mg)/final concentration (mg/mL)] – Volume of the concentrate (mL)

The concentrate can be diluted with either 9 mg/mL (0.9%) sodium chloride solution for injection or 50 mg/mL (5%) dextrose solution.

Administration

After the reconstituted concentrate is further diluted, the diluted solution may show fine white-to-translucent particulates of isavuconazole that do not sediment (but will be removed by in-line filtration). The diluted solution should be mixed gently, or the bag should be rolled to minimise the formation of particulates. Unnecessary vibration or vigorous shaking of the solution should be avoided. The solution for infusion must be administered via an infusion set with an in-line filter (pore size 0.2 μm to 1.2 μm) made of polyether sulfone (PES). Infusion pumps can be used and must be placed before the infusion set. Regardless of the infusion solution container size used, the entire volume of the container should be administered to ensure the complete dose is administered.

Isavuconazole should not be infused into the same line or cannula concomitantly with other intravenous products.

Storage conditions after reconstitution and dilution are provided in section 6.3.

If possible, the intravenous administration of isavuconazole should be completed within 6 hours after reconstitution and dilution at room temperature. If this is not possible, the infusion solution should be immediately refrigerated after dilution, and infusion should be completed within 24 hours. Further information regarding the storage conditions after reconstitution and dilution of the medicinal product is provided in section 6.3.

An existing intravenous line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) dextrose solution.

This medicinal product is for single use only. Discard partially-used vials.

This medicinal product may pose a risk to the environment (see section 5.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.