Posology : מינונים

4.2    Posology and method of administration

Lunsumio must only be administered under the supervision of a healthcare professional qualified in the use of anti-cancer therapies, in a setting with appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) (see section 4.4).
Posology

Prophylaxis and premedication

Lunsumio should be administered to well-hydrated patients.
Table 1 provides details on recommended premedication for CRS and infusion related reactions.

Table 1 Premedication to be administered to patients prior to Lunsumio infusion 
Patients requiring                  Premedication                          Administration premedication
Intravenous corticosteroids:           Complete at least 1 hour dexamethasone 20 mg or                 prior to Lunsumio infusion
Cycles 1 and 2: all patients        methylprednisolone 80 mg
Anti-histamine: 50-100 mg              At least 30 minutes prior to
Cycles 3 and beyond: patients       diphenhydramine hydrochloride or       Lunsumio infusion who experienced any grade CRS       equivalent oral or intravenous with previous dose                  anti-histamine
Anti-pyretic: 500-1000 mg paracetamol

The recommended dose of Lunsumio for each 21 day-cycle is detailed in Table 2.

Table 2 Dose of Lunsumio for patients with relapsed or refractory follicular lymphoma 
Day of treatment               Dose of Lunsumio        Rate of infusion Cycle 1       Day 1            1 mg                    Infusions of Lunsumio in Cycle 1 should be Day 8            2 mg                    administered over a minimum of 4 hours.
Day 15           60 mg
Cycle 2       Day 1            60 mg                   If the infusions were well-tolerated in Cycles 3 and Day 1             30 mg                   Cycle 1, subsequent infusions of Lunsumio beyond                                                 may be administered over 2 hours.

Duration of treatment

Lunsumio should be administered for 8 cycles, unless a patient experiences unacceptable toxicity or disease progression.

For patients who achieve a complete response, no further treatment beyond 8 cycles is required. For patients who achieve a partial response or have stable disease in response to treatment with Lunsumio after 8 cycles, an additional 9 cycles of treatment (17 cycles total) should be administered, unless a patient experiences unacceptable toxicity or disease progression.

Delayed or missed dose

If any dose in cycle 1 is delayed for > 7 days, the previous tolerated dose should be repeated prior to resuming the planned treatment schedule.

If a dose interruption occurs between Cycles 1 and 2 that results in a treatment-free interval of ≥ 6 weeks, Lunsumio should be administered at 1 mg on Day 1, 2 mg on Day 8, then resume the planned Cycle 2 treatment of 60 mg on Day 15.

If a dose interruption occurs that results in a treatment-free interval of ≥ 6 weeks between any Cycles in Cycle 3 onwards, Lunsumio should be administered at 1 mg on Day 1, 2 mg on Day 8, then resume the planned treatment schedule of 30 mg on Day 15.


Dose modification
Patients who experience grade 3 or 4 reactions (e.g. serious infection, tumour flare, tumour lysis syndrome) should have treatment temporarily withheld until symptoms are resolved (see section 4.4).

CRS should be identified based on clinical presentation (see section 4.4). Patients should be evaluated and treated for, other causes of fever, hypoxia, and hypotension, such as infections/sepsis. Infusion related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. If CRS or IRR is suspected, patients should be managed according to the recommendations in Table 3.

Table 3 CRS grading1 and management

CRS grade            CRS management2                                    Next scheduled infusion of Lunsumio

Grade 1              If CRS occurs during infusion:                     The symptoms should be • The infusion should be interrupted and       resolved for at least 72 hours Fever ≥ 38ºC                symptoms treated                            prior to next infusion • The infusion should be re-started at the same rate once the symptoms resolve         The patient should be monitored more frequently
• If symptoms recur with re-administration, the current infusion should be discontinued

If CRS occurs post-infusion:
• The symptoms should be treated

If CRS lasts > 48 hours after symptomatic management:
• Dexamethasone3 and/or tocilizumab4,5 should be considered
Grade 2            If CRS occurs during infusion:                       The symptoms should be • The infusion should be interrupted and         resolved for at least 72 hours Fever ≥ 38ºC              symptoms treated                              prior to next infusion and/or hypotension     • The infusion should be re-started at not requiring             50% the rate once the symptoms                Premedication should be vasopressors              resolve                                       maximized as appropriate7 and/or hypoxia
• If symptoms recur with re- requiring                                                               Consideration should be administration, the current infusion low-flow oxygen6                                                        given to administration of the should be discontinued by nasal cannula                                                        next infusion 50% rate, with or blow-by                                                              more frequent monitoring of If CRS occurs post-infusion: the patient
• The symptoms should be treated

If no improvement occurs after symptomatic management:
• Dexamethasone3 and/or tocilizumab4,5 should be considered

Grade 3            If CRS occurs during infusion:                       The symptoms should be • The current infusion should be                 resolved for at least 72 hours Fever ≥ 38ºC              discontinued                                  prior to next infusion and/or hypotension     • The symptoms should be treated requiring a                                                             Patients should be 

vasopressor             • Dexamethasone3 and tocilizumab4, 5           hospitalized for the next (with or without            should be administered                     infusion vasopressin) and/or              If CRS occurs post-infusion:                       Premedication should be hypoxia requiring       • The symptoms should be treated               maximized as appropriate7 high
• Dexamethasone3 and tocilizumab4, 5 flow oxygen8 by                                                        The next infusion should be should be administered nasal cannula, face                                                    administered at a 50% rate mask,
If CRS is refractory to dexamethasone and non-rebreather tocilizumab: mask, or Venturi mask                    • Alternative immunosuppressants9 and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement

Grade 4            If CRS occurs during or post-infusion:
• Treatment with Lunsumio should be permanently discontinued
Fever ≥ 38ºC           • The symptoms should be treated and/or hypotension
• Dexamethasone3 and tocilizumab4, 5 should be administered requiring multiple vasopressors
If CRS is refractory to dexamethasone and tocilizumab:
(excluding vasopressin)           • Alternative immunosuppressants9 and methylprednisolone and/or                     1 000 mg/day intravenously should be administered until clinical hypoxia requiring          improvement oxygen by positive pressure
(e.g., CPAP,
BiPAP,
intubation and mechanical ventilation)
1
ASTCT = American Society for Transplant and Cellular Therapy. Premedication may mask fever, therefore if clinical presentation is consistent with CRS, please follow these management guidelines.
2
If CRS is refractory to management, consider other causes including hemophagocytic lymphohistiocytosis
3
Dexamethasone should be administered at 10 mg intravenously every 6 hours (or equivalent) until clinical improvement
4
In study GO29781, tocilizumab was administered intravenously at a dose of 8 mg/kg (not to exceed 800 mg per infusion), as needed for CRS management
5
If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, a second dose of intravenous tocilizumab 8 mg/kg may be administered at least 8 hours apart (maximum 2 doses per CRS event). Within each time period of 6 weeks of Lunsumio treatment, the total amount of tocilizumab doses should not exceed 3 doses
6
Low-flow oxygen is defined as oxygen delivered at < 6 L/minute.
7
Refer to Table 1 for additional information
8
High-flow oxygen is defined as oxygen delivered at ≥ 6 L/minute
9
Riegler L et al. (2019)



Special populations

Elderly
No dose adjustment of Lunsumio is required in patients ≥ 65 years of age (see section 5.2).

Renal impairment

Lunsumio has not been studied in patients with severe renal impairment. Dose adjustments are not considered necessary in patients with mild to moderate renal impairment based on pharmacokinetics (see section 5.2).

Hepatic impairment

Lunsumio has not been studied in patients with hepatic impairment. Dose adjustments are not considered necessary based on pharmacokinetics (see section 5.2).

Paediatric population

The safety and efficacy of Lunsumio in children and adolescents below 18 years of age have not yet been established.

Method of administration

Lunsumio is for intravenous use only.
Lunsumio must be diluted using aseptic technique under the supervision of a healthcare professional. It should be administered as an intravenous infusion through a dedicated infusion line. Do not use an in- line filter to administer Lunsumio. Drip chamber filters can be used to administer Lunsumio.

The first cycle of Lunsumio should be administered over a minimum of 4 hours as intravenous infusion. If the infusions are well-tolerated in cycle 1, the subsequent cycles may be administered over a 2-hours infusion.

Lunsumio must not be administered as intravenous push or bolus.

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