Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Inrebic is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.
Treatment with Inrebic should be initiated and monitored under the supervision of physicians experienced in the use of anti-cancer medicinal products.
Patients who are on treatment with ruxolitinib, prior to starting treatment with Inrebic, must taper and discontinue ruxolitinib according to the ruxolitinib prescribing information.
Baseline testing of thiamine (vitamin B1) levels, complete blood count, hepatic panel, amylase/lipase, blood urea nitrogen (BUN) and creatinine should be obtained prior to starting treatment with Inrebic, periodically during treatment and as clinically indicated. Inrebic treatment should not be started in patients with thiamine deficiency, until thiamine levels have been corrected (see section 4.4). Initiating treatment with Inrebic is not recommended in patients with a baseline platelet count below 50 × 109/L and ANC <1.0 × 109/L.
It is recommended that prophylactic anti-emetics be used according to local practice for the first 8 weeks of treatment and continued thereafter as clinically indicated (see section 4.4). Administration of Inrebic with a high fat meal may reduce the incidence of nausea and vomiting.
The recommended dose of Inrebic is 400 mg once daily.
Treatment may be continued for as long as patients derive clinical benefit. Dose modifications should be considered for haematologic and non-haematologic toxicities (Table 1). Inrebic should be discontinued in patients who are unable to tolerate a dose of 200 mg daily.
If a dose is missed, the next scheduled dose should be taken the following day. Extra capsules should not be taken to make up for the missed dose.
Dose modifications for haematologic toxicities, non-haematologic toxicities and management of Wernicke’s encephalopathy (WE) are shown in Table 1.
Before treatment initiation and during treatment, thiamine levels should be replenished if they are low. During treatment, thiamine levels should be assessed periodically (e.g. monthly for the first 3 months and every 3 months thereafter) and as clinically indicated (see section 4.4).
If concomitant strong CYP3A4 inhibitors cannot be avoided, the dose of Inrebic should be reduced to 200 mg. Patients should be carefully monitored (e.g. at least weekly) for safety (see section 4.4 and 4.5).
In cases where co-administration with a strong CYP3A4 inhibitor is discontinued, the Inrebic dose should be increased to 300 mg once daily during the first two weeks after discontinuation of the CYP3A4 inhibitor and then 400 mg once daily thereafter as tolerated. Additional dose adjustments should be made as needed, based upon monitoring of Inrebic-related safety and efficacy.
If the adverse reaction due to Inrebic that resulted in a dose reduction is controlled with effective management and the toxicity is resolved for at least 28 days, the dose level may be re-escalated to one dose level higher per month up to the original dose level. Dose re-escalation is not recommended if the dose reduction was due to a Grade 4 non-haematologic toxicity, ≥ Grade 3 alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin elevation, or reoccurrence of a Grade 4 haematologic toxicity.
Table 1. Dose reductions for haematologic, non-haematologic treatment emergent toxicities and management of Wernicke’s encephalopathy:
| Haematologic toxicity | Dose reduction |
|---|---|
| Grade 3 thrombocytopenia with active bleeding (platelet count <50 × 109/L) or Grade 4 thrombocytopenia (platelet count <25 × 109/L) | Interrupt Inrebic dose until resolved to ≤ Grade 2 (platelet count <75 × 109/L) or baseline. Restart dose at 100 mg daily below the last given dose. |
| Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 × 109/L) | Interrupt Inrebic dose until resolved to ≤ Grade 2 (ANC <1.5 × 109/L) or baseline. Restart dose at 100 mg daily below the last given dose. Granulocyte growth factors may be used at the physician’s discretion (see sections 4.4 and 4.5). |
| Grade 3 and higher anaemia, transfusion indicated (haemoglobin level <8.0 g/dL) | Interrupt Inrebic dose until resolved to ≤ Grade 2 (haemoglobin level <10.0 g/dL) or baseline. Restart dose at 100 mg daily below the last given dose. |
| Recurrence of a Grade 4 haematologic toxicity | Inrebic discontinuation as per physician’s discretion. |
| Non-haematologic toxicity | Dose reduction |
| ≥ Grade 3 nausea, vomiting or diarrhoea not responding to supportive measures within 48 hours | Interrupt Inrebic dose until resolved to ≤ Grade 1 or baseline. Restart dose at 100 mg daily below the last given dose. |
| ≥ Grade 3 ALT/ AST (>5.0 to 20.0 x upper limit of normal [ULN]) or bilirubin (> 3.0 to 10.0 ULN) | Interrupt Inrebic dose until resolved to ≤ Grade 1 (AST/ALT (> ULN – 3.0 x ULN) or bilirubin (> ULN – 1.5 x ULN)) or baseline. Restart dose at 100 mg daily below the last given dose. Monitor ALT, AST and bilirubin (total and direct) every 2 weeks for at least 3 months following the dose reduction. If re-occurrence of a Grade 3 or higher elevation, discontinue treatment with Inrebic. |
| ≥ Grade 3 amylase / lipase (>2.0 to 5.0 x ULN) | Interrupt Inrebic dose until resolved to Grade 1 (> ULN – 1.5 x ULN) or baseline. Restart dose at 100 mg daily below the last given dose. Monitor amylase / lipase every 2 weeks for at least 3 months following the dose reduction. If re-occurrence of a Grade 3 or higher elevation, discontinue treatment with Inrebic. |
| ≥ Grade 3 other non-haematologic toxicities | Interrupt Inrebic dose until resolved to ≤ Grade 1 or baseline. Restart dose at 100 mg daily below the last given dose. |
| Management of thiamine levels and Wernicke’s encephalopathy | Dose reduction |
| For thiamine levels < normal range (74 to 222 nmol/L)* but ≥30 nmol/L without signs or symptoms of WE | Interrupt Inrebic treatment. Dose with daily 100 mg oral thiamine until thiamine levels are restored to normal range*. Consider re-starting Inrebic treatment when thiamine levels are within normal range*. |
| For thiamine levels <30 nmol/L without signs or symptoms of WE | Interrupt Inrebic treatment. Initiate treatment with parenteral thiamine at therapeutic dosages until thiamine levels are restored to normal range*. Consider re-starting Inrebic treatment when thiamine levels are within normal range*. |
| For signs or symptoms of WE regardless of thiamine levels | Discontinue Inrebic treatment and immediately administer parenteral thiamine at therapeutic dosages. |
* the normal thiamine range may differ depending on the methods used by the laboratory
For patients with severe renal impairment (creatinine clearance [CLcr] 15 mL/min to 29 mL/min by Cockcroft-Gault [C-G]), the dose should be reduced to 200 mg. No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CLcr 30 mL/min to 89 mL/min by C-G). Due to potential increase of exposure, patients with pre-existing moderate renal impairment may require at least weekly safety monitoring and if necessary, dose modifications based on adverse reactions.
Inrebic pharmacokinetics have not been evaluated in patients with severe hepatic impairment. Use of Inrebic in patients with severe hepatic impairment (Child-Pugh class C or total bilirubin >3 times ULN and any AST increase) should be avoided. No modification of the starting dose is required for patients with mild to moderate hepatic impairment.
No additional dose adjustments are required in elderly patients (>65 years of age).
The safety and efficacy of Inrebic in children and adolescents aged up to 18 years have not been established. No data are available.
Inrebic is for oral use.
The capsules should not be opened, broken or chewed. They should be swallowed whole, preferably with water, and may be taken with or without food. Administration with a high fat meal may reduce the incidence of nausea and vomiting, therefore it is recommended to be taken with food.
Experience with overdose of Inrebic is limited. During clinical studies of Inrebic in myelofibrosis patients, doses were escalated up to 600 mg per day including 1 accidental overdose at 800 mg. At doses above 400 mg, gastrointestinal toxicity, fatigue and dizziness aswell as anaemia and thrombocytopenia tended to occur more commonly. In pooled clinical studies data encephalopathy including Wernicke’s encephalopathy was associated with doses of 500 mg. In the event of an overdose, no further Inrebic should be administered; the individual should be monitored clinically and supportive measures should be undertaken as clinically indicated.
4 years.
Keep the bottle tightly closed in order to protect from moisture.
This medicinal product does not require any special temperature storage conditions.
High-density polyethylene (HDPE) bottle with polypropylene child resistant cap and heat induction seal.
Each bottle contains 120 hard capsules and is packed in a cardboard carton.
Any unused product or waste material should be returned to the pharmacist for safe disposal in accordance with local requirements.
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