Inrebic

Treatment with Inrebic should be initiated and monitored under the supervision of physicians experienced in the use of anti-cancer medicinal products. Posology 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.

4). 0 x 109/L. 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. 3 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 Dose modifications for haematologic toxicities, non-haematologic toxicities and management of Wernicke’s encephalopathy (WE) are shown in Table 1.

Dose management of thiamine levels Before treatment initiation and during treatment, thiamine levels should be replenished if they are low. While on treatment, all patients should receive prophylaxis with daily 100 mg oral thiamine and should have thiamine levels assessed.

Dose modifications with concomitant use of strong CYP3A4 inhibitors If concomitant strong CYP3A4 inhibitors cannot be avoided, the dose of Inrebic should be reduced to 200 mg. g. 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. Dose re-escalation 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.

Summary of the safety profile The overall safety information of Inrebic was assessed in 608 patients who received continuous doses of Inrebic in Phase 1, 2 and 3 clinical studies. 6 weeks) and the median number of cycles (1 cycle = 28 days) initiated was 9 cycles.

Sixty-three percent of 203 patients were exposed for 6 months or longer and 38% were exposed for 12 months or longer. 8%). 5%) based on laboratory values (Table 2). 5%). Permanent discontinuation due to adverse event regardless of causality occurred in 24% of patients receiving 400 mg of Inrebic.

Tabulated list of adverse reactions Adverse reactions from clinical studies for entire treatment duration (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from available data).

Table 2:

All adverse reactions by system organ class and preferred term System organ class Adverse reaction All grades frequency Infections and infestations Urinary tract infection Very common Blood and lymphatic system disorders Anaemiaa Very common Thrombocytopeniaa Very common Neutropeniaa Very common Bleedingb Very common Metabolism and nutrition disorders Lipase increaseda Very common Amylase increaseda Very common Nervous system disorders Headache Very common Wernicke's encephalopathy Common Dizziness Common Eye disorders Uveitis Commonc Vascular disorders Hypertension Common Gastrointestinal disorders Diarrhoea Very common Vomiting Very common Nausea Very common Constipation Very common Dyspepsia Common Hepatobiliary disorders Alanine aminotransferase increaseda Very common Aspartate aminotransferase increaseda Very common 12 System organ class Adverse reaction All grades frequency Musculoskeletal and connective tissue disorders Bone pain Common Muscle spasms Very common Pain in extremity Common Renal and urinary disorders Blood creatinine increaseda Very common Dysuria Common General disorders and administration site conditions Fatigue/ Asthenia Very common Investigations Weight increased Common MedDRA = Medical dictionary of regulatory activities SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept).

Encephalopathy, including Wernicke’s encephalopathy Cases of serious and fatal encephalopathy, including Wernicke’s, were reported in patients taking Inrebic. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (vitamin B1) deficiency.

g. nystagmus, diplopia). 8). Thiamine levels and nutritional status in patients should be assessed before starting treatment with Inrebic. Inrebic treatment should not be started in patients with thiamine deficiency. Before treatment initiation, thiamine levels should be replenished if they are low.

While on treatment, all patients should receive prophylaxis with oral thiamine and should have thiamine levels assessed as clinically indicated. If encephalopathy is suspected, Inrebic treatment should be discontinued immediately and parenteral thiamine treatment should be initiated while evaluating for all possible causes.

8). Anaemia, thrombocytopenia and neutropenia Treatment with Inrebic may cause anaemia, thrombocytopenia and neutropenia. 8). 0 x 109/L. 6 Anaemia Anaemia generally occurs within the first 3 months of treatment. g. once weekly for the first month until haemoglobin levels improve).

Patients developing anaemia may require blood transfusions. 8). Thrombocytopenia Thrombocytopenia generally occurs within the first 3 months of treatment. g. 8). Thrombocytopenia is generally reversible and is usually managed by supportive treatment such as dose interruptions, dose reduction and/or platelet transfusions if necessary.

Patients should be made aware of the increased risk of bleeding associated with thrombocytopenia. 8). Gastrointestinal events Nausea, vomiting and diarrhoea are among the most frequent adverse reactions in Inrebic-treated patients. Most of the adverse reactions are Grade 1 or 2 and typically occur within the first 2 weeks of treatment.

g. 5-HT3 receptor antagonists) during Inrebic treatment. Treat diarrhoea with anti-diarrhoeal medicinal products promptly at the first onset of symptoms. For cases of Grade 3 or higher nausea, vomiting, and diarrhoea that are not responsive to supportive measures within 48 hours, the dose of Inrebic should be interrupted until resolved to Grade 1 or less/baseline.

1. 6).