OGSIVEO

Ogsiveo should be initiated and monitored by a physician experienced in the use of anticancer therapies. Posology The recommended dose is 150 mg Ogsiveo twice daily, one dose in the morning and one dose in the evening. This dose should not be exceeded.

Duration of treatment Ogsiveo should be continued until disease progression or unacceptable toxicity. Missed dose If a dose of Ogsiveo is missed, patients should not take an additional dose. Patients should take the next prescribed dose.

Dose adjustments for adverse reactions The recommended dose modifications for selected adverse reactions are provided in Table 1. For other severe adverse reactions, or in the event of life-threatening adverse reactions, Ogsiveo should be withheld until the reaction is resolved to Grade ≤ 1 or baseline.

Ogsiveo should only be restarted at a dose of 100 mg twice daily and only after carefully considering the potential benefit and likelihood of recurrence of the adverse reaction. Ogsiveo should be permanently discontinued for recurrence of severe or life-threatening adverse reaction upon rechallenge at the reduced dose.

Dose modifications should be made if patients experience the following adverse reactions (grades refer to Common Terminology Criteria for Adverse Events): Table 1: Recommended dose modifications for adverse reactions in patients treated with Ogsiveo Adverse reaction Recommended action Diarrhoea Grade 3 diarrhoea persisting for ≥ 3 days despite maximal medical therapy Ogsiveo should be withheld until reaction is resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily.

Skin reactions Grade 3 folliculitis Ogsiveo should be withheld until reaction is resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily. Grade 3 maculopapular rash Ogsiveo should be withheld until reaction is resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily.

Grade 3 hidradenitis Ogsiveo should be withheld until reaction is resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily. Electrolyte abnormalities Grade 3 hypophosphataemia persisting for ≥ 7 days despite maximal replacement therapy Ogsiveo should be withheld until reaction is resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily.

Summary of the safety profile The most common adverse reactions are: diarrhoea (85%), rash (65%), ovarian toxicity in women of childbearing potential (60%), nausea (59%), fatigue (50%), hypophosphataemia (50%), headache (40%), and stomatitis (40%).

The most frequently reported serious adverse reaction was ovarian toxicity (premature menopause, 3%). The most common severe adverse reactions were diarrhoea (16%) and hypophosphataemia (13%). Permanent discontinuation of nirogacestat due to an adverse event occurred in 19% of patients.

The most common adverse reactions leading to discontinuation were diarrhoea (5%), ovarian toxicity (5%), and increased ALT (3%). The frequency of dose interruption of nirogacestat due to adverse reactions was 59%. The most common adverse reactions leading to dose interruption were diarrhoea (11%), rash maculo-papular (10%), hypophosphatemia (6%) and nausea (5%).

The frequency of dose reduction of nirogacestat due to adverse reactions was 44%. The most common adverse reactions leading to dose reduction were diarrhoea (9%), rash maculo-papular (6%), stomatitis (3%), and hypophosphatemia (3%).

5 months in clinical studies. The adverse reactions are ranked under heading of frequency using the following convention: 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 the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2:

Adverse reactions reported System organ class Adverse reaction All grades Grades 3-4 Diarrhoea Very common Very common Nausea Very common Common Stomatitisa Very common Common Gastrointestinal disorders Dry mouth Very common -- Rashb Very common Common Alopecia Very common -- Folliculitis Very common Common Hidradenitis Common Common Dry skin Very common -- Skin and subcutaneous disorders Pruritis Very common -- Basal cell carcinoma Common --Neoplasms benign, malignant and unspecified Squamous cellc carcinoma Common -- Hypophosphataemia Very common Very commonMetabolism and nutrition disorders Hypokalaemia Very common Common Headache Very common --Nervous system disorders Dizziness Very common -- Proteinuria Very common --Investigation Glycosuria Very common -- System organ class Adverse reaction All grades Grades 3-4 Blood and lymphatic system disorders Eosinophilia Very common -- Renal and urinary disorders Renal tubular disorder Common -- Injury, poisoning and procedural complications Bone fractured Common -- ALT increased Very common CommonHepatobiliary disorders AST increased Very common Common Reproductive system and breast disorders Ovarian toxicitye Very common -- Cough Very common -- Upper respiratory tract infectionf Very common -- Dyspnoea Very common -- Respiratory, thoracic and mediastinal disorders Epistaxis Very common -- Fatigue Very common CommonGeneral disorders and administration site conditions Influenza-like illness Very common -- a Stomatitis includes stomatitis, mouth ulceration, oral pain, and oropharyngeal pain.

8). Patients who experience diarrhoea during treatment with nirogacestat should be monitored and managed using anti-diarrhoeal medicinal products. 2). 8). Patients should be monitored for dermatologic reactions throughout the course of treatment and managed as clinically indicated.

2). 8). Ovarian toxicity, identified based on abnormal reproductive hormone levels or peri-menopausal symptoms, was reported in 75% of women of childbearing potential receiving nirogacestat in the DeFi study. Ovarian toxicity has been reported to resolve in 79% of women of childbearing potential during treatment.

8). Effects of nirogacestat on human fertility are unknown. Based on findings from animal studies, female fertility may be impaired. Women of childbearing potential should be advised about the risk of ovarian toxicity before initiating treatment with nirogacestat.

Patients should be monitored for changes in menstrual cycle regularity or the development of symptoms of oestrogen deficiency, including hot flashes, night sweats, and vaginal dryness. 8). Phosphate and potassium levels should be monitored regularly and supplemented as necessary.

2). 2). 8). Liver function tests should be monitored regularly. For ALT or AST ≥ 3 to 5 x ULN, nirogacestat should be withheld until ALT, AST, or both are resolved to < 3 x ULN or baseline, then it should be restarted at a dose of 100 mg twice daily.

2). 8). Skin examinations should be performed prior to initiation of nirogacestat and routinely during treatment with nirogacestat. Cases should be managed according to clinical practices and patients may continue with nirogacestat treatment without dose adjustment.

3). Patients should be advised of the potential risk to a foetus. Women of childbearing potential must have a negative pregnancy test prior to initiating nirogacestat treatment. Pregnancy testing during treatment with nirogacestat should be considered for women of childbearing potential experiencing amenorrhoea.

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