Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: SpringWorks Therapeutics Ireland Limited, Hamilton House, 28 Fitzwilliam Place, Dublin 2, D02 P283, Ireland
Diarrhoea was reported in patients receiving nirogacestat (see section 4.8). Patients who experience diarrhoea during treatment with nirogacestat should be monitored and managed using anti‑diarrhoeal medicinal products. For Grade 3 diarrhoea that persists for ≥ 3 days despite maximal medical therapy, nirogacestat should be withheld until diarrhoea is resolved to Grade ≤ 1 or baseline, then it should be restarted at 100 mg twice daily (see section 4.2).
Dermatologic reactions, including maculopapular rash, folliculitis, and hidradenitis, were reported in patients receiving nirogacestat (see section 4.8). Patients should be monitored for dermatologic reactions throughout the course of treatment and managed as clinically indicated. For Grade 3 dermatologic reactions, nirogacestat should be withheld until resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily (see section 4.2).
Ovarian toxicity was reported in female patients of childbearing potential receiving nirogacestat (see section 4.8). 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. Follow up information is available for all but two out of 27 patients; after stopping treatment, ovarian toxicity was reported to resolve in all women of childbearing potential for whom data are available (see section 4.8). 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.
Electrolyte abnormalities, including hypophosphataemia and hypokalaemia, were reported in patients receiving nirogacestat (see section 4.8). Phosphate and potassium levels should be monitored regularly and supplemented as necessary. For Grade 3 hypophosphataemia persisting for ≥ 7 days despite maximal replacement therapy, nirogacestat should be withheld until resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily (see section 4.2). For Grade 3 hypokalaemia of any duration, despite maximal replacement therapy, nirogacestat should be withheld until resolved to Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily (see section 4.2).
ALT or AST elevations were reported in patients who received nirogacestat (see section 4.8). 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. For ALT or AST > 5 x ULN, nirogacestat should be permanently discontinued (see section 4.2).
Non‑melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) were reported in patients receiving nirogacestat (see section 4.8). Skin examinations should be performed prior to initiation of nirogacestat and routinely during treatment with nirogacestat. Cases should be managed 6 according to clinical practices and patients may continue with nirogacestat treatment without dose adjustment.
Nirogacestat may cause foetal harm when administered to a pregnant woman (see sections 4.6 and 5.3). 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. Women of childbearing potential receiving nirogacestat must use highly effective contraceptive methods during treatment with nirogacestat and for 1 week after the last dose of nirogacestat (see section 4.6). Women of childbearing potential should be advised to inform their healthcare provider immediately of a known or suspected pregnancy, and they must stop taking nirogacestat if they become pregnant.
Male patients with female partners of childbearing potential should be advised to use highly effective contraceptive methods during treatment with nirogacestat and for 1 week after the last dose of nirogacestat (see section 4.6).
This medicinal product contains lactose (see sections 2 and 6.1). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.
This medicinal product contains sunset yellow FCF (E110) (see sections 2 and 6.1), which may cause allergic reactions.
Each film‑coated tablet contains less than 1 mmol sodium (23 mg), that is to say essentially sodium‑free (see section 6.1).
Interaction studies have only been performed in adults.
Nirogacestat is primarily metabolized by CYP3A4 and is a substrate of P‑glycoprotein (P-gp).
In a clinical study, co‑administration of itraconazole (a strong CYP3A4 inhibitor and P‑gp inhibitor) increased nirogacestat Cmax by 2.5‑fold and AUC by 8.2‑fold. Co‑administration with moderate CYP3A4 inhibitors is also expected to result in clinically relevant increases in exposure.
Concomitant use with strong inhibitors of CYP3A4 (e.g., clarithromycin, oral ketoconazole, itraconazole) and moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) should therefore be avoided.
Alternative concomitant medicinal products with no or minimal CYP3A4 inhibition should be considered. If therapeutic alternatives are not available, Ogsiveo should be immediately interrupted for the period of time in which a strong or moderate CYP3A4 inhibitor is given.
Patients should avoid consuming grapefruit and grapefruit juice when taking Ogsiveo since they include inhibitors of CYP3A4 (see section 4.2).
The effects of CYP3A4 inducers on nirogacestat exposure have not been evaluated in a clinical study. Moderate and strong inducers are expected to result in clinically relevant decreases in exposure of nirogacestat that could lead to reduced efficacy. Concomitant treatment with strong inducers of CYP3A4 (e.g., carbamazepine, phenytoin, rifampicin, phenobarbital and St. John's wort) and moderate CYP3A inducers (e.g., efavirenz and etravirine) should therefore be avoided. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected.
Nirogacestat has pH‑dependent solubility, with substantially reduced solubility at pH greater than 6.0. The effects of acid reducing agents (i.e., H2‑receptor antagonists, proton pump inhibitors and antacids) on nirogacestat exposure have not been evaluated in a clinical study, however, co‑administration of these medicinal products may reduce the bioavailability of nirogacestat. Concomitant use of Ogsiveo with proton pump inhibitors and H2 blockers is not recommended. However, if concomitant use with acid reducing agents cannot be avoided, Ogsiveo can be staggered with antacids by administering Ogsiveo 2 hours before or 2 hours after antacid use.
A drug‑drug interaction study in healthy volunteers investigating the effects of multiple doses of nirogacestat at a dose of 95 mg once daily on the exposure of midazolam, a sensitive CYP3A4 substrate, resulted in a 1.3‑fold increase in midazolam Cmax and a 1.6‑fold increase in midazolam AUC. The effect of the clinical dose of nirogacestat (150 mg twice daily) on midazolam exposure has not been studied and may be different. Ogsiveo should not be used with concomitant administration of CYP3A4 substrates that have narrow therapeutic indices (e.g., cyclosporine, tacrolimus, digitoxin, warfarin, carbamazepine).
Since no study has been performed investigating the effect of nirogacestat on systemic contraceptive steroid exposure, it is unknown whether nirogacestat reduces the effectiveness of systemically acting hormonal contraceptives. Women of childbearing potential must use highly effective contraceptive methods (see section 4.6).
In vitro studies showed that nirogacestat may induce CYP2C8, CYP2C9, CYP2C19, and CYP2B6 and thus there is a risk that nirogacestat can cause decreased exposure of substrates of these enzymes. When substrates of CYP2C8, CYP2C9, CYP2C19, and CYP2B6 are administered with Ogsiveo, evaluation for reduced efficacy of the substrate should be performed and dose adjustment of the substrate may be required to maintain optimal plasma concentrations.
A single-dose drug‑drug interaction study demonstrated that nirogacestat did not affect the exposure of dabigatran, a P‑gp substrate, which supports the absence of clinically meaningful P‑gp inhibition by nirogacestat.
Women of childbearing potential and men with female partners of childbearing potential should be advised to avoid pregnancy while on Ogsiveo (see section 4.4).
Women of childbearing potential must use highly effective contraceptive methods during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.4). It is unknown whether nirogacestat reduces the effectiveness of systemically acting hormonal contraceptives. Patients should be advised to use at least one highly effective method of contraception (such as an intrauterine device) or two complementary forms of contraception including a barrier method during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo. Women of childbearing potential should be advised to inform their healthcare provider immediately of a known or suspected pregnancy, and they must stop taking Ogsiveo if they become pregnant. Women of childbearing potential should not donate eggs (oocytes) during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo.
Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.4). Male patients should not donate sperm during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo.
Based on findings from animal studies and its mechanism of action, Ogsiveo may cause foetal harm when administered to a pregnant woman. Ogsiveo is contraindicated in pregnant women (see sections 4.3 and 5.3). Women of childbearing potential must have a negative pregnancy test prior to initiating Ogsiveo treatment. Pregnancy testing during treatment with Ogsiveo should be considered for women of childbearing potential experiencing amenorrhoea. Patients should be advised of the potential risk to a foetus. If a patient becomes pregnant while taking Ogsiveo, treatment must be discontinued. A spontaneous abortion was reported by a woman in the DeFi study who conceived while receiving nirogacestat.
There are no data regarding the presence of nirogacestat or its metabolites in either human or animal milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, women must not breastfeed during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.3).
Fertility studies were not conducted in humans. The effect of Ogsiveo on fertility in humans is not known. Based on findings from animal studies, male and female fertility may be impaired (see section 5.3).
Ogsiveo has no or negligible influence on the ability to drive and use machines. Since fatigue and dizziness may occur in patients taking nirogacestat (see section 4.8), caution should be observed by patients who experience those adverse reactions when driving or operating machinery.
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%).
Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 88 patients exposed to nirogacestat 150 mg twice daily during a median duration of 21.5 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 |
|---|---|---|---|
| Gastrointestinal disorders | Diarrhoea | Very common | Very common |
| Nausea | Very common | Common | |
| Stomatitisa | Very common | Common | |
| Dry mouth | Very common | -- | |
| Skin and subcutaneous disorders | Rashb | Very common | Common |
| Alopecia | Very common | -- | |
| Folliculitis | Very common | Common | |
| Hidradenitis | Common | Common | |
| Dry skin | Very common | -- | |
| Pruritis | Very common | -- | |
| Neoplasms benign, malignant and unspecified | Basal cell carcinoma | Common | -- |
| Squamous cellc carcinoma | Common | -- | |
| Metabolism and nutrition disorders | Hypophosphataemia | Very common | Very common |
| Hypokalaemia | Very common | Common | |
| Nervous system disorders | Headache | Very common | -- |
| Dizziness | Very common | -- | |
| Investigation | Proteinuria | Very common | -- |
| Glycosuria | Very common | -- | |
| Blood and lymphatic system disorders | Eosinophilia | Very common | -- |
| Renal and urinary disorders | Renal tubular disorder | Common | -- |
| Injury, poisoning and procedural complications | Bone fractured | Common | -- |
| Hepatobiliary disorders | ALT increased | Very common | Common |
| AST increased | Very common | Common | |
| Reproductive system and breast disorders | Ovarian toxicitye | Very common | -- |
| Respiratory, thoracic and mediastinal disorders | Cough | Very common | -- |
| Upper respiratory tract infectionf | Very common | -- | |
| Dyspnoea | Very common | -- | |
| Epistaxis | Very common | -- | |
| General disorders and administration site conditions | Fatigue | Very common | Common |
| Influenza-like illness | Very common | -- |
a Stomatitis includes stomatitis, mouth ulceration, oral pain, and oropharyngeal pain.
b Rash includes rash maculo-papular, dermatitis acneiform, rash, rash erythematous, rash pruritic, and rash papular.
c Squamous cell carcinoma included squamous cell carcinoma of skin and squamous cell carcinoma.
d Bone fracture includes fracture, foot fracture, hand fracture, radius fracture, hip fracture and rib fracture.
e Ovarian toxicity includes ovarian failure, premature menopause, amenorrhoea, oligomenorrhoea, menstruation irregular, dysmenorrhoea, heavy menstrual bleeding, vulvovaginal dryness, hot flush, decreased anti-Müllerian hormone (AMH) and increased follicle-stimulating hormone (FSH).
f Upper respiratory tract infection (URTI) includes URTI, viral URTI, acute sinusitis, and sinusitis.
-- Represents no cases were reported.
The data described below reflect results of the randomised, double-blind, Phase 3 DeFi study in patients with desmoid tumours treated with 150 mg BID nirogacestat (N=69) or placebo (N=72) twice daily.
In the double-blind phase of the DeFi study, diarrhoea was reported in 84% of patients receiving nirogacestat compared to 35% in patients receiving placebo. Grade 3 events occurred in 16% and 1% of patients, respectively (see section 4.4). Grade ≤ 2 diarrhoea resolved in 74% of patients who continued on nirogacestat treatment. The median time to first onset of diarrhoea in patients receiving nirogacestat was 9 days (range 2 to 234 days). Diarrhoea led to dose reduction in 10% of patients and treatment discontinuation in 7% receiving nirogacestat.
In the double‑blind phase of the DeFi study, dermatologic reactions were reported at a higher incidence in patients receiving nirogacestat than in those receiving placebo; they included maculo‑papular rash (32% vs 6%), hidradenitis (9% vs 0), and folliculitis (13% vs 0) (see section 4.4). The median time to rash events was 22 days (range 2 to 603 days). Skin and subcutaneous disorders led to dose reduction in 9% of patients receiving nirogacestat, including maculo‑papular rash in 4% and hidradenitis in 3%. Maculo‑papular rash led to treatment discontinuation in 1%.
In the double‑blind phase of the DeFi study, 75% of women of childbearing potential receiving nirogacestat reported ovarian toxicity (defined as ovarian failure, premature menopause, amenorrhea, oligomenorrhea, and menopause) compared to no patients receiving placebo. There were three serious adverse reactions of ovarian toxicity, all premature menopause, representing 11% of all participants reporting ovarian toxicity. The median time to first onset of ovarian toxicity was 8.9 weeks (range 1 day to 54 weeks), and the overall median duration was 18.9 weeks (range 11 days to 215 weeks). Ovarian toxicity has been reported to resolve in 79% of women of childbearing potential during treatment. Follow up information is available for all but two out of 27 patients; after stopping treatment, ovarian toxicity was reported to resolve in all women of childbearing potential for whom data are available. The median time to resolution after discontinuing nirogacestat was 10.9 weeks (range 4 to 18 weeks). Effects of nirogacestat on fertility are unknown (see section 4.4). An exposure-response relationship was identified between nirogacestat and serum follicular stimulating hormone (FSH) levels, with FSH increasing linearly with increasing serum concentrations of nirogacestat.
Electrolyte abnormalities were reported in patients receiving nirogacestat in the double‑blind phase of the DeFi study, including hypophosphataemia (43%) and hypokalaemia (12%), compared to 7% and 1%, respectively, in patients receiving placebo. Median time to first onset of hypophosphataemia and hypokalaemia was 15 days (range 1 to 833 days) and 15 days (range 1 to 57 days), respectively. Grade 3 events of hypophosphataemia and hypokalaemia occurred in 3% of patients receiving nirogacestat compared to no patients receiving placebo (see section 4.4). Hypophosphataemia and hypokalaemia led to dose reduction in 4% and 1% of patients receiving nirogacestat, respectively. Hypophosphataemia led to dose discontinuation in 1% of patients receiving nirogacestat.
ALT and AST elevations were reported in 19% and 17%, respectively, of patients receiving nirogacestat in the double‑blind phase of the DeFi study compared to 8% and 11%, respectively, in patients receiving placebo. Median time to first onset of ALT and AST elevations was 22 days (ALT range 8 to 924 days; AST range 1 to 1023 days). Grade 3 ALT and AST elevations (>5 x ULN) occurred in 3% of patients treated with nirogacestat compared to 1% in the placebo arm (see section 4.4). ALT and AST elevations each led to dose reduction in 1% of patients receiving nirogacestat. ALT and AST elevations led to dose discontinuation in 4% and 3% of patients receiving nirogacestat, respectively.
Non-melanoma skin cancers were reported at a higher incidence in patients receiving nirogacestat than in those receiving placebo in the double‑blind phase of the DeFi study, including squamous cell carcinoma (3% vs 0) and basal cell carcinoma (1% vs 0), with one patient reporting both types of non‑melanoma skin cancer (see section 4.4). An additional two cases of non‑melanoma skin cancer were reported outside of the double‑blind phase of the DeFi study.
Glycosuria and proteinuria were observed in 52% and 46%, respectively, of patients receiving nirogacestat in the double‑blind phase of the DeFi study, compared with 1% and 39%, respectively, in patients receiving placebo. Median time to onset of glycosuria and proteinuria was 85 days (range 55 to 600 days) and 72 days (range 38 to 937 days), respectively. One patient in the DeFi study reported renal tubular disorder with increased urinary excretion of uric acid, glucose and phosphate, but no excess excretion of low molecular weight proteins (beta2‑microglobulin) or any change in renal function. The event was managed with dose reduction.
In the double‑blind phase of the DeFi study, bone fractures were reported in 6% of patients receiving nirogacestat compared with no patients receiving placebo. All reports of bone fracture were non‑serious and Grade 1 or 2. The median time to first onset of bone fracture events in patients receiving nirogacestat was 125 days (range 1 to 739 days). Bone fracture events did not lead to dose reduction or treatment discontinuation in any patient receiving nirogacestat.
Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, was reported in 4 of 26 (15%) paediatric patients with open growth plates treated with nirogacestat outside of the DeFi study. The events included epiphysiolysis, hip fracture, epiphyseal disorder, and osteonecrosis. All 4 paediatric patients were between the ages of 11 and 12 years. See section 4.2 for information on paediatric use.
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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