OGSIVEO Tablet Ref.[107378] Active ingredients: Nirogacestat

5.1 Diarrhea

Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO [see Adverse Reactions (6.1)].

In DeFi, diarrhea occurred in 84% of patients treated with OGSIVEO, and included Grade 3 events in 16% of patients. Median time to first diarrhea event for patients treated with OGSIVEO was 9 days (range: 2 to 434 days). Monitor patients and manage using antidiarrheal medications. Modify dose as recommended [see Dosage and Administration (2.2)].

5.2 Ovarian Toxicity

Female reproductive function and fertility may be impaired in patients being treated with OGSIVEO. Impact on fertility may depend on factors including the duration of therapy and the state of gonadal function at the time of treatment. The long-term effects of OGSIVEO on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment with OGSIVEO [see Use in Specific Populations (8.3)]. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.

5.3 Hepatotoxicity

ALT or AST elevations occurred in 30% and 33% of patients who received OGSIVEO in DeFi, respectively. Grade 3 ALT or AST elevations (> 5 × ULN) occurred in 6% and 2.9% of patients, respectively [see Adverse Reactions (6.1)]. Monitor liver function tests regularly and modify dose as recommended [see Dosage and Administration (2.2)].

5.4 Non-Melanoma Skin Cancers

New non-melanoma skin cancers can occur in patients treated with OGSIVEO. In DeFi, cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9% and 1.4% of patients, respectively [see Adverse Reactions (6.1)]. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment.

5.5 Electrolyte Abnormalities

Electrolyte abnormalities can occur in patients treated with OGSIVEO. In DeFi, these included decreased phosphate (65%) and decreased potassium (22%). Phosphate <2 mg/dL occurred in 20% of patients who received OGSIVEO. Grade 3 decreased potassium occurred in 1.4% of patients [see Adverse Reactions (6.1)]. Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended [see Dosage and Administration (2.2)].

5.6 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm when administered to pregnant women. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose [see Use in Specific Populations (8.1,8.3)].

The following serious adverse reactions are described elsewhere in the labeling:

• Diarrhea [see Warnings and Precautions (5.1)]
• Ovarian Toxicity [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Non-Melanoma Skin Cancers [see Warnings and Precautions (5.4)]
• Electrolyte Abnormalities [see Warnings and Precautions (5.5)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OGSIVEO was evaluated in 69 patients enrolled in DeFi with progressing desmoid tumor [see Clinical Studies (14)]. Patients received OGSIVEO 150 mg orally twice daily or placebo orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure to OGSIVEO was 20.6 months (range: 0.3 to 33.6).

Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in ≥ 2% of patients were ovarian toxicity (4%).

Permanent discontinuation of OGSIVEO due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of OGSIVEO in ≥ 2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST.

Dosage interruptions of OGSIVEO due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity.

Dose reductions of OGSIVEO due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity.

The most common (≥ 15% with a difference between arms of ≥ 5% compared to placebo) adverse reactions that occurred in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

Table 2 summarizes the adverse reactions that occurred in DeFi.

Table 2. Adverse Reactions (≥15%) in Patients with Desmoid Tumor Who Received OGSIVEO with a Difference Between Arms of ≥5% Compared to Placebo on DeFi:

^a Includes multiple related composite terms.
^b Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause
^c The number of females of reproductive potential in each arm is used as the denominator (OGSIVEO N=36, Placebo N=37)

Clinically relevant adverse reactions occurring in <15% of patients receiving OGSIVEO in DeFi included non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.

Table 3 summarizes laboratory abnormalities in DeFi.

Table 3. Laboratory Abnormalities (≥15%) that Worsened from Baseline in Patients with Desmoid Tumor Who Received OGSIVEO in DeFi:

^a The denominator used to calculate the rate was 69 for nirogacestat and 72 for placebo based on the number of patients with a baseline value and at least one post-treatment value.
^b CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN).
^c The denominator used to calculate the rate was 68 for nirogacestat and 69 for placebo based on the number of patients with a baseline value and at least one post-treatment value.
^d CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.

7.1 Effect s of Other Drugs on OGSIVEO

Table 4. Effects of Other Drugs on OGSIVEO:

7.2 Effects of OGSIVEO on Other Drugs

Table 5. Effects of OGSIVEO on Other Drugs:

Risk Summary

Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm or loss of pregnancy when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily [see Data]. There are no available data on the use of OGSIVEO in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Daily oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in decreased fetal body weights, pre- and post-implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the recommended dose of 150 mg twice daily based on area under the curve).

Risk Summary

There are no data on the presence of nirogacestat or its metabolites in human milk or the effects of nirogacestat on a breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with OGSIVEO and for 1 week after the last dose.

OGSIVEO can cause fetal harm when administered to a pregnant woman (see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating OGSIVEO [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

Infertility

Based on findings in animal studies, OGSIVEO can impair female and male fertility. OGSIVEO has been shown to interfere with folliculogenesis and spermatogenesis in nonclinical studies resulting in changes that included ovarian atrophy [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of OGSIVEO have not been established in pediatric patients. Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, has been reported in pediatric patients with open growth plates treated with OGSIVEO.

Of the total number of OGSIVEO-treated patients in the DeFi study, 3 (4%) were 65 years of age and older and none were 75 years of age and older. Clinical studies of OGSIVEO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adult patients.