Summary of Product Characteristics (SmPC) - Romvimza 14 mg hard capsules
1 NAME OF THE MEDICINAL PRODUCT
ROMVIMZA 14 mg hard capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 14 mg of vimseltinib (as dihydrate).
Excipients with known effect
Each hard capsule contains 121.32 mg of lactose monohydrate and 0.0855 mg of the azo colouring agent sunset yellow FCF (E 110).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Hard capsule.
The capsule is an orange opaque cap/white opaque body hard capsule of size 4 (approximate length 14 mm), imprinted with “DCV14” in black ink.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
ROMVIMZA is indicated for treatment of adult patients with symptomatic tenosynovial giant cell tumour (TGCT) associated with clinically relevant physical function deterioration and in whom surgical options have been exhausted or would induce unacceptable morbidity or disability.
4.2 Posology and method of administration
Therapy should be initiated by a healthcare professional experienced in the diagnosis and treatment of conditions for which ROMVIMZA is indicated.
Posology
Recommended dose
The recommended dose of ROMVIMZA is 30 mg taken twice weekly at least 72 hours apart as long as benefit is observed or until unacceptable toxicity.
If the patient misses a dose of ROMVIMZA by less than 48 hours, the patient should be instructed to take the missed dose as soon as possible and return to the usual dosing schedule. If the patient misses a dose of ROMVIMZA by more than 48 hours, the patient should be instructed not to take the missed dose and return to the usual dosing schedule.
Dose reduction
Dose interruptions or dose reductions may be required based on individual safety and tolerability. If patients are unable to tolerate a 30 mg dose of ROMVIMZA, treatment with ROMVIMZA should be temporarily withheld. When the clinical condition of the patient improves, a reduced dose of ROMVIMZA should be given as described in Table 1.
Table 1: Recommended dose reduction
| Dose reduction | Twice weekly dose |
| First | 20 mg |
| Second | 14 mg |
ROMVIMZA should be discontinued in patients unable to tolerate a 14 mg dose of vimseltinib.
Special populations
Renal impairment
No dose adjustment is recommended in patients with mild or moderate renal impairment (see section 5.2). No clinical data are available in patients with severe renal impairment. Therefore, ROMVIMZA should not be used in these patients (see section 5.2).
Hepatic impairment
No dose adjustment is recommended in patients with mild hepatic impairment (Child-Pugh A). Dose reductions to 14 mg twice weekly for patients with mild hepatic impairment have not been used and efficacy has not been established. No clinical data are available in patients with moderate and severe hepatic impairment. Therefore, ROMVIMZA should not be used in these patients (see section 5.2).
Elderly (≥ 65 years)
No dose adjustments are necessary in patients aged ≥
65 years (see sections 4.8, 5.1 and 5.2).
Body weight
Dose reductions to 14 mg twice weekly for patients of ≥
115 kg body weight have not been used and efficacy has not been established.
Paediatric population
ROMVIMZA should not be used in children from birth to pre-pubertal age because of safety concerns based on preclinical safety data (see section 5.3).
The safety and efficacy of ROMVIMZA in children from post-pubertal to less than 18 years of age have not been established (see section 5.1). No clinical data are available.
Method of administration
ROMVIMZA is to be taken orally, with or without food.
Prescribers should instruct patients to swallow the hard capsules whole and not to open, break or chew them. Patients should not ingest the hard capsules if they are broken, cracked, or otherwise not intact as the potential effects of these alterations have not been evaluated.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.Pregnancy (see sections 4.4 and 4.6).
4.4 Special warnings and precautions for use
Long-term safety
The long-term safety of ROMVIMZA has not been established. ROMVIMZA has a novel mechanism of action by inhibition of the colony stimulating factor 1 receptor (CSF1R). The long-term implications of the resulting macrophage depletion, particularly in organs such as the liver, skin, central nervous system and bone marrow are currently uncertain.
Arterial hypertension
Treatment with ROMVIMZA in clinical studies was frequently associated with an increase in blood pressure.
Increase in creatinine
Treatment with ROMVIMZA in clinical studies was frequently associated with an increase in creatinine. The underlying reason is currently unknown.
Embryo-foetal toxicity
Based on data from animal studies, vimseltinib may cause foetal harm when administered to pregnant women (see sections 4.6 and 5.3). Women should be advised to avoid pregnancy while taking vimseltinib. Pregnant women should be informed of the potential risk to the foetus. Women of childbearing potential must use effective contraception during treatment with vimseltinib and for 30 days after the final dose. Effects of vimseltinib on hormonal contraceptives have not been studied. A barrier method contraception should be added if systemic contraceptives are used.
Pruritus
Pruritus has been reported in patients receiving vimseltinib. In the pooled safety population, pruritus was reported in 27% of patients (see section 4.8). Pruritus has also been reported after single doses of vimseltinib in healthy participants. Dose interruptions or dose reductions may be required based on individual safety and tolerability (see section 4.2).
Serum enzyme elevations
Vimseltinib has been associated with serum enzyme elevations, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and creatine phosphokinase (CPK). Although currently these elevations did not result in any cases of liver injury or rhabdomyolysis in clinical studies, this is not excluded since experience in this rare clinical condition is very limited. Thus, ROMVIMZA treatment should be avoided in patients with pre-existing serum transaminase elevations, total bilirubin or direct bilirubin elevations, or active liver or biliary tract disease.
Patients should be monitored for liver function prior to the start of ROMVIMZA, once a month for the first two months and once every 3 months for the first year of therapy and as clinically indicated thereafter.
Excipients with known effect
Lactose
ROMVIMZA contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sunset yellow FCF (E 110)
ROMVIMZA 14 mg and 20 mg hard capsules contain sunset yellow FCF (E 110), which may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on vimseltinib
P-glycoprotein (P-gp) inhibitors
Concomitant administration of single-dose vimseltinib with 200 mg of itraconazole (a P-gp inhibitor) once daily showed that peak exposure (Cmax) of vimseltinib was comparable to that when administered alone, total exposure of vimseltinib (AUC0-t and AUC0-inf) was approximately 17% to 22% higher in the presence of itraconazole. Dose adjustment is not required.
Proton pump inhibitors
Concomitant administration of vimseltinib with rabeprazole (a proton pump inhibitor) 20 mg once daily under fasted conditions reduced Cmax and AUC0-t and AUC0-inf of vimseltinib by approximately 21% to 26%, which is not clinically relevant. Dose adjustment is not required.
Effects of vimseltinib on other medicinal products
Breast cancer resistance protein (BCRP) substrates
Vimseltinib is an inhibitor of BCRP in vitro. Concomitant use of vimseltinib with BCRP substrates (e.g. rosuvastatin) may increase the concentrations of BCRP substrates and increase the risk of adverse reactions related to these substrates. Clinical studies with BCRP substrates have not been conducted.
The concomitant use of BCRP substrates should be avoided. Refer to the Summary of Product Characteristics of the BCRP substrate for dose modifications if concomitant use cannot be avoided.
Organic cation transporter 2 (OCT2) substrates
Vimseltinib is an inhibitor of OCT2 in vitro. Concomitant use of vimseltinib with OCT2 substrates (e.g. metformin) may increase the concentrations of OCT2 substrates and increase the risk of adverse reactions related to these substrates. Clinical studies with OCT2 substrates have not been conducted.
The concomitant use of OCT2 substrates should be avoided. Refer to the Summary of Product Characteristics of the OCT2 substrate for dose modifications if concomitant use cannot be avoided.
P-gp substrates
Vimseltinib is an inhibitor of P-gp in vitro. Concomitant use of vimseltinib with P-gp substrates (e.g. digoxin, dabigatran) may increase the concentrations of P-gp substrates and increase the risk of adverse reactions related to these substrates. Clinical studies with P-gp substrates have not been conducted.
The concomitant use of P-gp substrates should be avoided. Refer to the Summary of Product Characteristics of the P-gp substrate for dose modifications if concomitant use cannot be avoided.
Effects of vimseltinib on other substances
Hormonal contraceptives
It is unknown whether vimseltinib may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a barrier method.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential / Contraception in females
Women of childbearing potential must use effective contraception during treatment with vimseltinib and for 30 days after the final dose. The pregnancy status of women of childbearing potential must be verified prior to initiating vimseltinib and during treatment.
Effects of vimseltinib on hormonal contraceptive have not been studied. Therefore, a barrier method should be added if hormonal contraceptives are used.
Pregnancy
There are no available data from the use of vimseltinib in pregnant women. Based on findings from animal studies, vimseltinib may cause foetal harm when administered to pregnant women (see sections 4.4 and 5.3). Studies in animals have shown reproductive toxicity (foetal structural abnormalities and cardiac malformations, see section 5.3). Vimseltinib is contraindicated in pregnant women (see section 4.3).
Breast-feeding
It is unknown whether vimseltinib is excreted in human milk. A risk to the breast-fed child cannot be excluded. Women should not breast-feed during treatment with vimseltinib.
Fertility
Based on findings from animal studies, ROMVIMZA may impair fertility in males (see section 5.3).
4.7 Effects on ability to drive and use machines
ROMVIMZA has minor influence on the ability to drive and use machines. Fatigue or blurred vision may occur following administration of ROMVIMZA (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
The safety of ROMVIMZA is based on pooled data from 184 patients with TGCT who received ROMVIMZA at a dose of 30 mg twice weekly in 2 clinical studies. The MOTION study, a phase 3, double-blind, multicentre, randomised (2:1), placebo-controlled study, included 122 adult patients who received vimseltinib (n = 83) or placebo (n = 39) in the double-blind period; 35 patients crossed over from placebo and received vimseltinib in the open-label period. The phase 1/2 study DCC-3014-01-001 included a total of 66 patients with TGCT who received vimseltinib at a dose of 30 mg twice weekly.
The median duration of treatment in the pooled safety population was 13 months. The median age of patients who received vimseltinib was 44 years (range from 20 to 78 years) and the population was 60% female and 72% White.
The most frequently observed adverse reactions were increased aspartate aminotransferase (AST) (92%), periorbital oedema (63%), increased cholesterol (53%), rash (51%), increased creatinine (43%), decreased neutrophils (36%), fatigue (30%), face oedema (28%), increased alanine aminotransferase (ALT) (27%), pruritus (27%), peripheral oedema (22%) and hypertension (21%).
Grade 3/4 adverse reactions were hypertension (9%), rash (3%), pruritus (3%), decreased neutrophils (3%), periorbital oedema (2%), fatigue (2%), increased cholesterol (1%), neuropathy (0.5%), face oedema (0.5%), generalised oedema (0.5%), and increased AST (0.5%). Serious adverse reactions were peripheral oedema (0.5%) and increased creatine phosphokinase (CPK) (0.5%).
Permanent discontinuation due to an adverse reaction occurred in 7% of patients. The most frequently observed adverse reactions leading to permanent discontinuation were rash (3%), periorbital oedema (2%), neuropathy (1%) and pruritus (1%).
Dose reductions or interruptions due to an adverse reaction occurred in 59% of patients. The most frequently observed adverse reactions leading to dose reductions or interruptions were rash (21%), periorbital oedema (18%), increased creatine phosphokinase (CPK) (17%), pruritus (10%), face oedema (7%), generalised oedema (7%), fatigue (6%) and peripheral oedema (5%).
Tabulated list of adverse reactions
The adverse reactions are listed below by system organ class and frequency categories, 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), not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
Table 2: Adverse reactions observed in MOTION and DCC-3014-01-001 studies
| System organ class | Frequency category | Adverse reaction |
| Nervous system disorders | Very common | Neuropathy1 |
| Eye disorders | Very common | Periorbital oedema2, lacrimation increased |
| Common | Dry eye, vision blurred | |
| Vascular disorders | Very common | Hypertension |
| Skin and subcutaneous tissue disorders | Very common | Rash3, pruritus, dry skin |
| General disorders and administration site conditions | Very common | Peripheral oedema, fatigue, face oedema, generalised oedema |
| Investigations4 | Very common | Blood creatine phosphokinase increased5, aspartate aminotransferase increased, blood cholesterol increased, blood creatinine increased, neutrophil count decreased, alanine aminotransferase increased, alkaline phosphatase increased |
1 Neuropathy comprises peripheral neuropathy, paraesthesia, hypoaesthesia, peripheral sensory neuropathy.
2 Periorbital oedema comprises eye oedema, eyelid oedema, swelling of eyelid, periorbital oedema, periorbital swelling.
3 Rash comprises rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, dermatitis acneiform, erythema.
4 Terms based on laboratory parameters.
5 Frequency category for blood creatine phosphokinase increased is based on laboratory data from DCC-3014-01-001 only.
Description of selected adverse reactions
Creatine phosphokinase (CPK)
Consistent with the mechanism of action, increased CPK was reported during the MOTION study in vimseltinib-treated patients. The frequency of increased CPK cannot be determined from the MOTION study because CPK was not assessed at baseline. In the phase 1/2 study conducted in 66 patients receiving vimseltinib 30 mg twice weekly, increased CPK was observed in all patients.
Other special populations
Elderly
No overall differences in safety were observed between patients ≥
65 years of age and patients < 65 years of age.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
In the event of suspected overdose, treatment consists of observation and general supportive measures instituted as required.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX29
Mechanism of action
Vimseltinib is a selective small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R). The CSF1/CSF1R signalling axis has a critical role in the development of TGCT. In vitro enzyme and cell-based assays have shown that vimseltinib inhibited CSF1R autophosphorylation and signalling induced by CSF1 ligand binding, as well as cellular function and proliferation of cells expressing CSF1R. Vimseltinib also inhibited CSF1R expressing cells and blocked downstream signalling in preclinical models in vivo.
Vimseltinib exerts its anti-tumour effects via depletion of CSF1R-dependent macrophages and inflammatory cells.
A decline in the number of hepatic Kupffer cells due to CSF1R inhibition leads to decreased clearance of serum enzymes, including AST, ALT, and CPK. This results in an increase in the serum levels of these enzymes.
Pharmacodynamic effects
Exposure-response relationship
Positive exposure-response relationships were observed between vimseltinib exposure and all grades of oedema, pruritus, rash, and increases of AST ALT, CPK and creatinine.
Clinical efficacy
MOTION, a phase 3, double-blind, multicentre, randomised (2:1), placebo-controlled study, evaluated the efficacy and safety of vimseltinib in patients with symptomatic TGCT with at least moderate pain or at least moderate stiffness for whom surgical resection may have caused worsening functional limitation or severe morbidity. Eligible patients had a confirmed diagnosis of TGCT with measurable disease per the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) with at least one lesion having a minimum size of 2 cm. Patients were randomised to placebo or vimseltinib 30 mg twice weekly for 24 weeks. At Week 25, patients who completed the double-blind, randomised part of the trial were eligible to advance to an ongoing, open-label extension study in which all patients received vimseltinib.
A total of 123 patients were randomised: 40 patients were randomised to placebo and 83 were randomised to vimseltinib during the double-blind period of the study. The median age was 44 years (range 20 to 78 years with 7% of patients ≥
65 years old); 59% patients were female; 65% were White.
Efficacy was established based on overall response rate (ORR) assessed by blinded independent radiological review (IRR) per RECIST v1.1 at Week 25. Additional efficacy outcomes measured at Week 25 included ORR per tumour volume score (TVS, defined as the estimated volume of maximally distended synovial cavity or tendon sheath involved, measured in 10% increments), active range of motion of the affected joint and patient reported outcomes. All efficacy endpoints achieved statistical significance in the MOTION study.
Overall response rate (ORR)
Statistically significant improvement in ORR was shown in patients randomised to vimseltinib compared with placebo as measured by RECIST v1.1 and TVS based on assessment by IRR. Results for ORR from the MOTION clinical study are summarised in Table 3.
Other key secondary endpoints
Active range of motion
Active range of motion (ROM) was assessed using a goniometer to determine the mean change from baseline, relative to a reference standard, at Week 25. The active ROM measurements showed a clinically meaningful and statistically significant improvement at Week 25 and are presented in Table 3.
Patient-reported outcomes
Additional efficacy measures assessed at Week 25 included physical function (using Patient-Reported Outcomes Measurement Information System-Physical Function [PROMIS-PF]), worst stiffness (using Worst Stiffness Numeric Rating Scale [NRS]), quality of life (using EuroQol Visual Analogue Scale [EQ-VAS]) and worst pain responder (using Brief Pain Inventory [BPI]). The results from patient-reported outcome measures resulted in clinically meaningful and statistically significant improvements at Week 25 in all efficacy parameters and are presented in Table 3.
Table 3: Efficacy results assessed at Week 25
| Efficacy parameter | Vimseltinib N = 83 | Placebo N = 40 |
| Primary endpoint | ||
| Overall response rate per RECIST v1.1 | ||
| Baseline mean (SD) sum of longest diameters, mm | 69.1 (42.6) | 64.5 (30.8) |
| ORR (95% CI) | 40% (29%, 51%) | 0% (0%, 9%) |
| Complete response | 5% | 0% |
| Partial response | 35% | 0% |
| p-value | < 0.0001 | |
| Duration of response median (range), months1,2 | NR (2.5+, 30.9+) | N/A |
| Key secondary endpoints | ||
| Overall response rate per tumour volume score3 | ||
| Baseline mean (SD) tumour volume score | 10.4 (14.2) | 12.8 (17.7) |
| ORR (95% CI) | 67% (56%, 77%) | 0% (0%, 9%) |
| p-value | < 0.0001 | |
| Duration of response median (range), months1,2 | NR (2.5+, 33.1+) | N/A |
| Active ROM4 | ||
| Baseline mean (SD) active ROM, % points5 | 63.0 (29.4) | 62.9 (32.2) |
| LS Mean change from baseline in active ROM (95% CI)5 | 18.4 (5.6, 31.2) | 3.8 (-10.5, 18.0) |
| Difference in LS Means (95% CI) | 14.6 (4.0, 25.3) | |
| p-value | 0.0077 | |
| PROMIS-PF | ||
| Baseline mean (SD) PROMIS-PF5 | 39.0 (6.1) | 38.5 (6.0) |
| LS Mean change from baseline in PROMIS-PF (95% CI)5 | 4.6 (2.7, 6.5) | 1.3 (-0.5, 3.0) |
| Difference in LS Means (95% CI) | 3.3 (1.4, 5.2) | |
| p-value | 0.0007 | |
| Worst stiffness NRS | ||
| Baseline mean (SD) worst stiffness NRS5 | 5.1 (2.0) | 5.2 (1.8) |
| LS Mean change from baseline in worst stiffness NRS (95% CI)5 | -2.1 (-2.5, -1.6) | -0.3 (-0.8, 0.3) |
| Difference in LS Means (95% CI) | -1.8 (-2.5, -1.1) | |
| p-value | < 0.0001 | |
| EQ-VAS | ||
| Baseline mean (SD) EQ-VAS5 | 61.4 (19.5) | 60.2 (20.6) |
| LS Mean change from baseline in EQ-VAS (95% CI)5 | 13.5 (8.9, 18.2) | 6.1 (0.5, 11.8) |
| Difference in LS Means (95% CI) | 7.4 (1.4, 13.4) | |
| p-value | 0.0155 | |
| BPI-30 response6 | ||
| Response rate (95% CI) | 48.2% (37.1%, 59.4%) | 22.5% (10.8%, 38.5%) |
| Difference in responder rate (95% CI)7 | 26.2% (9.5%, 42.8%) | |
| p-value | 0.0056 | |
NR = Not reached; N/A = Not applicable; BPI = Brief Pain Inventory; CI = confidence interval; LS = least squares; N = sample size; PROMIS-PF = Patient-Reported Outcomes Measurement Information System-Physical Function; ROM = range of motion; SD = Standard deviation. 1 The median duration of response (DOR) was estimated using the Kaplan-Meier method. “+” indicates that the patient`s response was ongoing at last assessment as of the data cutoff date. DOR results are based on an additional 18 months of follow-up from the time of ORR analysis.
2 Data cut-off date: 22 February 2025.
3 TVS was defined as the estimated volume of maximally distended synovial cavity or tendon sheath involved, measured in 10% increments.
4 Active ROM was assessed using a goniometer and was normalised to a reference standard.
5 Mean change from baseline was estimated from the mixed model of repeated measures (MMRM) for each corresponding endpoint. Baseline means presented include all participants and not only the ones with data at baseline and Week 25. 6 BPI response in worst pain is defined as at least a 30% improvement in the mean BPI worst pain NRS score without a 30% or greater increase in narcotic analgesic use at Week 25.
7 95% CI for the difference in response rates based on the stratified Mantel-Haenszel method.
In a descriptive analysis conducted at Week 97 in the open-label phase of the study, 19 of 83 patients randomised to vimseltinib (23%) had a best overall response of CR according to RECIST v1.1, as assessed by blinded IRR, with a median time to CR of 11.5 months.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with ROMVIMZA in all subsets of the paediatric population in the treatment of tenosynovial giant cell tumour (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Vimseltinib reaches peak plasma concentrations at a median of 1 hour after oral administration of single 30 mg dose of vimseltinib under fasted conditions. Vimseltinib pharmacokinetic (PK) parameters estimated by population PK (popPK) model and provided as geometric mean (coefficient of variation [%]; CV%), were determined following a single oral dose of 30 mg or at steady state following multiple doses of 30 mg twice weekly in TGCT patients. Vimseltinib Cmax is 283 ng/mL (36%) or 747 ng/mL (39%) after a 30 mg single dose or at steady state, respectively, AUC0-inf is 46.9 µg*h/mL (45%) after a single dose and AUC0-24 h is 13.4 µg*h/mL (45%) at steady state. Steady state plasma concentrations were similar in patients and healthy volunteers and were achieved after approximately 5 weeks with an accumulation ratio of 2.6.
No clinically significant differences in vimseltinib pharmacokinetics were observed following administration of a high-fat meal, compared to fasted conditions.
Distribution
The geometric mean (CV%) apparent volume of distribution (Vz/F) of vimseltinib is 90 L (16%). Vimseltinib is 96.5% bound to human plasma proteins in vitro.
Biotransformation
Vimseltinib has no major circulating metabolite. Primary metabolism occurred by oxidation, N-demethylation, and N-dealkylation; secondary biotransformation pathways included N-demethylation, dehydrogenation and oxidation.
CYPs are not anticipated to play a major role in vimseltinib’s metabolism.
Elimination
The geometric mean (geometric CV%) apparent clearance (CL/F) of vimseltinib is 0.5 L/h (23%) with an elimination half-life of approximately 6 days following single-dose administration.
Approximately 43% of the dose was recovered in faeces (9.1% unchanged) and 38% in urine (5.1% unchanged) after a single oral radiolabelled dose.
Dose proportionality
Vimseltinib pharmacokinetics are dose proportional.
Special populations
No clinically relevant differences in the pharmacokinetics of vimseltinib were observed based on age (20 to 91 years), sex, race (Asian, Black or African American, White) and body weight (43 to 150 kg).
Renal impairment
Based on a popPK analysis, no significant differences in the pharmacokinetics of vimseltinib were observed in subjects with mild renal impairment (eGFR ≥
60 mL/min) compared to subjects with normal renal function. Based on limited data, popPK estimated 8% and 27% higher Cmax,ss and Cavg,ss in patients with moderate renal impairment, respectively, but this increase in exposure is not considered clinically relevant. No clinical data are available in patients with severe renal impairment.
Hepatic impairment
In subjects with mild hepatic impairment (Child-Pugh A), AUCinf was 24% lower and Cmax was 41.5% lower than in matched healthy participants. This reduction in exposure is not considered clinically relevant. PopPK and
Pharmacokinetics/Pharmacodynamics (PKPD) modelling estimated that a dose reduction to 14 mg twice weekly in patients with mild hepatic impairment may result in reduced response. No clinical data are available. The effect of moderate to severe hepatic impairment (Child-Pugh B and C) on vimseltinib pharmacokinetics is unknown.
Body weight
PopPK and PKPD modelling estimated that a dose reduction to 14 mg twice weekly in patients with a body weight of ≥
115 kg may result in reduced response. No clinical data are available.
In vitro findings related to metabolism
In vitro data in human hepatocytes showed that vimseltinib caused a concentration-dependent reduction of CYP1A2 mRNA expression by > 50%, suggesting a down-regulation phenomenon. The clinical relevance of this finding is currently unknown.
5.3 Preclinical safety data
Carcinogenicity
Vimseltinib was not carcinogenic in an oral 6-month transgenic mouse carcinogenicity study at systemic exposures up to 7.6-times the vimseltinib exposure at the recommended human dose based on AUC.
In a 2-year oral rat carcinogenicity study, 2 out of 60 high dose males were identified as having histomorphologically different sarcomas in the synovium of the femorotibial joint at exposures approximately < 1 and 1.4 times (unbound and total, respectively) the recommended human dose based on AUC. Both were classified as sarcoma, not otherwise specified. The relevance of this finding to humans is unknown but considering all available clinical and nonclinical data the carcinogenic risk after vimseltinib administration is considered low.
Developmental and reproductive toxicity
Vimseltinib toxicity was observed in a fertility and early embryonic development study in female rats at approximately 1.6-times the unbound vimseltinib exposure at the recommended human dose based on AUC. Post-implantation loss and increased uterine weights were observed at approximately 6-times the unbound vimseltinib exposure at the recommended human dose based on AUC. There were no treatment-related effects on mating, fertility, or pregnancy indices, and estrous cycles at any dose level tested. Male rats had lower epididymal and testes weights at approximately 3.6-times the unbound vimseltinib exposure at the recommended human dose based on AUC and there were no treatment-related effects on mating, fertility, or sperm parameters at any dose tested.
Administration of vimseltinib in rats resulted in foetal abnormalities of the cardiovascular (malformations) and skeletal (variations) systems, as well as additional indications of developmental toxicity, at a maternal exposure approximately 7- and 0.9-times the unbound vimseltinib exposure at the recommended human dose based on AUC.
In the pre- and postnatal developmental toxicity study, maternal mortality, total litter losses, reduced fetal body weights, and lower mean pup survival were observed at approximately 1.7-times the unbound vimseltinib exposure at the recommended human dose based on AUC. Total litter loss was also reported in groups treated at doses corresponding to unbound vimseltinib exposures lower than those at the recommended human dose.
In a 26-week repeat-dose toxicity study, recovery male rats that were administered 2.5 or 5 mg/kg/day had moderate to marked reductions in sperm and marked testicular atrophy (1 of 5 and 2 of 5 animals, respectively) corresponding to approximately 1.8 and 3.6-times the unbound vimseltinib exposure at the recommended human dose based on AUC, respectively. In a 39-week repeat-dose toxicity study, minimal to moderate epididymal mineralisation occurred in male dogs administered ≥
4 mg/kg/day corresponding to exposures lower than the exposure at the recommended human dose based on AUC.
Repeat-dose toxicity
In repeat-dose toxicity studies of up to 26 weeks in rats, there were findings of swollen head and/or limbs, and abnormal teeth at doses of 1 mg/kg/day (approximately 0.96-times the unbound vimseltinib exposure at the recommended human dose based on AUC). The dental effects at doses of 5 mg/kg/day in male rats were associated with lower food consumption and reduced body weight. Chronic progressive nephropathy occurred in animals receiving ≥
2.5 mg/kg/day (approximately ≥
1.8-times the unbound vimseltinib exposure at the recommended human dose based on AUC). Degeneration of blood vessels in multiple tissues and increased physis thickness was observed in rats receiving 5 mg/kg/day (approximately 4-times the unbound vimseltinib exposure at the recommended human dose based on AUC).
Low recovery of total radioactivity in mass balance studies and slow elimination of vimseltinib are indicative of potential tissue accumulation. In a rat distribution study, prolonged retention of vimseltinib in eye uveal tract, eye(s), eye vitreous humor, and meninges due to melanin binding was observed. No CNS effects were noted in dogs up to the highest tested dose of 8 mg/kg corresponding to exposure below the anticipated clinical exposure at the recommended human dose. Therefore, clinical relevance of potential accumulation of vimseltinib in meninges remains unknown. Periocular swelling and epiphora observed in dogs at 8 mg/kg at exposures below the expected exposure in humans may be related to prolonged retention of vimseltinib in ocular tissues.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule content
Lactose monohydrate
Crospovidone (E 1202)
Magnesium stearate (E 470b)
Capsule shell
Gelatin
Titanium dioxide (E 171)
Sunset yellow FCF (E 110)
Printing ink
Shellac (E 904)
Propylene glycol (E 1520)
Potassium hydroxide (E 525)
Black iron oxide (E 172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
oPA/Aluminium foil/PVC-film blister with push-through aluminium foil lidding sealed into a child-resistant cardboard wallet pack containing 8 hard capsules. One carton contains one wallet.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Deciphera Pharmaceuticals (Netherlands) B.V.
Strawinskylaan 3051
1077 ZX, Amsterdam
Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 55295/0005
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/08/2026
10 DATE OF REVISION OF THE TEXT
14/08/2026