Safety profile with ONTOZRY^®▼ (cenobamate)

C017 was a multicentre, randomised, double-blind, placebo-controlled dose-response study.

Safety results from the double-blind phase:

• Most TEAEs were mild or moderate in severity
• Patients who had at least one TEAE:
  • 70% (76 of 108) in the placebo group
  • 65% (70 of 108) in the 100 mg ONTOZRY^® group
  • 76% (84 of 110) in the 200 mg ONTOZRY^® group
  • 90% (100 of 111) in the 400 mg ONTOZRY^® group
• The most frequent (≥10%) TEAEs with ONTOZRY^®: somnolence, dizziness, headache, fatigue, and diplopia
• 37 serious TEAEs in 28 patients, with those occurring in >1 patient in any group: seizures (n=2), ataxia (n=2), dizziness (n=2), nystagmus (n=2), and suicidal ideation (n=2)
  • One suicide attempt occurred
• TEAEs leading to discontinuation occurred in 53 patients, with the most common being (>1 patient in any group): ataxia (n=7), dizziness (n=4), somnolence (n=5), nystagmus (n=3), and vertigo (n=3)
• Hypersensitivity reactions* occurred in 3 patients (all 3 patients recovered following discontinuation): drug reaction with eosinophilia and systemic symptoms (DRESS), pruritic rash with pyrexia, rash and facial swelling (all n=1)
• There were no deaths

Open-label extension (OLE)

Patients who completed the 18-week double-blind study (n=360) could enter the OLE. The safety population comprised 355 patients (265 originally randomised to ONTOZRY^®, 90 originally randomised to placebo).

Safety results from the OLE

• TEAEs occurred in 88.2% (313/355) of patients during the OLE⁵
• TEAEs reported in ≥10% of patients in any group were: dizziness, somnolence, fatigue, headache, diplopia, gait disturbances, and upper respiratory tract infection⁵
• Commonly reported TEAEs most frequently occurred during the first month of treatment during the OLE conversion
• Serious TEAEs occurred in 20.3% (n=72/355) of patients; seizure (n=5) and vertigo (n=4) were the only serious TEAEs reported in >1% of patients
• One event of sudden unexplained death in epilepsy (SUDEP) occurred
• TEAEs leading to ONTOZRY^® discontinuation occurred in 8.7% (n=31/355) of patients:
  • Nervous system disorders (n=12); dizziness (n=3), somnolence (n=2), balance disorder (n=2), and depression (n=2)
  • Psychiatric disorders (n=6): depression (n=2), and bradyphrenia, hallucination, persistent depressive disorder, and psychotic disorder (all n=1)
  • Skin and subcutaneous tissue disorders (n=6): alopecia, angioedema, pruritus, maculopapular rash, skin lesion, and toxic skin eruption (all n=1)
  • Others occurring in >1 patient: infections and infestations (n=2), and eye disorders (n=2)
• At data cut-off, 6 deaths had been reported in the OLE (pneumonia/sepsis, septicaemia, fatal injuries after being struck by a car, cardiogenic shock, myocardial infarction, and suicide. All were considered to be unrelated to the study drug by the investigator)

Footnotes: *Hypersensitivity reactions characterised as rash with involvement of ≥1 other body system.

C013 was a multicentre, randomised, double-blind, placebo-controlled efficacy and safety study.⁶

Safety results during the double-blind phase:⁶

• Most TEAEs were mild or moderate in severity
• The most frequently (>10%) reported TEAEs for ONTOZRY^® were:
  • Somnolence (22.1%)
  • Dizziness (22.1%)
  • Headache (12.4%)
  • Nausea (11.5%)
  • Fatigue (10.6%)
• Five patients discontinued due to adverse events AEs: tachycardia, gastroesophageal reflux disease, drug hypersensitivity, nystagmus, aggression, depression, and dyspnoea (some patients had >1 AE)
• Serious TEAEs were reported in 2 ONTOZRY^®-treated patients: drug hypersensitivity reaction, and urinary tract infection (n=1 each)
• No other serious dermatological TEAEs, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS) or Stevens-Johnson syndrome, were reported
• No deaths occurred during the double-blind treatment period

Supportive study (C013) Open label extension (OLE)⁷

Patients who completed the 12-week double-blind study were eligible for the OLE (n=149).⁷ At the data cut-off, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years).⁷

Safety results during the 7.8-year duration of the OLE:⁷

• TEAEs were primarily mild or moderate and occurred in 89.3% (133/149) of patients
• Most frequently reported TEAEs: dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149)
• Serious TEAEs occurred in 25.5% (38/149), with the most frequent (>1% of patients): seizure (n=6) and vomiting, pneumonia, sepsis, and osteoarthritis (all n=2)
• There were three deaths during the OLE: SUDEP, cardiac arrest, and suicide (all n=1)
• TEAEs leading to discontinuation were reported in 10.1% (15/149) of patients, with the most frequent (>1% of patients): fatigue (1.3%, n=2), ataxia (1.3%, n=2), and memory impairment or amnesia (1.3%, n=2)

C021 was an open-label Phase III safety study in 1347 adults with uncontrolled focal seizures taking stable doses of 1-3 ASMs.⁴ ONTOZRY^® was initiated at 12.5 mg/day and increased at 2-week intervals to 25, 50, 100, 150, and 200 mg/day. Additional biweekly 50 mg/day increases to 400 mg/day were allowed.⁴

Safety results (interim analysis)⁴

• The majority (77.8%, 1042/1339) of TEAEs were mild or moderate in severity
• At least one TEAE was reported in 84.2% of patients (1128/1339), with the most common being somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%)
  • Skin and subcutaneous tissue disorders were reported in 189 patients (14.1%)
• Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n=14), epilepsy (n=5), and pneumonia, fall, and dizziness (n=4 each)
  • Other serious TEAEs reported in >2 patients: fall, pneumonia, and dizziness (n=4 each); vomiting, appendicitis, mental status change, suicide attempt, and papular rash (n=3 each)
  • Serious skin and subcutaneous tissue disorders occurred in six patients: allergic dermatitis, erythema, rash, maculopapular rash, facial swelling, and urticaria (n=1 each)
• Psychiatric AEs occurring in ≥1% of patients: anxiety (n=31), irritability (n=29), insomnia (n=27), depression (n=26), and confusional state (n=16)
• At data cut-off, four deaths had been reported (sudden death, intracerebral haemorrhage after a fall, fatal injuries after being struck by a car, and respiratory failure in a patient with Angelman syndrome)
• TEAEs leading to discontinuation were reported in 11% (n=147) of patients and mostly occurred during the titration period; the most common were:
  • Nervous system disorders (n=45): dizziness (n=14), seizure (n=9), and somnolence (n=9)
  • Skin and subcutaneous tissue disorders (n=44): rash (n=9), rash erythematous, papular rash, pruritus, and urticaria (all n=3)
  • One patient discontinued due to a TEAE of hypersensitivity
• No cases of DRESS were identified

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products in several indications, including cenobamate. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for ONTOZRY®. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered.^1,2

Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.^1,2

 See the Summary of Product Characteristics for full prescribing information.^1,2

Drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, has been reported in association with ONTOZRY^® when started at higher doses and titrated rapidly (weekly or faster titration). When cenobamate was initiated at 12.5 mg/day and titrated every two weeks, in an open-label safety study of 1340 epilepsy patients (study C021), no cases of DRESS were reported.^1,2

At the time of prescription, patients should be advised of the signs and symptoms of DRESS and monitored closely for skin reactions. Symptoms of DRESS typically, although not exclusively, include fever, rash associated with other organ system involvement, lymphadenopathy, liver function test abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If signs and symptoms suggestive of these reactions appear, ONTOZRY^® should be withdrawn immediately and an alternative treatment considered (as appropriate).^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

A dose-dependent shortening of the QTcF interval has been observed with ONTOZRY®. Reductions of the QTcF interval below 340 msec were not observed. In clinical trials there was no evidence that the combination of ONTOZRY^® with other anti-epileptic medicines led to further QT-shortening. Use caution when prescribing cenobamate in combination with other medicinal products that are known to shorten the QT.^1,2

Familial Short QT syndrome is a rare genetic syndrome, which is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Cenobamate must not be used in patients with Familial Short-QT syndrome.^1,2

 See the Summary of Product Characteristics for full prescribing information.^1,2

Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

ONTOZRY^® should be used with caution and reduction of the target dose may be considered in patients with mild to moderate (creatinine clearance 30 to <90 ml/min) or severe (creatinine clearance <30 ml/min) renal impairment. The maximum recommended dose for patients with mild, moderate, or severe renal impairment is 300 mg/day. ONTOZRY^® should not be used in patients with end-stage renal disease or patients undergoing haemodialysis.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

Exposure to ONTOZRY^® was increased in patients with chronic hepatic disease. A change in the starting dose is not required; however, a decrease in target doses of up to 50% may need to be considered. The maximum recommended dose in patients with mild and moderate hepatic impairment is 200 mg/day. ONTOZRY^® should not be used in patients with severe hepatic impairment.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

A 45% decrease in exposure has been estimated across a body weight range from 54 kg to 112 kg. This variability is not considered to be clinically relevant when establishing a dose of cenobamate. However, cenobamate dose adjustments may need to be considered in patients who experience weight changes of ≥30% of their initial body weight, or more.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

Clinical studies of ONTOZRY^® did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger patients. It has been reported that elderly subjects on anti-epileptic medicinal products have a higher incidence of adverse reactions such as fatigue, gait disturbance, fall, ataxia, balance disorder, dizziness and somnolence. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or renal function and of concomitant disease as well as the potential interactions in polymedicated patients.^1,2 No clinically significant differences in the pharmacokinetics of cenobamate were observed based on age based on data from subjects aged 18 years to 77 years.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

Women of childbearing potential and contraception in males and females

Cenobamate is not recommended in women of childbearing potential not using contraception. Women of reproductive potential concomitantly using oral contraceptives should practise additional or alternative non-hormonal measures of birth control during treatment with cenobamate and until 4 weeks after treatment discontinuation.^1,2

Pregnancy

Risk related to epilepsy and anti-epileptic medicinal products in general

It has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.^1,2

Risk related to cenobamate

There are no adequate data from the use of ONTOZRY® in pregnant women. Animal studies have shown that cenobamate crosses the placenta of rats. Studies in animals have shown reproductive toxicity at levels below clinical exposure. ONTOZRY® should not be used during pregnancy unless the clinical condition of the woman requires treatment with cenobamate. Women of childbearing potential must use effective contraception during use of cenobamate and until 4 weeks after treatment discontinuation.^1,2

Breast-feeding

It is unknown whether cenobamate or its metabolites are excreted in human milk. Studies in rats showed excretion of cenobamate in the maternal milk. A risk to the suckling child cannot be excluded. As a precautionary measure, breast-feeding should be discontinued during treatment with ONTOZRY^®.^1,2

Fertility

The effects of cenobamate on human fertility are unknown. Animal data are insufficient due to exposure below clinical levels.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

Safety and effectiveness of ONTOZRY^® in patients less than 18 years of age has not been established. No data are available.^1,2

See the Summary of Product Characteristics for full prescribing information.^1,2

Familial Short QT syndrome is a rare genetic syndrome, which is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Cenobamate must not be used in patients with Familial Short-QT syndrome.^1,2

 See the Summary of Product Characteristics for full prescribing information.^1,2

• Lactose monohydrate
• Magnesium stearate (E470b)
• Microcrystalline cellulose (E460)
• Silica, colloidal anhydrous (E551)
• Sodium starch glycolate

25 mg and 100 mg film-coated tablets

• indigo carmine aluminium lake (E132)
• iron oxide red (E172)
• iron oxide yellow (E172)
• macrogol
• partially hydrolysed poly(vinyl alcohol) (E1203)
• talc (E553b)
• titanium dioxide (E171)

50 mg film-coated tablets

• iron oxide yellow (E172)
• macrogol
• partially hydrolysed poly(vinyl alcohol) (E1203)
• talc (E553b)
• titanium dioxide (171)

150 mg and 200 mg film-coated tablets

• iron oxide red (E172)
• iron oxide yellow (E172)
• macrogol
• partially hydrolysed poly(vinyl alcohol) (E1203)
• talc (E553b)
• titanium dioxide (E171)