RAYVOW Film-coated tablet Ref.[112844] Active ingredients: Lasmiditan

Central nervous system (CNS) effects and driving impairment

Lasmiditan is associated with CNS adverse reactions. In a simulated driving study in healthy subjects, lasmiditan significantly impaired the ability to drive (see section 4.7). Patients should be advised not to drive or engage in other activities requiring heightened attention until at least 8 hours after taking each dose of lasmiditan, even if they feel well enough to do so. Patients who cannot follow this advice should not take lasmiditan.

Serotonin syndrome

Serotonin syndrome has been reported and may occur with lasmiditan or when administered with other serotonergic medicinal products [e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors]. Clinical experience for the use of lasmiditan and triptans in temporal proximity is limited. The risks of developing serotonin syndrome may be additive. Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (e.g. hyperreflexia, incoordination), and/or gastrointestinal signs and symptoms (e.g. nausea, vomiting, diarrhoea). These reactions can be severe. The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medicinal product. If concomitant treatment with other serotonergic medicinal products is clinically warranted, appropriate observation of the patient is advised, particularly during treatment initiation, and with dose increases. Lasmiditan should be discontinued if serotonin syndrome is suspected.

CNS depressants

Because of the potential of lasmiditan to cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions, lasmiditan should be used with caution if used in combination with alcohol or other CNS depressants.

Medicinal products misuse or abuse potential

In a human abuse potential study with recreational drug users, single lasmiditan doses of 100 or 200 mg were associated with greater drug-liking than placebo. In a separate study, there was no evidence of physical withdrawal in healthy subjects following abrupt cessation after 7 days of dosing. Patients should be evaluated for risk of drug abuse and observed for signs of lasmiditan misuse or abuse.

Medication overuse headache (MOH)

Overuse of any type of medicinal products for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained, and treatment should be discontinued. The diagnosis of MOH should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medicinal products.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Heart rate lowering medicinal products

Lasmiditan has been associated with a lowering of heart rate (HR). Propranolol and lasmiditan together decreased HR by a mean maximum of 19.3 beats per minute (bpm), i.e., an additional lowering of 5.1 bpm compared to propranolol alone. This should be taken into consideration for patients in whom these magnitudes of HR decrease may pose a concern, including patients taking medicinal products that lower heart rate.

Serotonergic medicinal products

Concomitant administration of lasmiditan and medicinal products (e.g., SSRIs, SNRIs, TCAs) that increase serotonin may increase the risk of serotonin syndrome. Clinical experience for the use of lasmiditan and triptans in temporal proximity is limited. The risks of developing serotonin syndrome may be additive. Caution is advised (see section 4.4).

Potential for lasmiditan to affect other medicinal products

Daily dosing of lasmiditan did not alter the PK of midazolam, caffeine, or tolbutamide, which are substrates of CYP3A, CYP1A2, and CYP2C9, respectively. Coadministration of lasmiditan with sumatriptan (MAO-A and OCT1 substrate) or propranolol (CYP2D6 substrate) resulted in no clinically meaningful changes in exposure of these medicinal products. Following a single dose of lasmiditan, creatinine renal clearance over 24 hours decreased slightly (11%) compared with placebo, without changes in glomerular filtration rate (GFR).

Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). In a drug interaction study, lasmiditan increased the systemic exposure of coadministered dabigatran (P-gp substrate) by approximately 25%. Therefore, when RAYVOW is administered with P-gp substrates that have a narrow therapeutic index (such as digoxin), increases in the systemic exposure of the coadministered medication may be clinically meaningful (see section 5.2). In the same study, no significant change in rosuvastatin (BCRP substrate) PK was observed when it was coadministered with lasmiditan.

Potential for other medicinal products to affect lasmiditan

No change in lasmiditan PK was observed when coadministered with dabigatran etexilate, rosuvastatin, sumatriptan, or propranolol. Based on its metabolism clearance pathways, CYP inhibitors or inducers are unlikely to affect lasmiditan exposure and no change in lasmiditan PK was observed when coadministered with topiramate (CYP3A4 inducer and CYP2C19 inhibitor).

Pregnancy

There is a limited amount of data from the use of lasmiditan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The effects of lasmiditan on human foetal development are not known. RAYVOW is not recommended during pregnancy.

Breast-feeding

Lasmiditan and/or its metabolites were excreted into the milk of lactating rats (see section 5.3). There are no data on the presence of lasmiditan in human milk, the effects of lasmiditan on the breastfed infant, or the effects of lasmiditan on milk production.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from RAYVOW therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Exposure of the newborn can be minimised by avoiding breast-feeding for 24 hours after treatment.

Fertility

It is unknown whether lasmiditan affects human reproductive potential. Animal studies do not indicate any effect on fertility (see section 5.3).

Lasmiditan has major influence on the ability to drive and use machines. Driving performance was evaluated using a computer-based driving simulation. The primary outcome measure was the difference from placebo in the Standard Deviation of Lateral Position (SDLP), a measure of driving performance. Administration of single 50 mg, 100 mg, or 200 mg doses of lasmiditan significantly impaired subjects' ability to drive 90 minutes after dosing. In another study of lasmiditan 100 mg or 200 mg, driving performance did not reach the threshold for driving impairment at 8 hours or later after administration of RAYVOW at either dose.

Patients should be advised not to engage in activities requiring heightened attention, such as operating machinery or driving, for at least 8 hours after taking each dose of lasmiditan, even if they feel well enough to do so. Patients who cannot follow this advice should not take lasmiditan (see section 4.4).

Summary of the safety profile

The most commonly occurring adverse reactions are dizziness (19.9%), somnolence (7.8%), fatigue (7.7%), paraesthesia (6.8%), nausea (4.9%), vertigo (2.6%), hypoaesthesia (2.5%), and muscular weakness (2.3%). Most of the adverse events showed a dose response.

Tabulated list of adverse reactions

In the following table, adverse reactions are listed in order of MedDRA body system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequency gradings are: 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).

Table 1. Adverse reactions:

Description of selected adverse reactions

Heart rate decrease

In clinical pharmacology studies, lasmiditan was associated with decreases in heart rate of 5 to 10 bpm compared to a decrease of 2-5 bpm for placebo. Incidence of bradycardia (<50 bpm and a decrease from baseline ≥15 bpm) observed in lasmiditan-treated subjects was 7% for 50 mg, 3% for 100 mg, 4% for 200 mg, and 1% for placebo.

Blood pressure increase

Single dose administration of lasmiditan may lead to a transient increase in blood pressure. In non-elderly healthy volunteers a mean increase from baseline in ambulatory systolic and diastolic blood pressure of approximately 2 to 3 mm Hg one hour after administration of 200 mg lasmiditan was observed, compared to an increase of about 1 mm Hg for placebo. In healthy volunteers over 65 years of age, the mean increase from baseline in ambulatory systolic blood pressure was 7 mm Hg one hour after administration of 200 mg lasmiditan compared to a mean increase of 4 mm Hg for placebo. By 2 hours, there were no increases in mean blood pressure with lasmiditan compared to placebo. Clinical data for the use of lasmiditan in patients with ischemic heart disease is limited.

Hypersensitivity

Events of hypersensitivity, including angioedema, rash, and photosensitivity reaction, occurred in patients treated with lasmiditan. In clinical trials, hypersensitivity was reported in 0.1% of patients treated with lasmiditan compared to no patients in the placebo group; all events were mild to moderate in severity and occurred within minutes to a day after dosing with lasmiditan. If a serious or severe hypersensitivity reaction occurs, appropriate therapy should be initiated and administration of lasmiditan should be discontinued.

Dizziness

In clinical trials, dizziness was the most common adverse reaction, reported in 19.9% of patients. It was generally mild to moderate in severity (severe dizziness 1.2%) and self-limiting with a median time to onset of 0.7 hours and a median duration of 2 hours. No accidents or injuries were reported in patients reporting dizziness. The frequency of patients reporting dizziness, and other common adverse events, typically decreases with repeat dosing.

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 national reporting system listed in Appendix V.

Not applicable.