Fintepla

/ Medison

Without concomitant stiripentol
Day 0 (Starting dose): 0.1 mg/kg taken twice daily
Day 7: 0.2 mg/kg twice daily
Day 14: 0.35 mg/kg twice daily
Maximal recommended daily dose: 26 mg (13 mg twice daily, i.e., 6.0 mL twice daily)
With concomitant stiripentol (DS patients only)
Day 0 (Starting dose): 0.1 mg/kg taken twice daily
Day 7: Maintenance dose of 0.2 mg/kg twice daily
Day 14: Not applicable
Maximal recommended daily dose: 17 mg (8.6 mg twice daily, i.e., 4.0 mL twice daily)
To calculate the dose volume up to the maximal recommended dose, you must use the formula: Weight (kg) x Weight-based dosage (mg/kg) ÷ 2.2 mg/ml = ml dose to be taken twice daily.
The calculated dose should be rounded to the nearest graduated increment.
See prescribing information for full details.

Treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older.

* Hypersensitivity to the active substance or any of the excipients
* Aortic or mitral valvular heart disease
* Pulmonary arterial hypertension
* Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk of serotonin syndrome

Risk Management Plan
A risk management plan has been created to
1) prevent off-label use in weight management in obese patients and
2) confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring.
Potential for Abuse and Dependence
Fenfluramine is an amphetamine-like structure product. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy.
Aortic or mitral valvular heart disease and pulmonary arterial hypertension
Because of reported cases of valvular heart disease and pulmonary arterial hypertension that may have been caused by fenfluramine at higher doses used to treat adult obesity, cardiac monitoring must be performed using echocardiography. Neither pulmonary arterial hypertension nor valvular heart disease were observed during these studies.
However, post-marketing data show that they can also occur with doses used to treat Dravet syndrome and Lennox-Gastaut syndrome.
Patients must undergo an echocardiogram to establish a baseline prior to
initiating treatment and exclude any pre-existing valvular heart disease or pulmonary
hypertension.
Echocardiogram monitoring should be conducted every 6 months for the first 2 years and annually thereafter. If an echocardiogram indicates pathological valvular changes, a follow-up echocardiogram should be considered at an earlier timeframe to evaluate whether the abnormality is persistent. If pathological abnormalities on the echocardiogram are observed, it is recommended to evaluate the benefit versus risk of continuing fenfluramine treatment.
If echocardiogram findings are suggestive of pulmonary arterial hypertension, a repeat echocardiogram should be performed as soon as possible and within 3 months to confirm these findings. If the echocardiogram finding is confirmed suggestive of an increased probability of pulmonary arterial hypertension defined as “intermediate probability” by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Guidelines, it should lead to a benefit-risk evaluation of continuation. If the echocardiogram finding, after confirmation, suggests of a high probability of pulmonary arterial hypertension, as defined by the ESC and ERS Guidelines, it is recommended fenfluramine treatment should be stopped.
Decreased appetite and weight loss
An additive effect on decreased appetite can occur when fenfluramine is combined with other anti-epileptic medicines, for example stiripentol. The decrease in weight appears to be dose related. Most subjects resumed weight
gain over time while continuing treatment. The patient’s weight should be monitored. A benefit risk evaluation should be undertaken prior to commencing treatment with fenfluramine in patients with a history of anorexia nervosa or bulimia nervosa.
Suicidal behaviour and ideation
Patients and caregivers of patients should be advised to seek medical advice should any signs of suicidal behaviour and ideation emerge.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); with agents that impair metabolism of serotonin such as MAOIs; or with antipsychotics that may affect the serotonergic neurotransmitter systems.
Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea).
If concomitant treatment with fenfluramine and other serotonergic agents that may affect the serotonergic systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. If serotonin syndrome is suspected, a dose reduction or discontinuation of the therapy with fenfluramine and/or other serotonergic agents should be considered.
Increased seizure frequency
As with other anti-epileptic medicines, a clinically relevant increase in seizure frequency may occur during treatment with fenfluramine, which may require adjustment in the dose of fenfluramine and/or concomitant anti-epileptic medicines, or discontinuation of fenfluramine, should the benefit-risk be negative.
Cyproheptadine
Cyproheptadine is a potent serotonin receptor antagonist and may therefore decrease the efficacy of fenfluramine. If cyproheptadine is added to treatment with fenfluramine, patients should be monitored for worsening of seizures. If fenfluramine treatment is initiated in a patient taking cyproheptadine, fenfluramine’s efficacy may be reduced.
Glaucoma
Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Discontinue therapy in patients with acute decreases in visual acuity. Consider discontinuation if there is ocular pain and another cause cannot be determined.
Effect of CYP1A2 and CYP2B6 inducers
Coadministration with strong CYP1A2 inducers or CYP2B6 inducers will decrease fenfluramine plasma concentrations, which may lower the efficacy of fenfluramine.
If coadministration of a strong CYP1A2 or CYP2B6 inducer with fenfluramine is considered necessary, the patient should be monitored for reduced efficacy and a dose increase of fenfluramine could be considered provided that it does not exceed twice the maximum daily dose (52 mg/day). If a strong CYP1A2 or CYP2B6 inducer is discontinued during maintenance treatment with fenfluramine, consider gradual
reduction of the fenfluramine dosage to the dose administered prior to initiating the inducer.
Effect of CYP1A2 or CYP2D6 inhibitors
Initiation of concomitant treatment with a strong CYP1A2 or CYP2D6 inhibitor may result in higher exposure and, therefore, adverse events should be monitored, and a dose reduction may be needed in some patients. Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0-t of fenfluramine by a ratio of 2.1-fold and the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t of norfenfluramine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared to fenfluramine administered alone.
See prescribing information for full details.

Very common: Decreased appetite, Somnolence, Diarrhoea, Fatigue
Common: Bronchitis, Abnormal behaviour, Aggression, Agitation, Insomnia, Mood swings, Ataxia, Hypotonia, Lethargy, Seizure, Status epilepticus, Tremor, Rash, Constipation, Salivary, Hypersecretion, Vomiting, Weight decreased, Blood glucose Decreased, Blood prolactin increased.
See prescribing information for full details

Pharmacodyamic interactions
Pharmacodynamic interactions with other central nervous system depressants increase the risk of aggravated central nervous system depression.
Pharmacokinetic interactions
Effect of rifampicin
(a strong inducer of CYP3A and 2C19 and a moderate inducer of CYP1A2, 2B6, 2C8
and 2C9), or strong CYP1A2 or CYP2B6 inducers Rifampicin induces multiple CYP enzymes which metabolize fenfluramine and norfenfluramine. Coadministration of a single 0.354 mg/kg dose of fenfluramine with rifampicin at steady state (600 mg once daily) in healthy volunteers decreased the AUC0–t of fenfluramine by 58% and the Cmax by 40%, and decreased the AUC0-t of norfenfluramine by 50%, and increased the Cmax of norfenfluramine by 13%, as compared to fenfluramine administered alone.
An increase in fenfluramine dose may be necessary when coadministered with rifampicin or a strong CYP1A2 or CYP2B6 inducer.
See prescribing information for full details.

Pregnancy: There are limited data (less than 300 pregnancy outcomes) from the use of fenfluramine in pregnant women. As a precautionary measure, it is preferable to avoid the use during pregnanc.
Lactation: It is unknown whether fenfluramine/metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No effects of fenfluramine on human fertility up to clinical doses of 104 mg/day were noted.       
See prescribing information for full details.

Only limited data have been reported concerning clinical effects and management of overdose of fenfluramine. Agitation, drowsiness, confusion, flushing, tremor (or shivering), fever, sweating, abdominal pain, hyperventilation, and dilated non-reactive pupils were reported at much higher doses of fenfluramine than those included in the clinical trial program.
Vital functions should be monitored closely, and supportive treatment administered in case of convulsions, arrhythmias, or respiratory difficulties.

fenfluramine has moderate influence on the ability to drive and use machines because it may cause somnolence and fatigue. Patients should be advised not to drive or operate machinery until they have gained sufficient experience to gauge whether it adversely affects their abilities