Fintepla (fenfluramine HCl)

Dosage of fenfluramine hydrochloride is expressed in terms of fenfluramine.

The initial starting and maintenance dosage of fenfluramine for the treatment of seizures associated with Dravet syndrome in adults and pediatric patients 2 years of age or older is 0.1 mg/kg twice daily. Dosage may be increased weekly based on efficacy and tolerability.

If dosage titration is necessary in patients not receiving concomitant stiripentol, the manufacturer recommends an increase to 0.2 mg/kg twice daily on day 7, and then to 0.35 mg/kg twice daily on day 14 if further increase is needed; the maximum total daily dosage is 26 mg in these patients. For patients not receiving concomitant stiripentol in whom a more rapid titration is warranted, the dose may be increased every 4 days.

If dosage titration of fenfluramine is necessary in patients receiving stiripentol and clobazam concomitantly, the manufacturer recommends an increase to 0.15 mg/kg twice daily on day 7, and then to 0.2 mg/kg twice daily on day 14 if further increase is needed; the maximum total daily dosage is 17 mg in these patients.

Fenfluramine is administered orally twice daily as an oral solution. The drug may be administered with or without food.

A calibrated measuring device (i.e., either a 3- or 6-mL oral dosing syringe) should be used to measure and administer the prescribed dose of fenfluramine oral solution; a household teaspoon or tablespoon is not an adequate measuring device. Any unused portions of the oral solution should be discarded 3 months after the bottle is first opened or if the ''discard after'' date has passed, whichever is sooner.

Fenfluramine oral solution is compatible with commercially available gastric and nasogastric feeding tubes.

No dosing information is available for this tab.

No dosing information is available for this tab.

Fenfluramine is metabolized principally by cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, and 2D6, and to a lesser extent by CYP2C9, 2C19, and 3A4/5.

Fenfluramine does not inhibit or induce CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 at clinically relevant concentrations.

Fenfluramine and its active metabolite (norfenfluramine) are not inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport proteins (OATP) 1B1 or OATP1B3, organic anion transporters (OAT) 1 or OAT3, organic cation transporter (OCT) 2, or multidrug and toxin extrusion transporters (MATE) 1 and MATE2K.

Fenfluramine and norfenfluramine are not substrates of P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2K transporters.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Dexfenfluramine; Fenfluramine/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of serotonergic drugs with MAOIs may result in serotonin syndrome.

CLINICAL EFFECTS: Concurrent therapy may result in serotonin syndrome, which may result in death. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent administration of these agents should be avoided. The manufacturer of dexfenfluramine recommends a two week wash-out period discontinuing a MAOI and initiating therapy with dexfenfluramine and a three week wash-out between discontinuing dexfenfluramine and initiating a MAOI. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Although this interaction has not been reported with dexfenfluramine or fenfluramine, the manufacturer 's product information for dexfenfluramine states that concurrent therapy with MAOI's is contraindicated. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Selected Cyp2d6 Substrates/Mavorixafor

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

Sympathomimetics/Dihydroergotamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1)

CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1)

DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Buspirone; Dexfenfluramine; Fenfluramine/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase. Buspirone is a 5-HT1A and moderate D2 agonist, while fenfluramine is an agonist of 5HT-2. Combination of these agents may result an increase in endogenous serotonin and dopamine.(1-6)

CLINICAL EFFECTS: Concurrent use of buspirone, dexfenfluramine or fenfluramine with linezolid may result in elevated blood pressure leading to hypertensive crisis.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of buspirone and fenfluramine state that concurrent use of linezolid is contraindicated.(1,2) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(3) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(8,9) In non-emergency situations in patients maintained on buspirone, dexfenfluramine or fenfluramine, when linezolid therapy is planned, discontinue the patient's buspirone, dexfenfluramine or fenfluramine at least 2 weeks in advance of linezolid therapy.(6) In emergency situations in patients maintained on buspirone, dexfenfluramine or fenfluramine, weigh the availability and safety of alternatives to linezolid against the risk of hypertensive crisis. If linezolid therapy is required, the patient's buspirone, dexfenfluramine or fenfluramine should be immediately discontinued. Patients should be monitored for hypertensive crisis for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first.(6) The patient's buspirone, dexfenfluramine or fenfluramine therapy may be resumed 24 hours after the last dose of linezolid.(6) If concurrent therapy is warranted, patients should be monitored closely for hypertensive crisis.

DISCUSSION: Several cases of elevated blood pressure have been reported in patients receiving MAOIs who were given buspirone.(1) No adverse sequelae have been reported in these patients.

Fenfluramine/St. John's Wort

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: St. John's wort, a strong CYP3A4 inducer, may increase the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. CYP2C9, CYP2C19, and CYP3A4 play a minor role in fenfluramine metabolism.(1) Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use with St. John's wort may result in decreased levels and effectiveness of fenfluramine.(1) May result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fenfluramine recommends avoiding coadministration with strong CYP3A4 inducers. Patients who must receive concurrent therapy should be monitored for decreased efficacy.(1) Fenfluramine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors, sumatriptan, or dihydroergotamine. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study with healthy volunteers, steady-state rifampin (a CYP1A2, CYP2B6, and CYP3A4 inducer) 600 mg daily decreased the area-under curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 58% and 40%, respectively, and increased the AUC and Cmax of norfenfluramine by 50% and 13%, respectively.(1) The serotonin syndrome interaction is based on FDA mandated class labeling for these agents. Although there is no clinical documentation for an interaction between dexfenfluramine or fenfluramine and either the selective serotonin reuptake inhibitors, sumatriptan, or dihydroergotamine, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Fenfluramine/Strong Cyp1a2, Cyp2b6 Or Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inducers of CYP1A2, CYP2B6, or CYP3A4 may increase the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. CYP2C9, CYP2C19, and CYP3A4 play a minor role in fenfluramine metabolism.(1)

CLINICAL EFFECTS: Concurrent use of agents that are strong inducers of CYP1A2, CYP2B6, or CYP3A4 may result in decreased levels and effectiveness of fenfluramine.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of fenfluramine recommends avoiding coadministration with strong CYP1A2, CYP2B6, or CYP3A4 inducers. Patients who must receive concurrent therapy should be monitored for decreased efficacy and may require increased dosages of fenfluramine, not to exceed the maximum fenfluramine dosages below.(1) The maximum daily dose for patients with concomitant stiripentol and clobazam is 17 mg.(1) The maximum daily dose for patients without concomitant stiripentol is 26 mg.(1) If a strong CYP1A2, CYP2B6, or CYP3A4 inducer is discontinued, gradually lower the fenfluramine dosage to the dose administered before initiation of the inducer.(1)

DISCUSSION: In a study with healthy volunteers, steady-state rifampin (a CYP1A2, CYP2B6, and CYP3A4 inducer) 600 mg daily decreased the area-under curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 58% and 40%, respectively, and increased the AUC and Cmax of norfenfluramine by 50% and 13%, respectively.(1) Strong inducers of CYP1A2, CYP2B6, or CYP3A4 linked to this monograph include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(1-3)

Select Indirect-Acting Sympathomimetics/Tricyclic Compounds

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use of tricyclic compounds and indirect-acting sympathomimetics should be approached with caution. Monitor patients receiving concurrent therapy for decreased sympathomimetic efficacy.

DISCUSSION: The pressor effects of the indirect-acting sympathomimetic amines (e.g., amphetamines, ephedrine, and methylphenidate) are antagonized by tricyclic antidepressants.

Sympathomimetics (Indirect Acting)/Guanethidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Indirect-acting sympathomimetics may displace guanethidine from adrenergic neurons, thereby antagonizing the clinical effect.

CLINICAL EFFECTS: Blood pressure may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, use an alternative antihypertensive agent or sympathomimetic.

DISCUSSION: This interaction has been demonstrated with concomitant administration of anorexiant-type indirect-acting sympathomimetics and guanethidine. Increased blood pressure has been reported.

Sympathomimetics/Ergot Alkaloids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.

CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary.

DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine.

Sympathomimetics/Selected Inhalation Anesthetic Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1)

CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1)

DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Dexfenfluramine; Fenfluramine/Serotonergic Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: May result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fenfluramine states that fenfluramine should be used with caution with other serotonergic agents such as the selective serotonin reuptake inhibitors. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: This interaction is based on FDA mandated class labeling for these agents. Although there is no clinical documentation for an interaction between dexfenfluramine or fenfluramine and either the selective serotonin reuptake inhibitors, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents.

Fenfluramine/Cyproheptadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fenfluramine and the metabolite, norfenfluramine, exhibit agonist activity at serotonin 5-HT2 receptors.(1) Cyproheptadine is a serotonin receptor antagonist and may inhibit the activity of fenfluramine and metabolite at serotonin 5-HT2 receptors.(1-2)

CLINICAL EFFECTS: Concurrent use of fenfluramine and cyproheptadine may result in decreased levels and effectiveness of fenfluramine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fenfluramine states cyproheptadine may decrease the efficacy of fenfluramine. If cyproheptadine is coadministered with fenfluramine, patients should be monitored appropriately.(1)

DISCUSSION: Although there is no clinical documentation for an interaction between fenfluramine and cyproheptadine, caution is still warranted.(1-2)

Fenfluramine/Selected Ssris That Inhibit Cyp1a2 Or Cyp2d6

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP1A2 or CYP2D6 inhibitors may decrease the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1) Concurrent administration may also result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine, including CNS depression, hypertension, and serotonin syndrome.(1) Serotonin syndrome is a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of fenfluramine states that the maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6 inhibitor in patients not on stiripentol is 20 mg. In patients on concomitant stiripentol and clobazam, the maximum fenfluramine dosage with strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1) If the strong CYP1A2 or CYP2D6 inhibitor is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1) The manufacturer of fenfluramine states that fenfluramine should be used with caution with other serotonergic agents such as selective serotonin reuptake inhibitors. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study of healthy volunteers, fluvoxamine 50 mg daily (a strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%, respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and 44%, respectively.(1) In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6 inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg by 81% and 13%, respectively, and decreased the AUC and Cmax of norfenfluramine by 13% and 29%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include: fluvoxamine.(3,4) Strong CYP2D6 inhibitors linked to this monograph include: fluoxetine and paroxetine.(3,4)

Fenfluramine/Strong Cyp1a2 Or Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP1A2 or CYP2D6 inhibitors may decrease the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of fenfluramine states that the maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6 inhibitor in patients not on stiripentol is 20 mg. In patients on concomitant stiripentol and clobazam, the maximum fenfluramine dosage with strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1) If the strong CYP1A2 or CYP2D6 inhibitors is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1)

DISCUSSION: In a study of healthy volunteers, fluvoxamine 50 mg daily (a strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%, respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and 44%, respectively.(1) In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6 inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg by 81% and 13%, respectively, and decreased the AUC and Cmax of norfenfluramine by 13% and 29%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include: Angelica root, ciprofloxacin, enasidenib, vemurafenib, and viloxazine. Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, and quinidine.(1-4)

Fenfluramine;Dexfenfluramine/Insulin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fenfluramine increases glucose uptake at the receptor site (ie, skeletal muscle).

CLINICAL EFFECTS: The hypoglycemic effect of insulin is increased.

PREDISPOSING FACTORS: Diabetes.

PATIENT MANAGEMENT: In diabetic patients receiving insulin, monitor blood glucose levels and observe the patient for signs of hypoglycemia when initiating therapy with fenfluramine and for symptoms of hyperglycemia when fenfluramine is discontinued.

DISCUSSION: When administered before meals or to fasting patients, fenfluramine has been found to have hypoglycemic action. Numerous reports have demonstrated fenfluramine to potentiate the hypoglycemic effect of insulin in diabetic patients.

Serotonergic Agents/Ziprasidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1)

DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6)

Fenfluramine is contraindicated in patients with hypersensitivity to fenfluramine or any excipients in the preparation.

Fenfluramine is contraindicated during or within 14 days of administration of monoamine oxidase (MAO) inhibitors due to increased risk of serotonin syndrome. (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

• Glaucoma
• Serotonin syndrome
• Suicidal ideation

• Alcohol use disorder
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Depression
• Drug abuse
• Pulmonary arterial hypertension
• Valvular heart disease

• Hypertension
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Weight loss

Adverse effects reported in at least 10% of patients with Dravet syndrome receiving fenfluramine in clinical trials and more frequently than placebo include decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased blood pressure, drooling, salivary hypersecretion, pyrexia, upper respiratory tract infection, vomiting, decreased weight, falls, and status epilepticus.

More Frequent

• Abnormal ECG
• Hypertension
• Status epilepticus

Rare or Very Rare

• Accidental fall
• Pulmonary hypertension
• Secondary angle-closure glaucoma
• Serotonin syndrome
• Suicidal ideation
• Valvular heart disease

More Frequent

• Anorexia
• Ataxia
• Constipation
• Diarrhea
• Drowsy
• Fatigue
• Fever
• Gait abnormality
• General weakness
• Insomnia
• Lethargy
• Malaise
• Sedation
• Sialorrhea
• Upper respiratory infection
• Vomiting
• Weight loss

Less Frequent

• Behavioral disorders
• Bronchitis
• Croup
• Gastroenteritis
• Headache disorder
• Increased urinary frequency
• Infection of ear
• Irritability
• Rhinitis
• Skin rash
• Tachycardia
• Tremor
• Urinary incontinence
• Urinary tract infection

Rare or Very Rare

• Aggressive behavior
• Mydriasis

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Safety and efficacy of fenfluramine in pediatric patients younger than 2 years of age have not been established.

There are no adequate human or animal data on the developmental risks associated with the use of fenfluramine in pregnant women.

Women who are pregnant while receiving fenfluramine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or http://www.aedpregnancyregistry.org/.

It is not known whether fenfluramine or its metabolites are distributed into milk, or if the drug affects milk production or the breast-fed infant. The benefits of breast-feeding should be considered along with the importance of fenfluramine to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Clinical studies of fenfluramine for the treatment of Dravet syndrome did not include patients 65 years of age and over to determine whether they respond differently from younger patients. In general, dosage selection in geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.