Migraine, prevention (alternative agent):
Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (Ref).
Oral: Initial: 0.5 mg at bedtime; may increase daily dose in 0.5 mg/day increments every week based on response and tolerability to 1.5 mg/day administered as a single dose at bedtime or in 3 divided doses; average maintenance dose: 1.5 mg/day. Maximum single dose: 3 mg/dose; maximum daily dose: 6 mg/day (Ref).
Discontinuation of therapy: Avoid abrupt discontinuation to minimize withdrawal symptoms (eg, rebound headache, depression, nausea, tremor, anxiety, malaise, dizziness, sleep disorder, loss of consciousness, anorexia, rapid weight loss). The manufacturer recommends a gradual dose reduction over 2 weeks.
Missed dose: Patients taking ≥2 times daily: Administer the missed dose, as soon as possible. If there is <4 hours before the next scheduled dose, then skip the missed dose and resume regular dosing schedule. Do not double dose or administer more than maximum daily dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.
Hepatic impairment prior to treatment initiation:
There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.
Hepatotoxicity during treatment:
Discontinue use; do not resume therapy until etiology of hepatic dysfunction is identified.
Use with caution. Refer to adult dosing.
Migraine, prophylaxis: Children ≥12 years and Adolescents: Oral: Initial: 0.5 mg at bedtime; may increase dose gradually up to maximum of 1 mg at bedtime or a maximum of 1.5 mg/day.
Note: Therapeutic response may require several weeks of therapy. Drug holidays are recommended periodically to assess the need for ongoing therapy. Do not discontinue abruptly (reduce gradually over 2-week period).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.
There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Postmarketing:
Dermatologic: Skin rash, urticaria
Endocrine & metabolic: Amenorrhea, weight gain
Gastrointestinal: Constipation, increased appetite, nausea, xerostomia
Genitourinary: Breast hypertrophy, mastalgia, nonpuerperal lactation
Hepatic: Fulminant hepatitis, hepatic injury, hepatitis (can be severe), increased liver enzymes, jaundice
Hypersensitivity: Facial edema, hypersensitivity reaction
Nervous system: Anxiety, central nervous system stimulation (including agitation and aggressive behavior), depression, dizziness, drowsiness, fatigue, hallucination, insomnia, paresthesia, sedated state, seizure (including exacerbation of epilepsy), sleep disorder, withdrawal syndrome (following abrupt cessation of therapy)
Neuromuscular & skeletal: Arthralgia, muscle cramps, myalgia
Ophthalmic: Diplopia, increased intraocular pressure, mydriasis
Miscellaneous: Drug tolerance (prolonged use)
Hypersensitivity to pizotifen or any component of the formulation; concomitant use with or within 14 days following monoamine oxidase inhibitor therapy; gastric outlet obstruction (pyloroduodenal obstruction, stenosing pyloric ulcer); use in children <12 years of age.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Anticholinergic effects: Although anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention) are limited, use with caution in patients with decreased gastrointestinal motility, myasthenia gravis, paralytic ileus, urinary retention, BPH, xerostomia, narrow-angle glaucoma, or other vision problems.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Gradual titration of dose may help minimize sedative effects (eg, drowsiness).
• Hepatotoxicity: Hepatotoxic effects may occur with prolonged used; monitor liver function during therapy.
• Visual disturbances: Use has been associated with increased intraocular pressure, diplopia, and pupil dilation; limited number of patients experienced lens opacities but effect was not considered drug-related. Instruct patients to report visual disturbances during therapy.
• Weight gain/loss: Increased appetite and weight gain are common adverse effects; patients may experience rapid weight loss upon discontinuation. Use with caution in obese or other patients who may be vulnerable to these effects.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease.
• Diabetes: Use with caution in patients with diabetes mellitus.
• Epilepsy: Use with caution in patients with epilepsy; seizures have been reported very rarely with use.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Dose adjustment may be necessary.
• Renal impairment: Use with caution in patients with renal impairment. Dose adjustment may be necessary.
Dosage forms specific issues:
• Lactose: May contain lactose; avoid use in patients with galactose or fructose intolerance, lactase deficiency, sucrose-isomaltase insufficiency, or glucose-galactose malabsorption.
Other warnings/precautions:
• Abrupt discontinuation: Avoid abrupt discontinuation which may cause acute withdrawal reactions (eg, depression, tremor, nausea, malaise, sleep disorder, dizziness, anxiety, loss of consciousness, anorexia and rapid weight loss); taper dosage over 2 weeks prior to discontinuation.
• Appropriate use: Not for use in acute treatment of migraine attacks or of tension headaches. Not considered first-line agent for migraine prophylaxis but may be considered when other therapies have failed (CHS [Pringsheim 2012]).
• Tolerance: May develop in some patients; effect may be overcome by dose increases (not to exceed maximum dosage). Consider drug-free period after several months of treatment.
Not available in the US
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Sandomigran: 0.5 mg [DSC] [contains fd&c yellow #5 (tartrazine)]
Sandomigran DS: 1 mg
Oral: Administer daily dose as a single dose at bedtime or in divided doses; doses >3 mg should be administered in divided doses.
Oral: Administer daily dose as a single dose at bedtime or in divided doses
Children ≥12 years and Adolescents: Doses >1 mg should be administered in divided doses
Note: Not available in the US.
Migraine, prevention: Prophylactic management of migraine.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amezinium: Antihistamines may increase stimulatory effects of Amezinium. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benzylpenicilloyl Polylysine: Coadministration of Antihistamines and Benzylpenicilloyl Polylysine may alter diagnostic results. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Risk D: Consider Therapy Modification
Betahistine: Antihistamines may decrease therapeutic effects of Betahistine. Betahistine may decrease therapeutic effects of Antihistamines. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Certoparin: Antihistamines may increase therapeutic effects of Certoparin. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CNS Depressants: Pizotifen may increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Guanethidine: Pizotifen may decrease therapeutic effects of Guanethidine. Risk C: Monitor
Hyaluronidase: Antihistamines may decrease therapeutic effects of Hyaluronidase. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Monoamine Oxidase Inhibitors: May increase anticholinergic effects of Pizotifen. Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pitolisant: Antihistamines may decrease therapeutic effects of Pitolisant. Risk X: Avoid
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Reserpine: Pizotifen may decrease antihypertensive effects of Reserpine. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
In general, preventive treatment for migraine in patients trying to become pregnant should be avoided. Options for patients planning a pregnancy should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data and needs of the patient should pregnancy occur. A gradual discontinuation of preventive medications is generally preferred when the decision is made to stop treatment prior to conception (ACOG 2022; AHS [Ailani 2021]).
Adverse events were not observed in animal reproduction studies.
In general, preventive treatment for migraine should be avoided during pregnancy. Options for pregnant patients should be considered as part of a shared decision-making process. Nonpharmacologic interventions should be considered initially. When needed, preventive treatment should be individualized considering the available safety data, potential for adverse maternal and fetal events, and needs of the patient (ACOG 2022; AHS [Ailani 2021]).
If preventive therapy is needed, agents other than pizotifen are preferred (CHS [Pringsheim 2012]).
It is not known if pizotifen is present in breast milk (Davanzo 2014).
According to the manufacturer, pizotifen is unlikely to affect a breastfeeding infant; however, use is not recommended in breastfeeding patients. In general, preventive treatment for migraine in breastfeeding patients should be avoided. When needed, therapy should be individualized considering the available safety data and needs of the patient (AHS [Ailani 2021]). If preventive therapy is needed, agents other than pizotifen are preferred (CHS [Pringsheim 2012]).
Hepatic function tests (prolonged use); renal function tests; weight gain; BP; visual disturbance.
Pizotifen is a strong serotonin and tryptamine antagonist with weak antihistamine, anticholinergic and antikinin effects; also has appetite-stimulating and sedative properties. The mechanism of action in migraine prophylaxis has not been fully elucidated; may alter pain thresholds by inhibiting the permeability increasing effect of serotonin and histamine to control movement of plasmakinin across cranial vessel membranes. Inhibits serotonin reuptake by platelets, affecting tonicity and reducing passive distension of extracranial arteries.
Onset of action: May require several weeks of therapy
Distribution: Vd: Parent drug: 833 L; N-glucuronide metabolite: 70 L
Protein binding: >90%
Metabolism: Hepatic (mainly by glucuronidation)
Bioavailability: 78%
Half-life elimination: ~23 hours (parent drug and N-glucuronide metabolite)
Time to peak: 5 hours
Excretion: Feces (~33% of dose); urine (55% as metabolites, <1% as unchanged drug)