Pizotifen

Pharmacologic Category

Serotonin and Histamine Antagonist

Dosing: Adult

Migraine prophylaxis: Oral: Initial: 0.5 mg at bedtime; may increase dose gradually to 1.5 mg daily administered as single dose at bedtime or in 3 divided doses; average maintenance dose: 1.5 mg daily; usual dosage range: 1 to 6 mg daily (maximum dose: 6 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).

Dosing: Geriatric

Elderly (>65 years): Use with caution. Refer to adult dosing.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.

Dosing: Pediatric

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).

Dosing: Renal Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustments may be necessary. Use with caution.

Use: Labeled Indications

Note: Not available in the US

Migraine prophylaxis: Prophylactic management of migraine.

Clinical Practice Guidelines

Canadian Headache Society Guideline for Migraine Prophylaxis, 2012

Administration: Oral

Administer daily dose as a single dose at bedtime or in divided doses; doses >3 mg should be administered in divided doses.

Administration: Pediatric

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

Storage/Stability

Store at 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Contraindications

Hypersensitivity to pizotifen or any component of the formulation; concurrent use of MAO inhibitors; gastric outlet obstruction (pyloroduodenal obstruction, stenosing pyloric ulcer); use in children <12 years of age

Warnings/Precautions

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. Ophthalmic screening is recommended.

• 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; periodic evaluation of liver function is recommended during therapy. Discontinue use for signs/symptoms of hepatic dysfunction and do not resume therapy until etiology of hepatic dysfunction is identified.

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 (Pringsheim, 2012).

• Response to therapy: Therapeutic response may require several weeks of therapy. Some patients may experience a decrease in therapeutic response over time.

• 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.

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. If possible, drug therapy for migraine prophylaxis should be avoided during pregnancy. If therapy is needed, other agents are preferred (Pringsheim, 2012).

Breast-Feeding Considerations

The concentration of pizotifen measured in the milk of nursing mothers is unlikely to affect a nursing infant; however, the manufacturer does not recommend use in nursing mothers. If possible, drug therapy for migraine prophylaxis should be avoided in nursing women. If therapy is needed, other agents are preferred (Pringsheim, 2012).

Adverse Reactions

≥10%:

Endocrine & metabolic: Weight gain

Gastrointestinal: Increased appetite

1% to <10%:

Central nervous system: Dizziness, drowsiness (including fatigue)

Gastrointestinal: Nausea, xerostomia

<1%, postmarketing, and/or case reports: Agitation (children), aggressive behavior (children), amenorrhea, anorexia, anxiety, arthralgia, breast hypertrophy, constipation, depression, diplopia, facial edema, fulminant hepatitis, hallucination, hepatitis, hypersensitivity reaction, increased intraocular pressure, increased liver enzymes, insomnia, jaundice, lactation (nonpuerperal), loss of consciousness, mastalgia, muscle cramps, myalgia, mydriasis, paresthesia, sedation, seizure, skin rash, sleep disorder, tremor, urticaria, weight loss (rapid), withdrawal syndrome (following abrupt cessation of therapy)

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Acetylcholinesterase Inhibitors: Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Risk C: Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Amezinium: Antihistamines may enhance the stimulatory effect of Amezinium. Risk C: Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Benzylpenicilloyl Polylysine: Antihistamines may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. 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 diminish the therapeutic effect of Betahistine. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Risk D: Consider therapy modification

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect 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

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination

CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Guanethidine: Pizotifen may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

Hyaluronidase: Antihistamines may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect 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

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the anticholinergic effect of Pizotifen. Risk X: Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect 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

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pitolisant: Antihistamines may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Risk X: Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk D: Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Reserpine: Pizotifen may diminish the antihypertensive effect of Reserpine. Risk C: Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect 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

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect 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

Monitoring Parameters

Hepatic function tests (prolonged use); renal function tests, weight gain; blood pressure

Product Availability

Not available in the US

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Sandomigran: 0.5 mg [contains tartrazine (fd&c yellow #5)]

Sandomigran DS: 1 mg [contains tartrazine (fd&c yellow #5)]

Anatomic Therapeutic Chemical (ATC) Classification

• N02CX01

Generic Available (US)

Yes

Mechanism of Action

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.

Pharmacodynamics/Kinetics

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)

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: May have anticholinergic effects resulting in xerostomia (normal salivary flow resumes upon discontinuation)

Effects on Bleeding

No information available to require special precautions

Index Terms

Pizotifen Malate

References

Elouni B, Ben Salem C, Zamy M, et al, “Fulminant Hepatitis Possibly Related to Pizotifen Therapy,” Ann Pharmacother, 2010, 44(7-8):1348-9.[PubMed 20571104]

Pringsheim T, Davenport W, Mackie G, et al, “Canadian Headache Society Guideline for Migraine Prophylaxis,” Can J Neurol Sci, 2012, 39(2 Suppl 2):1-59.[PubMed 22683887]

Sandomigran and Sandomigran DS (pizotifen) [product monograph]. Montreal, Quebec, Canada: Paladin Labs, Inc; October 2012.

Brand Names: International

Acugrain (MY); Anorsia (TH); Apizine (LB); Avidro (BD); Duotifen (VN); Lematite (PK); Litec (PH); Lysagor (ID); Migranex (BD); Mor-Vita (PH); Mosegor (AE, BH, CH, DE, ES, GR, LU, PH, PK, PT, QA, SA); Mozifen-EF (TH); Pizofen (JO, LK); Pizogran (TR); Pizomed (TH); Raiteck (KR); Sandmigrin (IS); Sandomigran (AR, AT, AU, BR, CZ, DE, ES, FR, GB, HK, HU, IE, IT, JO, LK, LU, MY, NL, NZ, SK, VE, ZW); Sandomigrin (DK, SE, TR); Zofen (AE, BD, SA); Zonil (BD)

Last Updated 3/20/20