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Pizotifen | CAS No: 15574-96-6 | GMP-certified suppliers

A medication that provides prophylactic management of migraines by reducing frequency and severity through modulation of multiple neurotransmitter systems.

Therapeutic categories

Adrenergic alpha-1 Receptor AntagonistsAdrenergic alpha-AntagonistsAdrenergic AntagonistsAgents producing tachycardiaAgents that produce hypertensionAnalgesics

Generic name

Pizotifen

Molecule type

small molecule

CAS number

15574-96-6

DrugBank ID

DB06153

Approval status

Approved drug

ATC code

N02CX01

Primary indications

Indicated for the prophylactic management of migraines

Product Snapshot

Pizotifen is formulated as an oral small molecule in various tablet forms and syrup
It is primarily used for the prophylactic management of migraines
The product is approved for use in the Canadian market

Clinical Overview

Pizotifen (CAS number 15574-96-6) is a cycloheptathiophene derivative classified within the class of antamines and chemically related to cyproheptadine. It is primarily indicated for the prophylactic management of migraines. Pizotifen’s clinical utility is established in reducing the frequency and severity of vascular headaches by modulating multiple neurotransmitter systems.

Pharmacodynamically, pizotifen acts as a potent antagonist at serotonin 5-HT2 receptors, which is central to its antimigraine effects. It also exhibits antagonism at histamine H1 receptors and weak anticholinergic activity. Additional receptor interactions include binding to α1- and α2-adrenergic receptors and dopamine receptors, though effects at these sites are less pronounced. Pizotifen’s blockade of 5-HT2 receptors interferes with serotonin-mediated cranial vasoconstriction and platelet aggregation, attenuating migraine pathophysiology. The drug also exerts inhibitory effects on serotonin uptake and may influence bradykinin-mediated pathways. Sedative properties have been reported in preclinical species, correlating with observed clinical sedation and appetite stimulation.

Mechanistically, pizotifen inhibits peripheral serotonin and histamine actions that increase vascular permeability and stimulate nociceptive pathways in cranial tissues. Appetite stimulation and weight gain seen clinically are presumed to result from metabolic modulation rather than central appetite center activation.

Key pharmacokinetic parameters including absorption, distribution, metabolism, and excretion profiles are not extensively detailed in the referenced literature and may vary by formulation.

Safety considerations include the development of tolerance with prolonged use and potential central nervous system effects such as sedation. Neuropsychiatric effects require caution in patients with comorbid depression or schizophrenia, as clinical studies indicate variable effects on depressive symptoms. Pizotifen exhibits minimal cardiopulmonary effects but may cause transient hypotension upon intravenous administration in animal models.

Pizotifen hydrochloride is the active pharmaceutical ingredient in products such as Sandomigran, utilized for migraine prophylaxis in several countries. However, it is not approved by the FDA or EMA.

From an API procurement perspective, priority should be given to sourcing material that meets stringent pharmaceutical quality standards including established purity, impurity profiles, and stability data. Given its complex pharmacology and clinical applications, consistent batch quality and verified supplier documentation are essential for regulatory compliance and formulation reliability.

Identification & chemistry

Generic name	Pizotifen
Molecule type	Small molecule
CAS	15574-96-6
UNII	0BY8440V3N
DrugBank ID	DB06153

Pharmacology

Summary	Pizotifen acts primarily as an antagonist of serotonin 5-HT2 and histamine H1 receptors, modulating vascular permeability and neurotransmission involved in migraine pathophysiology. It also interacts with muscarinic acetylcholine, adrenergic, and dopamine receptors, contributing to its pharmacodynamic profile. These activities collectively reduce migraine frequency and severity through vascular and neuronal mechanisms.
Mechanism of action	While the mechanism of action is not fully understood, it is proposed that pizotifen works by inhibiting the peripheral actions of serotonin and histamine in increasing the membrane permeability of cranial vessels and transudation of plasmakinin, while altering pain thresholds in migraines . By blocking 5-HT receptors, pizotifen attenuates the signalling of serotonin in causing cranial vasoconstriction, as well as serotonin-enhanced platelet function and aggregation [A32540, A32550]. There is evidence that it also inhibits the peripheral actions of bradykinin . Pizotifen may inhibit serotonin reuptake by blood platelets, which affects the tonicity and decreases passive distension of extracranial arteries . The effects of pizotifen leading to appetite stimulation may be due to the drug acting at the metabolic level rather than a direct stimulation of the appetite centre .
Pharmacodynamics	Various studies have shown pizotifen to be effective in the prophylaxis of migraines in reducing the frequency and severity of vascular headaches . Evidence from studies _in vivo_ and _in vitro_ demonstrate antagonistic actions towards serotonin and histamine. Pizotifen blocks the postsynaptic 5-HT2 receptors, as supported by antagonism of several direct agonists of 5-HT receptors . It is an antagonist at histamine H1 receptors, and is weakly anticholinergic . It also binds to α1- and α2-adrenergic receptors, and dopamine receptors . Pizotifen elicits a minimal effect as an epinephrine or bradykinin antagonist . Pizotifen exhibits weak sedative properties in mouse and monkey studies, as indicated by inhibition of locomotion and potentiation of barbiturates, without changes in cardiac or respiratory rates . In dogs, intravenous administration of pizotifen cause rapid hypotension but was reversed to normal within 30 minutes . Pizotifen was shown to inhibit serotonin uptake in the isolated perfused cat spleen and, _in vivo_, inhibits serotonin-induced contractions in rat uterus and cat nictiating membrane . In contrast, pizotifen demonstrated a venoconstrictor activity _in vivo_ when orally or intravenously administered to saphenous veins in conscious dogs . Pizotifen has the potential to stimulate the appetite and may cause weight gain upon treatment . In a double-blind clinical study of patients with mild to moderate depression, treatment of pizotifen led to clinical improvement of the depressive symptoms. However, deterioration of the schizophrenic emotional symptoms was also observed in patients with depression and chronic schizophrenia . This indicates that pizotifen may potentially improve the symptoms of patients with depressions in conjunction with migraines . Neuroprotective effect of pizotifen was investigated _in vitro_ in a mouse cell model of Huntington's disease (HD). According to a chemical screen of a mouse HdhQ111/Q111 striatal cell model of HD, treatment of pizotifen was associated with increased ATP levels and decreased activation of caspase-3, leading to enhanced cell viability . Transient activation of ERK signalling pathway lasting for less than 3 hours was also observed. In the R6/2 transgenic mouse model of HD, rotarod performance of the mouse treated with pizotifen was seen, accompanied by an increase in DARPP-32 protein expression and restoration of striatal area . However these effects being reflected _in vivo_ are not established.

Targets

Target	Organism	Actions
Muscarinic acetylcholine receptor M1	Humans	antagonist
Muscarinic acetylcholine receptor M2	Humans	antagonist
Muscarinic acetylcholine receptor M3	Humans	antagonist

ADME / PK

Absorption	The absorption half-life of pizotifen following oral administration is 0.5 to 0.8 hours in an adult male with nearly complete absorption rate of 80%. Maximum blood levels are reached 5 hours post-administration and the absolute bioavailability is 78% .
Half-life	The elimination half-life for pizotifen and N-glucuronide conjugate is about 23 hours .
Protein binding	Plasma protein binding of pizotifen is > 90% .
Metabolism	Pizotifen is extensively metabolized in the liver, where it primarily undergoes N-glucuronidation to form the main metabolite, N-glucuronide conjugate . N-glucuronide conjugate accounts for at least 50% of the plasma and 60-70% of the urinary-excreted radioactivity .
Route of elimination	About one third of the total orally administered dose is excreted into the feces. Less than 1% of the total dose is excreted in the urine as the unchanged parent drug, and up to 55% of the dose is excreted as its metabolites .
Volume of distribution	The volume of distribution in an adult male is 833L for pizotifen and 70L for the N-glucuronide conjugate .

Formulation & handling

Pizotifen is a small molecule oral formulation primarily available as tablets and syrup.
The compound exhibits low water solubility and high lipophilicity (LogP 4.49), which may influence dissolution and bioavailability.
Pizotifen absorption is not impacted by food, allowing flexible administration with regard to meals.

Regulatory status

Lifecycle	The API is marketed in Canada where key patents have expired, allowing for the availability of generic formulations and a competitive market environment. This reflects a mature product lifecycle with established clinical use and regulatory approval.

Markets	Canada

Supply Chain

Supply chain summary	The manufacturing and supply landscape for Pizotifen in Canada includes originator companies with branded products such as Sandomigran and Sandomigran DS. The presence of these branded products primarily in the Canadian market suggests limited global distribution in regions like the US or EU. Given the absence of recent patent exclusivity, there is potential for existing or upcoming generic competition.

Supply chain summary

The manufacturing and supply landscape for Pizotifen in Canada includes originator companies with branded products such as Sandomigran and Sandomigran DS. The presence of these branded products primarily in the Canadian market suggests limited global distribution in regions like the US or EU. Given the absence of recent patent exclusivity, there is potential for existing or upcoming generic competition.

Safety

Toxicity	The oral Lowest published toxic dose (TDLo) is 12.86 mg/kg in man [MSDS]. Oral LD50 ranges from 410 to 1500 mg/kg in rat [MSDS, L2292]. Oral LD50 in mouse and rabbit is 880 mg/kg and 700 mg/kg, respectively . The LD50 following intravenous administration in rat was 17 mg/kg . In adults, the symptoms of overdosage include sedation, drowsiness (preceding excitement, convulsions, and postictal depression), dizziness, hypotension, dryness of the mouth, confusion, tachycardia, ataxia, nausea, vomiting, dyspnea, cyanosis, convulsions, coma, respiratory paralysis and CNS depression . Antihistamine toxicity of pizotifen in children may involve excitation, hallucinations, ataxia, incoordination, convulsions, fixed dilated pupils, flushed faces, and fever, leading to coma and cardiorespiratory collapse . The use of activated charcoal is recommended in the management of overdose. For drug recent uptake, induction of emesis or gastric lavage and diuresis should be performed . Supportive measures should be initiated to maintain effective respiration while closely monitoring vital signs. While severe hypotension must be corrected, the use of adrenaline may produce paradoxical effects . As pizotifen has the potential to cause tachycardia, an ECG should be performed and attention directed at the QRS and QT intervals . Excitatory states or convulsions induced by pizotifen may be treated with short-acting barbiturates or benzodiazepines. However analeptics should be avoided .

Toxicity

The oral Lowest published toxic dose (TDLo) is 12.86 mg/kg in man [MSDS]. Oral LD50 ranges from 410 to 1500 mg/kg in rat [MSDS, L2292]. Oral LD50 in mouse and rabbit is 880 mg/kg and 700 mg/kg, respectively . The LD50 following intravenous administration in rat was 17 mg/kg . In adults, the symptoms of overdosage include sedation, drowsiness (preceding excitement, convulsions, and postictal depression), dizziness, hypotension, dryness of the mouth, confusion, tachycardia, ataxia, nausea, vomiting, dyspnea, cyanosis, convulsions, coma, respiratory paralysis and CNS depression . Antihistamine toxicity of pizotifen in children may involve excitation, hallucinations, ataxia, incoordination, convulsions, fixed dilated pupils, flushed faces, and fever, leading to coma and cardiorespiratory collapse . The use of activated charcoal is recommended in the management of overdose. For drug recent uptake, induction of emesis or gastric lavage and diuresis should be performed . Supportive measures should be initiated to maintain effective respiration while closely monitoring vital signs. While severe hypotension must be corrected, the use of adrenaline may produce paradoxical effects . As pizotifen has the potential to cause tachycardia, an ECG should be performed and attention directed at the QRS and QT intervals . Excitatory states or convulsions induced by pizotifen may be treated with short-acting barbiturates or benzodiazepines. However analeptics should be avoided .

High Level Warnings:

Oral LD50 values indicate moderate acute toxicity
Intravenous administration presents higher toxicity risk
Potential adverse effects include CNS depression, cardiovascular disturbances, and respiratory paralysis upon overexposure

Pizotifen is a type of Analgesics

Analgesics are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that are commonly used to relieve pain. They are designed to alleviate discomfort by targeting the body's pain receptors or by reducing inflammation. Analgesics are widely utilized in the medical field to manage various types of pain, ranging from mild to severe.

One of the primary classes of analgesics is nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs work by inhibiting the production of prostaglandins, substances that contribute to pain and inflammation. This class includes well-known drugs like ibuprofen and naproxen. Another class of analgesics is opioids, which are derived from opium or synthetic compounds that mimic the effects of opium. Opioids act on the central nervous system to reduce pain perception and provide potent pain relief. Examples of opioids include morphine, codeine, and oxycodone.

Analgesics are available in various forms, such as tablets, capsules, creams, and injections, allowing for different routes of administration based on the patient's needs. They are commonly used to manage pain associated with conditions like arthritis, headaches, dental procedures, and post-operative recovery.

It is important to note that analgesics should be used under medical supervision, as improper use or overuse can lead to adverse effects, including gastrointestinal complications, addiction, and respiratory depression in the case of opioids. Therefore, it is crucial for healthcare professionals to assess each patient's individual needs and prescribe the appropriate analgesic and dosage.

In summary, analgesics are a vital category of pharmaceutical APIs used to alleviate pain by targeting pain receptors or reducing inflammation. With various classes and forms available, they provide valuable options for pain management when used responsibly and under medical guidance.