Zuclopenthixol (United States: Not available): Drug information

For additional information see "Zuclopenthixol (United States: Not available): Patient drug information"

For abbreviations, symbols, and age group definitions show table

Brand Names: Canada

Clopixol;
Clopixol Acuphase;
Clopixol Depot

Pharmacologic Category

First Generation (Typical) Antipsychotic

Dosing: Adult

Agitation/Aggression associated with schizophrenia or psychotic episodes

Agitation/Aggression associated with schizophrenia or psychotic episodes:

Oral:

Initial: 10 to 50 mg/day in 2 to 3 divided doses; may increase daily dose based on response and tolerability in 10 to 20 mg increments every 2 to 3 days; usual therapeutic range: 20 to 60 mg/day; maximum dose: 100 mg/day.

IM: Short-acting zuclopenthixol acetate: Usual dose: 50 to 150 mg as a single dose; may be repeated in 2 to 3 days (some patients may require an additional dose 1 to 2 days after the initial dose and then repeat every 2 to 3 days as necessary); maximum: 400 mg or 4 injections during the course of treatment. Duration of treatment not to exceed 2 weeks.

Schizophrenia

Schizophrenia:

Oral: Initial: 10 to 50 mg/day in 2 to 3 divided doses; may increase daily dose based on response and tolerability in 10 to 20 mg increments every 2 to 3 days; usual therapeutic range: 20 to 60 mg/day; maximum dose: 100 mg/day; may be given as a single dose during maintenance treatment.

IM: Long-acting zuclopenthixol decanoate:

Test dose: Establish tolerability with oral tablets, short-acting IM zuclopenthixol acetate, or long-acting zuclopenthixol decanoate prior to initiation; recommendations vary internationally on preferred formulation for test dose (Ref).

Long-acting zuclopenthixol decanoate test dose: 100 mg to establish tolerability for the decanoate base oil. After the test dose, wait 4 to 10 days before giving the full therapeutic dose (Ref).

Usual maintenance dose: Long-acting zuclopenthixol decanoate: 150 to 300 mg every 2 to 4 weeks; see "Dosing Conversion" below. Doses up to 600 mg every 1 to 4 weeks may be considered for some patients based on response and tolerability; however, higher doses are associated with a greater risk of adverse effects (Ref).

Dosing conversion:

IM short-acting zuclopenthixol acetate to oral zuclopenthixol tablets: Note: Allow 2 to 3 days after final injection before initiating oral therapy; administer tablets in divided doses:

50 mg of zuclopenthixol acetate injection every 2 to 3 days = 20 mg/day of oral zuclopenthixol tablets.

100 mg of zuclopenthixol acetate injection every 2 to 3 days = 40 mg/day of oral zuclopenthixol tablets.

150 mg of zuclopenthixol acetate injection every 2 to 3 days = 60 mg/day of oral zuclopenthixol tablets.

Oral zuclopenthixol tablets to IM zuclopenthixol decanoate: Note: Supplemental oral dosing, with subsequent tapering, may be required during the transition period.

≤20 mg daily of oral zuclopenthixol tablets = 100 mg of zuclopenthixol decanoate injection every 2 weeks.

25 to 40 mg daily of oral zuclopenthixol tablets = 200 mg of zuclopenthixol decanoate injection every 2 weeks.

50 to 75 mg daily of oral zuclopenthixol tablets = 300 mg of zuclopenthixol decanoate injection every 2 weeks.

>75 mg/day of oral zuclopenthixol tablets = 400 mg of zuclopenthixol decanoate injection every 2 weeks.

IM short-acting zuclopenthixol acetate to IM zuclopenthixol decanoate: Note: When initiating maintenance therapy with decanoate, may administer initial dose concomitantly with final acetate injection:

50 mg of zuclopenthixol acetate injection every 2 to 3 days = 100 mg of zuclopenthixol decanoate injection every 2 weeks.

100 mg of zuclopenthixol acetate injection every 2 to 3 days = 200 mg of zuclopenthixol decanoate injection every 2 weeks.

150 mg of zuclopenthixol acetate injection every 2 to 3 days = 300 mg of zuclopenthixol decanoate injection every 2 weeks.

Discontinuation of therapy:

Oral: In the treatment of chronic psychiatric disease switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).

Long-acting injectable: Switching to other treatments is generally advised if side effects are intolerable or treatment is not effective. However, if a patient insists on stopping treatment, gradual dose reduction to avoid withdrawal reactions is generally not needed with long-acting injectable antipsychotics. The risk of withdrawal symptoms from discontinuation of long-acting injectables is low because the rate of drug elimination is slow. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).

Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Ref). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in manufacturer's labeling (has not been studied). Renal impairment is not likely to influence systemic exposure as the drug undergoes extensive hepatic metabolism and is primarily excreted in the feces. Use with caution.

Dosing: Liver Impairment: Adult

There are no dosage adjustments provided in manufacturer's labeling (has not been studied). Use with caution; zuclopenthixol undergoes extensive hepatic metabolism.

Dosing: Older Adult

Note: Avoid for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. If used, consider deprescribing attempts to assess continued need and/or lowest effective dose. Of note, use in certain indications may be appropriate (eg, schizophrenia) (Ref).

Refer to adult dosing. Consider initiating therapy at doses 25% to 50% of usual initial dose (Ref). Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for oral and injection (decanoate and/or acetate formulations), unless otherwise noted.

>10%:

Gastrointestinal: Xerostomia (13% to 25%)

Nervous system: Akathisia (13% to 16%), anxiety (≤17%), asthenia (≤15%), dizziness (7% to 21%), drowsiness (oral: 32%; injection: 16% to 20%), extrapyramidal reaction (≤13%), fatigue (≤15%), hypertonia (5% to 26%), insomnia (5% to 16%), nervousness (≤17%), tremor (8% to 21%)

Neuromuscular & skeletal: Dystonia (5% to 14%), hypokinesia (oral: 7%; injection: 10% to 21%)

Ophthalmic: Accommodation disturbance (4% to 11%)

1% to 10%:

Cardiovascular: Chest pain (≤1%), hypotension (2%), orthostatic hypotension (oral: 3%; injection: <1%), palpitations (1% to 2%), syncope (≤1%), tachycardia (3% to 10%)

Dermatologic: Dermatitis (≤1%), diaphoresis (1% to 6%), dyschromia (≤1%), pallor (oral: 1%), pruritus (injection: ≤2%), seborrhea (≤2%), skin photosensitivity (≤1%), skin rash (≤1%; including erythematous rash, psoriasiform eruption)

Endocrine & metabolic: Decreased libido (oral: 3%; injection: ≤1%), galactorrhea not associated with childbirth (≤1%), gynecomastia (≤1%), hot flash (≤1%), increased libido (≤1%), increased thirst (1% to 2%), menstrual disease (2% to 4%), weight gain (2% to 4%), weight loss (2% to 3%)

Gastrointestinal: Abdominal pain (≤1%), anorexia (2% to 4%), bloating (≤1%), constipation (≤8%), diarrhea (≤1%), dyspepsia (injection: 1%), dysphagia (≤1%), gastric ulcer (≤1%), glossitis (≤1%), increased appetite (≤2%), nausea (≤2%), sialorrhea (6% to 10%), toothache (≤1%), vomiting (1% to 3%)

Genitourinary: Anorgasmia (females: ≤1%), ejaculation failure (≤2%), erectile dysfunction (≤1%), polyuria (≤1%), urinary incontinence (≤1%), urinary retention (≤1%), urinary tract infection (≤1%), vaginal dryness (≤1%)

Hematologic & oncologic: Purpuric disease (≤1%)

Hypersensitivity: Hypersensitivity reaction (≤1%)

Local: Application-site reaction (≤1%)

Nervous system: Abnormal dreams (2%), abnormal gait (≤2%), agitation (oral: 10%; injection: 1%), amnesia (2% to 3%), apathy (≤3%), ataxia (≤1%), confusion (oral: 3%; injection: <1%), depressed mood (≤1%), depression (3% to 8%), drug dependence (≤1%), excitability (≤1%), hallucination (oral: 3%), headache (1% to 5%), hyperacusis (≤1%), hyperreflexia (≤1%), hypotonia (≤1%), irritability (≤1%), lack of concentration (3% to 8%), malaise (oral: 2%), migraine (≤1%), nightmares (≤1%), pain (oral: 2%), paresthesia (oral: 1%; injection: 2% to 3%), precordial pain (≤1%), seizure (≤1%), speech disturbance (≤1%), vertigo (1% to 5%)

Neuromuscular & skeletal: Acute dyskinesia (≤1%), arthritis (≤1%), back pain (≤1%), dyskinesia (injection: ≤1%), myalgia (injection: 1%), tardive dyskinesia (oral: 3%; injection: <1%)

Ophthalmic: Conjunctivitis (≤1%), mydriasis (≤1%), oculogyric crisis (≤1%), visual disturbance (2% to 4%)

Otic: Tinnitus (≤1%)

Respiratory: Dyspnea (≤1%), nasal congestion (≤1%), pharyngitis (≤1%), rhinitis (≤1%)

Miscellaneous: Fever (≤1%)

Postmarketing:

Cardiovascular: Peripheral edema, prolonged QT interval on ECG, torsades de pointes, venous thrombosis (cortical) (Andole 2011), ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia

Endocrine & metabolic: Amenorrhea, hyperglycemia, hyperlipidemia, hyperprolactinemia, impaired glucose tolerance

Genitourinary: Priapism (Mansour 2023)

Hematologic & oncologic: Agranulocytosis, granulocytopenia, leukopenia, neutropenia (Hirshberg 2000), thrombocytopenia (Hirshberg 2000)

Hepatic: Cholestatic hepatitis, hepatic impairment, hyperbilirubinemia, jaundice

Hypersensitivity: Anaphylaxis

Nervous system: Cerebral sinus thrombosis (Rillon 2023), hypothermia, neuroleptic malignant syndrome (Shouan 2020), parkinsonism, trismus

Neuromuscular & skeletal: Muscle rigidity, torticollis

Ophthalmic: Cataract

Contraindications

Hypersensitivity to zuclopenthixol, thioxanthenes, or any component of the formulation; acute intoxication (alcohol, barbiturate, or opioid); CNS depression; coma; suspected or established subcortical brain damage; circulatory collapse

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics. Avoid use in patients with underlying QT prolongation, in those taking medicines that prolong the QT interval, or cause polymorphic ventricular tachycardia; monitor ECG closely for dose-related QT effects. Adverse effects of decanoate may be prolonged.

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, zuclopenthixol has a low potency of cholinergic blockade. Advise patients to report onset or worsening of anticholinergic effects.

• Blood dyscrasias: Leukopenia, neutropenia, granulocytopenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Esophageal dysmotility/Aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (ie, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).

• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keepers 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability (Landi 2005; Seppala 2018).

• Hyperglycemia: Cases of diabetic ketoacidosis have occurred in patients with no reported history of hyperglycemia.

• Hyperprolactinemia: Use associated with increased prolactin levels; dosage adjustment or therapy discontinuation may be necessary with clinically significant hyperprolactinemia. Use with caution in patients with breast cancer, other prolactin-dependent tumors, and pituitary gland tumors. Prolonged hyperprolactinemia in association with hypogonadism may result in decreased bone mineral density in females and males.

• Neuroleptic malignant syndrome: Neuroleptic malignant syndrome (NMS) has been associated with use of antipsychotic agents, including zuclopenthixol; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability (risk may be increased in patients with Parkinson's disease or Lewy body dementia). Discontinue treatment immediately with onset of NMS; recurrence has been reported in patients rechallenged with antipsychotic therapy.

• Ocular effects: Similar drugs have been associated with pigmentary retinopathy, corneal deposits, and photosensitivity.

• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

• Sexual dysfunction: Decreased libido, menstrual disorders, erectile dysfunction (including priapism rarely) and ejaculation failure have been reported; significant dysfunction may require dosage adjustment or discontinuation of therapy. Effects are reversible upon discontinuation.

• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

• Venous thromboembolism (VTE): VTE has been reported with antipsychotics; evaluate VTE risk prior to and during therapy.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease.

• Dementia: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. An increased incidence of cerebrovascular adverse events (including fatalities) has been reported in elderly patients with dementia-related psychosis. Zuclopenthixol is not approved for use in elderly patients with dementia or dementia-related psychosis.

• Hepatic impairment: Use with caution in patients with hepatic impairment; undergoes hepatic metabolism.

• Renal impairment: Use with caution in patients with renal impairment; has not been studied.

• Seizure disorder: Use with caution in patients at risk of seizures.

Other warnings/precautions :

• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).

Product Availability

Not available in the US

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

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

Oil, Intramuscular, as acetate:

Clopixol Acuphase: 50 mg/mL (1 mL)

Oil, Intramuscular, as decanoate:

Clopixol Depot: 200 mg/mL (1 mL); 500 mg/mL (1 mL)

Tablet, Oral, as dihydrochloride:

Clopixol: 10 mg, 25 mg

Administration: Adult

IM: Acetate or decanoate: Administer by deep injection into the gluteal region. Injection volumes exceeding 2 mL should be distributed between 2 injection sites. When administration of the acetate and decanoate formulations is necessary (eg, exacerbation of chronic psychosis), may mix the acetate and decanoate formulations in the same syringe and administer as a single injection.

Oral: Tablets should be administered in 2 or 3 divided doses with initial dosing; may switch to once-daily administration at bedtime during maintenance treatment. May be administered without regards to meals.

Use: Labeled Indications

Note: Not approved in the United States.

Agitation/aggression (acute) associated with schizophrenia or psychotic episodes (short-acting acetate injection, tablet): Treatment of acute agitation associated with schizophrenia or psychotic episodes.

Schizophrenia (long-acting decanoate injection, tablet): Chronic management of schizophrenia.

Medication Safety Issues

Older Adult: High-Risk Medication:

Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of stroke and a greater rate of cognitive decline and mortality in patients with dementia. Evidence also suggests there may be an increased risk of mortality with use independent of dementia. Avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults. Use of antipsychotics may be appropriate for labeled indications including schizophrenia, bipolar disorder, Parkinson disease psychosis, adjunctive therapy in major depressive disorder, or for short-term use as an antiemetic (Beers Criteria [AGS 2023]).

Other safety concerns:

ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.

Metabolism/Transport Effects

Substrate of CYP2D6 (Major), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;

Drug Interactions

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.

Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor

Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Agents with Clinically Relevant Anticholinergic Effects: May increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor

Agents With Seizure Threshold Lowering Potential: May increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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

Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor

Amisulpride (Oral): May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased. Risk C: Monitor

Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (First Generation [Typical]) may decrease therapeutic effects of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider Therapy Modification

ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor

ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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

Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor

Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Benzgalantamine-Galantamine: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor

Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor

Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. 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

Bornaprine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, tardive dyskinesia symptoms may be potentiated. Risk C: Monitor

Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor

Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromopride: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid

Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Buclizine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor

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

BuPROPion: Zuclopenthixol may increase adverse/toxic effects of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase serum concentration of Zuclopenthixol. Risk C: Monitor

BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Cabergoline: May decrease therapeutic effects of Antipsychotic Agents. Risk X: Avoid

Cannabinoid-Containing Products: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor

Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor

Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. 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

ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor

Chlorprothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Chlorprothixene. Risk C: Monitor

Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid

Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

CloZAPine: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

CYP2D6 Inhibitors (Moderate): May increase serum concentration of Zuclopenthixol. Risk C: Monitor

CYP2D6 Inhibitors (Strong): May increase serum concentration of Zuclopenthixol. Risk C: Monitor

CYP3A4 Inducers (Strong): May decrease serum concentration of Zuclopenthixol. 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

Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor

Deutetrabenazine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor

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

Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may increase adverse/toxic effects of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor

Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor

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 (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor

Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Donepezil: May increase neurotoxic (central) effects of Antipsychotic Agents. 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

DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid

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

Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid

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

Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. 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

Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor

FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor

FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor

Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor

Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid

Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor

Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Guanethidine: Antipsychotic Agents may decrease therapeutic effects of Guanethidine. Risk C: Monitor

Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may increase QTc-prolonging effects of Haloperidol. Risk C: Monitor

Huperzine A: May increase neurotoxic (central) effects of Antipsychotic Agents. 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

Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification

Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor

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

Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may increase QTc-prolonging effects of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor

Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid

Lithium: May increase neurotoxic effects of Antipsychotic Agents. Lithium may decrease serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. 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

Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor

Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid

Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metergoline: Antipsychotic Agents may decrease therapeutic effects of Metergoline. Metergoline may decrease therapeutic effects of Antipsychotic Agents. 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

Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor

Metoclopramide: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid

MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor

MetyroSINE: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor

Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. Risk C: Monitor

Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor

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

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

Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid

OLANZapine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OLANZapine. Risk C: Monitor

OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

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 anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

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

Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. 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

OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor

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: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor

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

Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor

Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Perphenazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. Risk C: Monitor

Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pimozide: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor

Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid

Piribedil: Antipsychotic Agents may decrease therapeutic effects of Piribedil. Piribedil may decrease therapeutic effects of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid

Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor

Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects 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

Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid

Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid

Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor

Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor

Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor

QUEtiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Quinagolide: Antipsychotic Agents may decrease therapeutic effects of Quinagolide. Risk C: Monitor

QuiNIDine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor

Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor

Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid

Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

RisperiDONE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor

Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification

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

Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor

Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects 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

Serotonergic Agents (High Risk): May increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor

Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid

Sulpiride: Antipsychotic Agents may increase adverse/toxic effects of Sulpiride. Risk X: Avoid

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

Tetrabenazine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for NMS and extrapyramidal symptoms may be increased. Risk C: Monitor

Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid

Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor

Thioridazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor

Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor

Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor

Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid

Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor

Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor

Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor

Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor

Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor

Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid

Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ziprasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Ziprasidone. Specifically, the risk of seizures may be increased. 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

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.

Monitoring Parameters

Frequency of Antipsychotic Monitoring in Zuclopenthixol^a,b
Monitoring parameter	Frequency of monitoring	Comments
^a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline. ^b ADA 2004; APA [Keepers 2020]; Landi 2005; Seppala 2018; manufacturer's labeling. ^c Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic. ^d Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; and past or current EPS.
Adherence	Every visit
Blood chemistries (electrolytes, renal function, liver function, TSH)	As clinically indicated
CBC	As clinically indicated	Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia
Extrapyramidal symptoms	Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high risk.^c
Fall risk	As clinically indicated	Evaluate regularly in patients ≥60 years of age
Fasting plasma glucose/HbA_1c	4 months after initiation; annually	Check more frequently than annually if abnormal. Follow diabetes guidelines.
Lipid panel	4 months after initiation; annually	Check more frequently than annually if abnormal. Follow lipid guidelines.
Mental status and alertness	Every visit
Metabolic syndrome history	Annually	Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.
Ocular exam	As clinically indicated	Particularly important for those taking thioridazine or chlorpromazine, or those with diabetes and other conditions that impact sight.
Prolactin	Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported.	Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function.
Tardive dyskinesia	Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high risk.^d
Vital signs (BP, orthostatics, temperature, pulse, signs of infection)	As clinically indicated
Weight/Height/BMI	Every visit for first 6 months, then quarterly	Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome. Consider changing antipsychotic if BMI increases by ≥1 unit.

Reference Range

Timing of serum samples: Draw trough just before next dose (Hiemke 2018).

Therapeutic reference range: 4 to 50 ng/mL (SI: 9.96 to 124.5 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations, however therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).

Laboratory alert level: 100 ng/mL (SI: 249 nmol/L) (Hiemke 2018).

Mechanism of Action

Zuclopenthixol is a thioxanthene antipsychotic with a piperazine side chain; related to fluphenazine, the cis(z)-clopenthixol is the active isomer of this neuroleptic; blocks postsynaptic dopaminergic (D₁ and D₂) brain receptors. Also has high affinity for 5-HT₂ and alpha-1 adrenergic receptors, and a weaker affinity for histamine₁-receptors.

Pharmacokinetics (Adult Data Unless Noted)

Onset of action:

Agitation: Acetate injection: Sedation within 2 hours.

Schizophrenia: Oral: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).

Duration: Acetate injection: 2 to 3 days

Distribution: V_d: 20 L/kg

Protein binding: ~98%

Metabolism: Hepatic via sulfoxidation, and N-dealkylation; (in vitro data suggests that metabolism may occur via CYP2D6 and CYP3A4 [Davies, 2010]); also undergoes glucuronidation. Metabolites are inactive.

Half-life elimination: Terminal: Oral: ~20 hours; Depot: 19 days

Time to peak: Tablet: ~4 hours; Acetate injection: 24-48 hours; Decanoate injection: 3-7 days

Excretion: Mostly feces; urine (~10%; minimal amount as unchanged drug)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Geriatric: Note: Tablet and decanoate injection: Serum concentrations increased ~25% in older adults (Tveito 2021).

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Clopixol acuphase;
(AR) Argentina: Clopixol;
(AT) Austria: Cisordinol | Cisordinol acutard;
(AU) Australia: Clopixol | Clopixol acuphase | Zuclopenthixol;
(BD) Bangladesh: Clopixol | Zentixol a | Zentixol d;
(BE) Belgium: Clopixol | Clopixol acutard;
(BG) Bulgaria: Clopixol | Clopixol acuphase;
(BR) Brazil: Clopixol | Clopixol acuphase;
(CH) Switzerland: Clopixol;
(CL) Chile: Cisordinol;
(CN) China: Clopixol | Clopixol acuphase;
(CZ) Czech Republic: Cisordinol;
(DE) Germany: Ciatyl z | Clopixol | Clopixol depot;
(DK) Denmark: Cisordinol depot;
(DO) Dominican Republic: Zuclo P;
(EE) Estonia: Cisordinol;
(EG) Egypt: Clopixol;
(ES) Spain: Cisordinol | Clopixol;
(FI) Finland: Cisordinol;
(FR) France: Clopixol | Clopixol a action semi prolongee | Clopixol action prolongee;
(GB) United Kingdom: Clopixol;
(GR) Greece: Clopixol;
(HK) Hong Kong: Clopixol | Clopixol acuphase;
(HR) Croatia: Clopixol;
(HU) Hungary: Cisordinol;
(IE) Ireland: Clopixol;
(IL) Israel: Clopixol;
(IN) India: Clopixol;
(IT) Italy: Clopixol | Clopixol acuphase;
(JO) Jordan: Clopixol | Clopixol acuphase;
(KE) Kenya: Clopixol | Clopixol acuphase;
(KR) Korea, Republic of: Clopixol;
(KW) Kuwait: Clopixol | Clopixol acuphase;
(LB) Lebanon: Clopixol;
(LT) Lithuania: Cisordinol;
(LU) Luxembourg: Clopixol | Clopixol acutard;
(LV) Latvia: Cisordinol | Cisordinol acutard;
(MX) Mexico: Clopixol | Clopixol acuphase;
(MY) Malaysia: Clopixol;
(NL) Netherlands: Cisordinol | Clopixol | Zuclopent | Zuclopentixol decanoaat;
(NO) Norway: Cisordinol | Cisordinol acutard;
(NZ) New Zealand: Clopixol;
(PE) Peru: Cisordinol | Cisordinol acutard;
(PH) Philippines: Clopixol | Clopixol acuphase;
(PK) Pakistan: Clopixol | Zucloact | Zuclodept | Zupenth;
(PL) Poland: Cisordinol;
(PT) Portugal: Cisordinol;
(QA) Qatar: Clopixol Depot;
(RO) Romania: Clopixol | Clopixol acuphase;
(RU) Russian Federation: Clopixol | Clopixol acuphase;
(SA) Saudi Arabia: Clopixol | Clopixol acuphase;
(SE) Sweden: Cisordinol | Cisordinol acutard | Cisordinol depot | Clopixol | Clopixol acutard;
(SG) Singapore: Clopixol;
(SI) Slovenia: Clopixol | Clopixol acuphase;
(SK) Slovakia: Cisordinol;
(TH) Thailand: Clopixol | Clopixol acuphase;
(TR) Turkey: Clopixol;
(TW) Taiwan: Clopixol | Clopixol acuphase;
(UA) Ukraine: Clopixol | Clopixol acuphase;
(UG) Uganda: Clopixol | Clopixol acuphase;
(UY) Uruguay: Clopixol | Clopixol acuphase;
(ZA) South Africa: Clopixol | Clopixol acuphase

2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372 [PubMed 37139824]
Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry. 2003;60(12):1228-1235. doi:10.1001/archpsyc.60.12.1228 [PubMed 14662555]
American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-272. [PubMed 15003083]
Andole SN. An unusual presentation of cortical venous thrombosis and its association with typical antipsychotics. BMJ Case Rep. 2011;2011:bcr0720114542. doi:10.1136/bcr.07.2011.4542 [PubMed 22679157]
Cerovecki A, Musil R, Klimke A, et al. Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations. CNS Drugs. 2013;27(7):545-572. doi:10.1007/s40263-013-0079-5 [PubMed 23821039]
Clopixol, Clopixol-Acuphase, and Clopixol Depot (zuclopenthixol) [product monograph]. Montreal, Quebec, Canada: Lundbeck Canada Inc; April 2014.
Davies SJ, Westin AA, Castberg I, et al. Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. Acta Psychiatr Scand. 2010;122(6):444-453. doi:10.1111/j.1600-0447.2010.01619.x [PubMed 20946203]
Hasan A, Falkai P, Wobrock T, et al; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318-378. doi:10.3109/15622975.2012.696143 [PubMed 22834451]
Herzig SJ, LaSalvia MT, Naidus E, et al. Antipsychotics and the risk of aspiration pneumonia in individuals hospitalized for nonpsychiatric conditions: a cohort study. J Am Geriatr Soc. 2017;65(12):2580-2586. doi:10.1111/jgs.15066 [PubMed 29095482]
Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62. doi:10.1055/s-0043-116492 [PubMed 28910830]
Hirshberg B, Gural A, Caraco Y. Zuclopenthixol-associated neutropenia and thrombocytopenia. Ann Pharmacother. 2000;34(6):740-742. doi:10.1345/aph.18468 [PubMed 10860136]
Howard R, Rabins PV, Seeman MV, Jeste DV. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am J Psychiatry. 2000;157(2):172-178. doi:10.1176/appi.ajp.157.2.172 [PubMed 10671383]
Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi:10.1176/appi.ajp.2020.177901 [PubMed 32867516]
Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes. J Clin Psychiatry. 2007;68(suppl 6):10-13. [PubMed 17650054]
Landi F, Onder G, Cesari M, Barillaro C, Russo A, Bernabei R; Silver Network Home Care Study Group. Psychotropic medications and risk for falls among community-dwelling frail older people: an observational study. J Gerontol A Biol Sci Med Sci. 2005;60(5):622-6226. doi:10.1093/gerona/60.5.622 [PubMed 15972615]
Levine SZ, Rabinowitz J. Trajectories and antecedents of treatment response over time in early-episode psychosis. Schizophr Bull. 2010;36(3):624-632. doi:10.1093/schbul/sbn120 [PubMed 18849294]
Maddalena AS, Fox M, Hofmann M, Hock C. Esophageal dysfunction on psychotropic medication. A case report and literature review. Pharmacopsychiatry. 2004;37(3):134-138. [PubMed 15138897]
Mansour E, Danaf S, Ghousayneh D, Assaf G, Ghantous I, El-Khoury F. Zuclopenthixol induced ischemic priapism: case report and review of literature. J Family Reprod Health. 2023;17(2):109-112. doi:10.18502/jfrh.v17i2.12875 [PubMed 37547784]
Moncrieff J, Gupta S, Horowitz MA. Barriers to stopping neuroleptic (antipsychotic) treatment in people with schizophrenia, psychosis or bipolar disorder. Ther Adv Psychopharmacol. 2020;10:2045125320937910. doi:10.1177/2045125320937910 [PubMed 32670542]
National Health Service (NHS) Camden and Islington, NHS Foundation Trust. Depot antipsychotic medication: guidelines for prescribing and administering. https://www.candi.nhs.uk/sites/default/files/Depot%20Antipsychotic%20Medication%20Guidelines_PHA04_February%202020_0.pdf. Updated February 2020. Accessed May 1, 2023.
National Health Service (NHS) South West London and St. George’s Mental Health, NHS Trust. Treatment with antipsychotics. https://www.swlstg.nhs.uk/documents/publications/healthcare-professionals-1/guidelines-and-protocols/. Updated January 12, 2022a. Accessed May 1, 2023.
National Health Service (NHS) Sussex Partnership, NHS Foundation Trust. Antipsychotics guidelines. Updated October 31, 2022b. Accessed May 1, 2023.
Post R. Bipolar disorder in adults: choosing maintenance treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 24, 2020.
Refer to manufacturer's labeling.
Remington G, Chue P, Stip E, Kopala L, Girard T, Christensen B. The crossover approach to switching antipsychotics: what is the evidence? Schizophr Res. 2005;76(2-3):267-272. doi:10.1016/j.schres.2005.01.009 [PubMed 15949658]
Rillon P, Zdanowicz N, Jacques D, Dubois T. A case of central venous sinus thrombosis after injection of zuclopenthixol. Psychiatr Danub. 2023;35(Suppl 2):417-418. [PubMed 37800268]
Seppala LJ, Wermelink AMAT, de Vries M, et al; EUGMS task and Finish group on fall-risk-increasing drugs. Fall-risk-increasing drugs: a systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc. 2018;19(4):371.e11-371.e17. doi:10.1016/j.jamda.2017.12.098 [PubMed 29402652]
Shouan A, Sinha AK, Grover S. Neuroleptic malignant syndrome associated with the use of injection zuclopenthixol acetate. Ind Psychiatry J. 2020;29(2):349-351. doi:10.4103/ipj.ipj_49_19 [PubMed 34158726]
Soares-Weiser K, Fernandez HH. Tardive dyskinesia. Semin Neurol. 2007;27(2):159-169. [PubMed 17390261]
Spanarello S, La Ferla T. The pharmacokinetics of long-acting antipsychotic medications. Curr Clin Pharmacol. 2014;9(3):310-317. doi:10.2174/15748847113089990051 [PubMed 23343447]
Steinman M, Reeve E. Deprescribing. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 2, 2022.
Stroup TS, Marder S. Schizophrenia in adults: maintenance therapy and side effect management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 28, 2022.
Takeuchi H, Kantor N, Uchida H, Suzuki T, Remington G. Immediate vs gradual discontinuation in antipsychotic switching: a systematic review and meta-analysis. Schizophr Bull. 2017;43(4):862-871. doi:10.1093/schbul/sbw171 [PubMed 28044008]
Tveito M, Smith RL, Molden E, Høiseth G. Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation-an observational study including 2044 patients. Eur J Clin Pharmacol. 2021;77(2):215-221. doi:10.1007/s00228-020-03002-y [PubMed 33000414]
Whyte A, Parker C. A review of the efficacy and tolerability of antipsychotic long-acting injections. Progress. 2016;20(4):22-28. doi:10.1002/pnp.436
Wistedt B, Koskinen T, Thelander S, Nerdrum T, Pedersen V, Mølbjerg C. Zuclopenthixol decanoate and haloperidol decanoate in chronic schizophrenia: a double-blind multicentre study. Acta Psychiatr Scand. 1991;84(1):14-21. doi:10.1111/j.1600-0447.1991.tb01414.x [PubMed 1681680]

Topic 10127 Version 311.0

خرید پکیج

Zuclopenthixol (United States: Not available): Drug information