Management of schizophrenia/psychoses:
Acute psychosis:
Oral:
Acute psychosis: Initial: 10 to 50 mg/day in 2 to 3 divided doses; may titrate dose upward by 10 to 20 mg every 2 to 3 days; usual therapeutic range: 20 to 40 mg/day; maximum dose: 100 mg/day
Maintenance therapy: Maintain lowest effective dose; usual maintenance dose: 20 to 40 mg/day; may be given as a single dose
IM: Zuclopenthixol acetate: Usual dose: 50 to 150 mg; 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: no more than 400 mg or 4 injections should be given in the course of treatment. Duration of treatment not to exceed 2 weeks.
Transfer of patients from IM acetate to oral tablets: Note: Allow 2 to 3 days after final injection before initiating oral therapy:
50 mg of acetate injection every 2 to 3 days = 20 mg daily of oral tablets
100 mg of acetate injection every 2 to 3 days = 40 mg daily of oral tablets
150 mg of acetate injection every 2 to 3 days = 60 mg daily of oral tablets
Long-term management of psychosis: Zuclopenthixol decanoate: IM: Maintenance therapy: Usual maintenance dose: 150 to 300 mg every 2 to 4 weeks; dose increase or reduction and/or more frequent administration may be required in some patients. Maintain lowest effective dose.
Transfer of patients from oral tablets to IM decanoate: Note: Supplemental oral dosing, with subsequent tapering, may be required during the transition period.
≤20 mg daily of oral tablets = 100 mg of decanoate injection every 2 weeks
25 to 40 mg daily of oral tablets = 200 mg of decanoate injection every 2 weeks
50 to 75 mg daily of oral tablets = 300 mg of decanoate injection every 2 weeks
>75 mg/day of oral tablets = 400 mg of decanoate injection every 2 weeks
Transfer of patients from IM acetate to IM decanoate: Note: When initiating maintenance therapy with decanoate, may administer initial dose concomitantly with final acetate injection:
50 mg of acetate injection every 2 to 3 days = 100 mg of decanoate injection every 2 weeks
100 mg of acetate injection every 2 to 3 days = 200 mg of decanoate injection every 2 weeks
150 mg of acetate injection every 2 to 3 days = 300 mg of decanoate injection every 2 weeks
Discontinuation of therapy: 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 (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2020).
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 (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2020).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in 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.
There are no dosage adjustments provided in manufacturer's labeling (has not been studied). Use with caution; zuclopenthixol undergoes extensive hepatic metabolism.
Refer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Howard 2000).
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Oil, Intramuscular:
Clopixol Acuphase: 50 mg/mL (1 mL)
Clopixol Depot: 200 mg/mL (1 mL); 500 mg/mL (1 mL)
Tablet, Oral:
Clopixol: 10 mg, 25 mg
Not available in the US
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.
Note: Not approved in the US
Schizophrenia: Management of schizophrenia; acetate injection is intended for short-term acute treatment (initial treatment for acute psychosis or exacerbation of psychosis associated with schizophrenia); decanoate injection is for long-term management; tablets may be used in either the initial or maintenance phase
Beers Criteria: Based on pharmacologic class concerns for antipsychotics in the Beers Criteria, zuclopenthixol may be a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. 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 (Beers Criteria [AGS 2019]).
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Incidence reported with oral formulation unless otherwise noted. Reported incidence with injection includes decanoate and/or acetate formulations.
>10%:
Central nervous system: Drowsiness (32%; injection 16% to 20%), hypertonia (19%; injection 5% to 26%), anxiety (17%; injection 4% to 9%), insomnia (16%; injection 5% to 10%), akathisia (14%; injection 13% to 16%), extrapyramidal reaction (13%; injection 1% to 12%), dizziness (11%; injection 7% to 21%), dystonia (5%; injection 7% to 14%)
Gastrointestinal: Xerostomia (15%; injection 13% to 25%)
Neuromuscular & skeletal: Tremor (19%; injection 8% to 21%), weakness (15%; injection 8% to 14%), hypokinesia (7%; injection 10% to 21%)
Ophthalmic: Accommodation disturbance (6%; injection 4% to 11%)
1% to 10%:
Cardiovascular: Tachycardia (4%; injection 3% to 10%), orthostatic hypotension (3%; injection ≤1%), hypotension (2%), palpitations (1%; injection ≤2%), syncope (1%; injection <1%)
Central nervous system: Agitation (10%; injection 1%), depression (8%; injection 3% to 7%), lack of concentration (8%; injection 3% to 4%), headache (5%; injection 1% to 5%), vertigo (5%; injection 1% to 2%), amnesia (3%; injection 2%), apathy (3%; injection 1% to 2%), confusion (3%; injection ≤1%), hallucination (3%), tardive dyskinesia (3%; injection ≤1%), abnormal dreams (2%; injection 2%), abnormal gait (2%; injection ≤1%), malaise (2%), pain (2%), paresthesia (1%; injection 2% to 3%), anorgasmia (females ≤1%; injection ≤1%)
Dermatologic: Diaphoresis (3%; injection 1% to 6%), seborrhea (2%; injection ≤1%), pruritus (injection ≤2%), pallor (1%)
Endocrine & metabolic: Weight gain (4%; injection ≤2%), decreased libido (3%; injection ≤1%), weight loss (3%; injection ≤2%), menstrual disease (2%; injection ≤4%), increased thirst (1%; injection ≤2%)
Gastrointestinal: Constipation (8%; injection 1% to 6%), sialorrhea (8%; injection 6% to 10%), anorexia (4%; injection ≤2%), vomiting (3%; injection 1% to 2%), nausea (2%; injection 1%), increased appetite (1%; injection ≤2%), diarrhea (<1%; injection ≤1%), dyspepsia (injection ≤1%)
Genitourinary: Urination disorder (3%; injection 1% to 3%), ejaculatory disorder (≤1%; injection ≤2%)
Neuromuscular & skeletal: Myalgia (injection ≤1%)
Ophthalmic: Visual disturbance (4%; injection ≤2%)
All formulations: <1%, postmarketing, and/or case reports: Abdominal pain, agranulocytosis, anaphylaxis, apnea, application site reaction, arthritis, ataxia, back pain, bloating, cataract, chest pain, cholestatic hepatitis, conjunctivitis, convulsions, dermatitis, drug dependence, drug-induced Parkinson's disease, dyschromia, dyskinesia, dysphagia, dyspnea, erectile dysfunction, excitability, fever, galactorrhea, gastric ulcer, glossitis, gynecomastia, hepatic insufficiency, hot flash, hyperacusis, hyperbilirubinemia, hyperglycemia, hyperlipidemia, hyperprolactinemia, hyperreflexia, hypersensitivity reaction, hypothermia, hypotonia, impaired glucose tolerance, increased libido, increased serum alkaline phosphatase, increased serum ALT, irritability, jaundice, leukopenia, migraine, muscle rigidity, mydriasis, nasal congestion, neuroleptic malignant syndrome, neutropenia, nightmares, oculogyric crisis, peripheral edema, pharyngitis, polyuria, priapism, prolonged QT interval on ECG, purpura, rhinitis, skin photosensitivity, skin rash (including erythematous and psoriasiform rash), speech disturbance, thrombocytopenia, tinnitus, torsades de pointes, torticollis, trismus, urinary incontinence, urinary retention, urinary tract infection, vaginal dryness, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia
Hypersensitivity to zuclopenthixol, thioxanthenes, or any component of the formulation; acute intoxication (ethanol, barbiturate, or opioid); CNS depression; coma; suspected or established subcortical brain damage; circulatory collapse
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. Obtain blood counts prior to initiation and then periodically thereafter.
• 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. Obtain blood glucose level and body weight prior to initiation and then periodically thereafter.
• 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 (NMS): [Canadian Boxed Warning]: 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: 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]).
Substrate of CYP2D6 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
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
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome may be increased. Risk X: Avoid combination
Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect 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
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect 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
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 adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
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
BuPROPion: Zuclopenthixol may enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. 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
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect 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
Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy
Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of 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
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. 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. 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
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: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 enhance the adverse/toxic effect 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 enhance the adverse/toxic effect 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 (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 CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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
Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect 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 therapy
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination
Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. 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
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
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may 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
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect 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 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
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect 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 therapy
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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
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
Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination
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
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. 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
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
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
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.
Mental status; vital signs (as clinically indicated); ECG (patients with a history of QT prolongation or other cardiovascular disorders, electrolyte disturbances); weight, height, BMI, waist circumference (baseline; at every visit for the first 6 months; quarterly with stable antipsychotic dose); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); fasting plasma glucose level/ HbA1c (baseline, then yearly; in patients with diabetes risk factors or if gaining weight repeat 4 months after starting antipsychotic, then yearly); lipid panel (baseline; repeat every 2 years if LDL level is normal; repeat every 6 months if LDL level is >130 mg/dL); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 6 months; high-risk patients every 3 months); visual changes (inquire yearly); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004); fall risk (baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk) (Landi 2005; Seppala 2018).
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).
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.
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: Vd: 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)