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| ====== Clozapine (Clozaril) ====== | ====== Clozapine (Clozaril) ====== | ||
| + | {{INLINETOC}} | ||
| + | |||
| ===== Primer ===== | ===== Primer ===== | ||
| - | **Clozapine** (Tradename: //Clozaril//) is an [[meds:antipsychotics:home|atypical antipsychotic]]. It is used to treat both the positive and negative symptoms of schizophrenia, especially in patients who are resistant to other antipsychotics. It is the commonly referred to as a "last-line antipsychotic." It is a low potency antipsychotic and highly anticholingeric, which gives it a very low incidence of extrapyramidal side effects. However, it carries a risk of neutropenia and agranulocytosis, which requires intensive blood work and monitoring. Other serious side effects include the risk of constipation and related GI-issues. Norclozapine is the major metabolite of clozapine. | ||
| - | ===== Management ===== | ||
| <WRAP group> | <WRAP group> | ||
| <WRAP half column> | <WRAP half column> | ||
| - | ==== Pre-Treatment Investigations ==== | + | **Clozapine** (Trade name: //Clozaril//) is a an [[meds:antipsychotics:home|antipsychotic]] in the [[meds:antipsychotics:second-gen-atypical:home|atypical antipsychotic]] class used in the treatment of [[psychosis:schizophrenia-scz|schizophrenia]], especially in patients who are resistant to other antipsychotics. It is commonly referred to as a "last-line antipsychotic." It is a low potency antipsychotic and highly anticholingeric, which gives it a very low incidence of extrapyramidal side effects. However, it carries a risk of neutropenia and agranulocytosis, which requires intensive blood work and monitoring. Other serious side effects include the risk of constipation and related GI-issues. |
| - | <panel title="Pre-Treatment Investigations" no-body="true"> | + | |
| - | ^ Physical ^ Labwork ^ | + | |
| - | | • Height \\ • Weight \\ • Waist circumference \\ • Blood pressure \\ • Heart rate | • CBC \\ • Glucose fasting \\ • AST, ALT, ALP\\ • Lipid Panel \\ • HbA1C \\ • CRP \\ • High sensitivity troponin I \\ • Baseline ECG | | + | |
| - | </panel> | + | |
| </WRAP> | </WRAP> | ||
| <WRAP half column> | <WRAP half column> | ||
| - | ==== Starting Dose ==== | + | <catlist meds:antipsychotics:second-gen-atypical: -columns:1 -noAddPageButton -sortAscending -noNSInBold> |
| - | * Clozapine can be started at 25-50mg PO daily. The dose can be titrated by 25-50 mg per day up to 300 mg | + | </WRAP> |
| - | * Once at 300mg daily, the titration should not exceed by more than 25mg each day | + | </WRAP> |
| - | * Once at daily doses of 400mg, 500mg 600mg, 700mg, 800mg, and 900mg, these doses should be maintained for at least 14 days | + | |
| - | * Once past 500mg daily, consider increasing the dose by 25-50mg //only// every 2 weeks | + | |
| - | * The maximum daily dose of clozapine is 900mg | + | |
| + | ===== Pharmacokinetics ===== | ||
| + | <WRAP group> | ||
| + | <WRAP half column> | ||
| + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> | ||
| + | See also article: **[[meds:pharmacology:home|]]** | ||
| + | </alert> | ||
| + | <panel type="info" title="Pharmacokinetics of Clozapine" subtitle="" no-body="true" footer=""> | ||
| + | ^ [[meds:pharmacology:home#absorption|Absorption]] | Clozapine undergoes almost complete absorption. Oral bioavailability is 27-47% due to variable first pass metabolism, and peak concentration is around 2.5 hours following oral dosing.[([[https://pubmed.ncbi.nlm.nih.gov/36793249/|Reeves, S., Bertrand, J., Obee, S. J., Hunter, S., Howard, R., & Flanagan, R. J. (2023). A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status. British Journal of Clinical Pharmacology.]])] | | ||
| + | ^ [[meds:pharmacology:home#distribution|Distribution]] | 95% bound to plasma proteins[([[https://pubmed.ncbi.nlm.nih.gov/36793249/|Reeves, S., Bertrand, J., Obee, S. J., Hunter, S., Howard, R., & Flanagan, R. J. (2023). A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status. British Journal of Clinical Pharmacology.]])] | | ||
| + | ^ [[meds:pharmacology:home#metabolism|Metabolism]] | Norclozapine is the major metabolite of clozapine. | | ||
| + | ^ [[meds:pharmacology:home#excretionelimination|Elimination]] | | | ||
| + | ^ [[meds:pharmacology:home#half-life|Half-life]] | | | ||
| + | </panel> | ||
| + | </WRAP> | ||
| + | <WRAP half column> | ||
| + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> | ||
| + | See also article: **[[meds:cytochrome-p450|]]** | ||
| + | </alert> | ||
| + | <panel title="Clozapine: Cytochrome P450 Metabolism" no-body="true"> | ||
| + | ^ Substrate of (Metabolized by) | 1A2 | | ||
| + | ^ Induces | | | ||
| + | ^ Inhibits | | | ||
| + | </panel> | ||
| </WRAP> | </WRAP> | ||
| </WRAP> | </WRAP> | ||
| + | |||
| + | ===== Pharmacodynamics ===== | ||
| + | ==== Mechanism of Action ==== | ||
| + | * Clozapine has the second lowest affinity for the D2 receptor ([[meds:antipsychotics:second-gen-atypical:6-quetiapine|quetiapine]] is first).[([[https://pubmed.ncbi.nlm.nih.gov/11873706/|Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38.]])] It dissociates quickly from the D2 receptor (this has been referred to the "kiss and run" hypothesis).[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1408069/|Kapur, S., & Seeman, P. (2000). Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. Journal of Psychiatry and Neuroscience, 25(2), 161.]])][(Schatzberg, AF, Nemeroff, C . The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed. American Psychiatric Publishing, 2009.)] As a result, these two rapidly dissociating atypical antipsychotics have a very low incidence of EPS. | ||
| + | |||
| + | ==== Toxicity ==== | ||
| + | |||
| + | ===== Indications ===== | ||
| + | * [[psychosis:schizophrenia-scz|Schizophrenia]] | ||
| + | * [[geri:parkinsons|Parkinson's Disease]] psychosis | ||
| + | |||
| + | ===== Benefits ===== | ||
| + | ==== Low EPS ==== | ||
| + | Clozapine has the same incidence of [[meds:antipsychotics:eps|extrapyramidal symptoms]] as placebo.[([[https://www.ncbi.nlm.nih.gov/pubmed/12839431|Iqbal, M. M., Rahman, A., Husain, Z., Mahmud, S. Z., Ryan, W. G., & Feldman, J. M. (2003). Clozapine: a clinical review of adverse effects and management. Annals of Clinical Psychiatry, 15(1), 33-48.]])] This makes it a particularly useful switch antipsychotic for patients who are experiencing significant EPS from other antipsychotics. | ||
| + | |||
| + | ==== Suicide Prevention ==== | ||
| + | Clozapine is only one of two psychotropics (the other is [[meds:mood-stabilizers-anticonvulsants:1-lithium|lithium]]) that has been clinically shown to reduce the risk of suicide.[([[https://www.ncbi.nlm.nih.gov/pubmed/12511175|Meltzer, H. Y., Alphs, L., Green, A. I., Altamura, A. C., Anand, R., Bertoldi, A., ... & Krishnan, R. (2003). Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial (InterSePT). Archives of general psychiatry, 60(1), 82-91.]])] | ||
| + | ===== Dosing ===== | ||
| + | <panel type="info" title="Dosing for Clozapine" no-body="true"> | ||
| + | ^ Starting | 25-50 mg PO daily, can be titrated 25-50 mg per day up to 300 mg. | | ||
| + | ^ Once at 300 mg daily... | Titration should not exceed more than 25 mg each day | | ||
| + | ^ Once at daily doses of 400 mg, 500 mg 600 mg, 700 mg, 800 mg, and 900 mg... | Maintain at each interval for at least 2 weeks before moving on | | ||
| + | ^ Once past 500 mg daily... | Consider increasing the dose by 25-50 mg //only// every 2 weeks. | | ||
| + | ^ Maximum | 900 mg | | ||
| + | </panel> | ||
| + | |||
| + | Note that an adequate trial of clozapine is considered to be a minimum of ''8'' weeks, but preferably ''12'' weeks, reaching a minimum dose of 400 mg per day.[([[https://pubmed.ncbi.nlm.nih.gov/28703015/|Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.]])] | ||
| + | |||
| + | ==== Formulations ==== | ||
| + | * Clozapine comes in oral or liquid formulation. | ||
| + | |||
| + | ==== Pre-Treatment Investigations ==== | ||
| + | <panel title="Pre-Treatment Investigations" no-body="true"> | ||
| + | | ^ Investigations ^ | ||
| + | ^ Physical | • Height \\ • Weight \\ • Waist circumference \\ • Blood pressure \\ • Heart rate | | ||
| + | ^ Labwork | • CBC \\ • Glucose fasting \\ • AST, ALT, ALP\\ • Lipid Panel \\ • HbA1C \\ • CRP \\ • High sensitivity troponin I \\ • Baseline ECG | | ||
| + | </panel> | ||
| ==== Target Plasma Level ==== | ==== Target Plasma Level ==== | ||
| - | The dose of clozapine is not correlated with clinical response, rather, it is the clozapine //plasma level// that matters. The lowest effective clozapine plasma levels range from **250 to 550 µg/L** based on research consensus. Plasma levels below 200 μg/L may place patients at a higher risk of relapse, while above 1000 μg/L increases the risk of developing seizures. The recommended upper limit to prevent clozapine toxicity ranges from 600 to 2000 µg/L. The dose of clozapine taken does not always correspond to plasma levels. Plasma levels are generally lower in younger patients, males and smokers, while being higher in Asians. Other factors that can change clozapine levels include adherence, inflammation, and infection. Clozapine plasma levels correlates with seizure risk. Retrospective studies have been used to create nomograms to help determine whether serum levels are therapeutic based on specific patient demographics, including smoking, age, sex, and metabolic activity.[([[https://www.ncbi.nlm.nih.gov/pubmed/14709950|Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24(1):70-8.]])] | + | * The clozapine dose (i.e. - milligrams you take) is not correlated with clinical response, rather, it is the clozapine //plasma level// that matters. |
| + | * Additionally, the dose taken does not always correspond to plasma levels. Plasma levels are generally lower in younger patients, males and smokers, while being higher in Asians. | ||
| + | * Other factors that can change clozapine levels include adherence, inflammation, and infection. Retrospective studies have also been used to create nomograms to help determine whether serum levels are therapeutic based on specific patient demographics such as smoking, age, sex, and metabolic activity.[([[https://www.ncbi.nlm.nih.gov/pubmed/14709950|Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24(1):70-8.]])] | ||
| + | |||
| + | <panel type="info" title="Recommended Clozapine Levels" subtitle="" no-body="true" footer="* = nmol/L × 0.33 = ng/mL"> | ||
| + | ^ ^ ng/mL (µg/L) ^ nmol/L (nM/L)* ^ Notes ^ | ||
| + | ^ Lower bound | <200 | <600 | May place patients at a higher risk of relapse | | ||
| + | ^ Recommended level (divided dosing)[([[https://pubmed.ncbi.nlm.nih.gov/28703015/|Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.]])] | ≥250 | ≥765 | Typical dose is ~400mg to achieve this level | | ||
| + | ^ Recommended level (once daily dosing)[([[https://pubmed.ncbi.nlm.nih.gov/28703015/|Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. The Canadian Journal of Psychiatry, 62(9), 604-616.]])] | ≥350 | ≥1100 | Typical dose is ~400mg to achieve this level | | ||
| + | ^ Upper bound | >1000 | >3000 | Increased risk of seizures | | ||
| + | ^ Maximum/Toxic Levels[([[https://pubmed.ncbi.nlm.nih.gov/22327098/|Stark, A., & Scott, J. (2012). A review of the use of clozapine levels to guide treatment and determine cause of death. Australian & New Zealand Journal of Psychiatry, 46(9), 816-825.]])] | >2000 | >6000 | Risk of clozapine-related toxicity | | ||
| + | </panel> | ||
| ==== Hematological Monitoring ==== | ==== Hematological Monitoring ==== | ||
| Line 32: | Line 96: | ||
| <WRAP half column> | <WRAP half column> | ||
| <panel type="info" title="Hematological Monitoring" subtitle="Adapted from: Canadian AA-CLOZAPINE Product Monograph, AA Pharma, December 2, 2016" no-body="true" footer=" The change from a weekly to a once-every-two-weeks, or from a once-every-two-weeks to a once-every-four-weeks schedule should be based upon the hematological profile of the patient as well as the clinical judgment of the treating physician, and if deemed appropriate, a consulting hematologist, and on the patient’s willingness to pursue a given frequency of blood monitoring. The clinical evaluation should take into consideration possible factors that would place the patient in a higher risk group. "> | <panel type="info" title="Hematological Monitoring" subtitle="Adapted from: Canadian AA-CLOZAPINE Product Monograph, AA Pharma, December 2, 2016" no-body="true" footer=" The change from a weekly to a once-every-two-weeks, or from a once-every-two-weeks to a once-every-four-weeks schedule should be based upon the hematological profile of the patient as well as the clinical judgment of the treating physician, and if deemed appropriate, a consulting hematologist, and on the patient’s willingness to pursue a given frequency of blood monitoring. The clinical evaluation should take into consideration possible factors that would place the patient in a higher risk group. "> | ||
| - | ^ Treatment Status ^ Bloodwork ^ Action ^ | + | <mobiletable 1> |
| - | ^ {{fa>check fa-fw?&color=#5EC4F3}} Baseline | • WBC ≥3.5 x 10<sup>9</sup>/L\\ • ANC ≥2.0 x 10<sup>9</sup>/L | Begin clozapine treatment | | + | ^ Treatment Status ^ Bloodwork ^ Action ^ |
| - | ^ {{fa>circle fa-fw?&color=#85CBAF}} Green | • WBC ≥3.5 x 10<sup>9</sup>/L \\ • ANC ≥2.0 x 10<sup>9</sup>/L | • Continue treatment\\ • Monitor patient:\\ – Weekly for the first 26 weeks\\ – Every 2 weeks for the next 26 weeks\\ – Every 4 weeks thereafter | | + | ^ {{fa>check fa-fw?&color=#5EC4F3}} Baseline | • WBC ≥3.5 x 10<sup>9</sup>/L\\ • ANC ≥2.0 x 10<sup>9</sup>/L | Begin clozapine treatment | |
| - | ^ {{fa>circle fa-fw?&color=#FFFAAA}} Flashing Yellow | Any of the following: \\ • A single or sum of falls in WBC count of 3.0 x 10<sup>9</sup>/L over the last ''4'' weeks, reaching a value <4.0 x 10<sup>9</sup>/L\\ • A single or sum of falls in ANC of 1.5 x 10<sup>9</sup>/L over the last ''4'' weeks, reaching a value <2.5 x 10<sup>9</sup>/L | • Patient should be evaluated immediately\\ • Check WBC count and ANC twice weekly\\ • Continue treatment | | + | ^ {{fa>circle fa-fw?&color=#85CBAF}} Green | • WBC ≥3.5 x 10<sup>9</sup>/L \\ • ANC ≥2.0 x 10<sup>9</sup>/L | • Continue treatment\\ • Monitor patient:\\ – Weekly for the first 26 weeks\\ – q2 weeks for the next 26 weeks\\ – q4 weeks thereafter | |
| - | ^ {{fa>circle fa-fw?&color=#FFF888}} Yellow | Any of the following: \\ • WBC 2.0-3.5 x 10<sup>9</sup>/L\\ • ANC 1.5-2.0 x 10<sup>9</sup>/L | • Patient should be evaluated immediately\\ • Check WBC count and ANC twice weekly\\ • Continue treatment | | + | ^ {{fa>circle fa-fw?&color=#FFFAAA}} Flashing Yellow | Any of the following: \\ • A single (or sum of) fall in WBC of 3.0 x 10<sup>9</sup>/L over the last ''4'' weeks, reaching a value <4.0 x 10<sup>9</sup>/L\\ • A single (or sum of) fall in ANC of 1.5 x 10<sup>9</sup>/L over the last ''4'' weeks, reaching a value <2.5 x 10<sup>9</sup>/Lo | • Patient should be evaluated immediately\\ • Check WBC count and ANC twice weekly\\ • Continue treatment | |
| - | ^ {{fa>circle fa-fw?&color=#E8B5A2}} Red | Any of the following: \\ • WBC <2.0 x 10<sup>9</sup>/L\\ • ANC <1.5 x 10<sup>9</sup>/L | • Immediately stop treatment and confirm results within 24 hours\\ • Patient must be closely monitored\\ • Attention must be paid to any flu-like complaints or other symptoms which might suggest infection\\ • Clozapine must **NOT** be resumed if results are confirmed and the patient should be assigned a non-rechallengeable status | | + | ^ {{fa>circle fa-fw?&color=#FFF888}} Yellow | Any of the following: \\ • WBC 2.0-3.5 x 10<sup>9</sup>/L\\ • ANC 1.5-2.0 x 10<sup>9</sup>/L | • Patient should be evaluated immediately\\ • Check WBC count and ANC twice weekly\\ • Continue treatment | |
| - | ^ {{fa>circle fa-fw?&color=#D87B64}} Critical | Any of the following: \\ • WBC <1.0 x 10<sup>9</sup>/L\\ • ANC <0.5 x 10<sup>9</sup>/L | • Place the patient in protective isolation with close observation\\ • Physician must watch for signs of infection | | + | ^ {{fa>circle fa-fw?&color=#E8B5A2}} Red | Any of the following: \\ • WBC <2.0 x 10<sup>9</sup>/L\\ • ANC <1.5 x 10<sup>9</sup>/L | • Immediately stop treatment and confirm results within 24 hours\\ • Patient must be closely monitored\\ • Attention must be paid to any flu-like complaints or other symptoms which might suggest infection\\ • Clozapine must **NOT** be resumed if results are confirmed and the patient should be assigned a non-rechallengeable status | |
| + | ^ {{fa>circle fa-fw?&color=#D87B64}} Critical | Any of the following: \\ • WBC <1.0 x 10<sup>9</sup>/L\\ • ANC <0.5 x 10<sup>9</sup>/L | • Place the patient in protective isolation with close observation\\ • Physician must watch for signs of infection | | ||
| + | </mobiletable> | ||
| </panel> | </panel> | ||
| </WRAP> | </WRAP> | ||
| Line 47: | Line 113: | ||
| <callout type="tip" title="Morning Pseudoneutropenia" icon="true">Some patients have a very pronounced diurnal variation in their number of circulating neutrophils.[([[https://www.ncbi.nlm.nih.gov/pubmed/14608591|Esposito, D., Aouillé, J., Rouillon, F., & Limosin, F. (2003). Morning pseudoneutropenia during clozapine treatment. The World Journal of Biological Psychiatry, 4(4), 192-194.]])][([[https://www.ncbi.nlm.nih.gov/pubmed/16191205|Porter, R., & Mohamed, A. (2006). Diurnal variation of neutropenia during clozapine treatment. International Journal of Neuropsychopharmacology, 9(3), 373-374.]])] Thus, morning blood work may reveal a critical WBC count that falls below the normal range. In this case, it is wise to repeat a neutrophil count in the afternoon, before deciding to change clozapine treatment.[([[https://www.cjhp-online.ca/index.php/cjhp/article/view/188|Spina, S. P., & Corrigan, S. P. (2007). Continuing clozapine therapy despite morning pseudoneutropenia. The Canadian Journal of Hospital Pharmacy, 60(4).]])] | <callout type="tip" title="Morning Pseudoneutropenia" icon="true">Some patients have a very pronounced diurnal variation in their number of circulating neutrophils.[([[https://www.ncbi.nlm.nih.gov/pubmed/14608591|Esposito, D., Aouillé, J., Rouillon, F., & Limosin, F. (2003). Morning pseudoneutropenia during clozapine treatment. The World Journal of Biological Psychiatry, 4(4), 192-194.]])][([[https://www.ncbi.nlm.nih.gov/pubmed/16191205|Porter, R., & Mohamed, A. (2006). Diurnal variation of neutropenia during clozapine treatment. International Journal of Neuropsychopharmacology, 9(3), 373-374.]])] Thus, morning blood work may reveal a critical WBC count that falls below the normal range. In this case, it is wise to repeat a neutrophil count in the afternoon, before deciding to change clozapine treatment.[([[https://www.cjhp-online.ca/index.php/cjhp/article/view/188|Spina, S. P., & Corrigan, S. P. (2007). Continuing clozapine therapy despite morning pseudoneutropenia. The Canadian Journal of Hospital Pharmacy, 60(4).]])] | ||
| </callout> | </callout> | ||
| - | |||
| - | |||
| </WRAP> | </WRAP> | ||
| </WRAP> | </WRAP> | ||
| + | ==== Missed Doses ==== | ||
| + | * Doses missed for more than 48 hours (i.e. - 2 days) must be re-titrated! | ||
| + | * Stopping clozapine for 48 to 72 hours is considered a full treatment break, and thus must be retitrated | ||
| + | * Risks of continuing at the original dose include increased risk of seizures, orthostatic hypotension, and excessive sedation. | ||
| + | * If more than > 3 days are missed, increased frequency of WBC monitoring and CBC differential will be required as well | ||
| + | ==== Tapering or Discontinuation ==== | ||
| + | <callout type="danger" title="Don't Forget to Continue Bloodwork Monitoring!" icon="true"> | ||
| + | When discontinuing clozapine, a weekly white blood cell and absolute neutrophil count still needs ordered in the 4 weeks post-discontinuation![(Clozapine Product Monograph)] | ||
| + | </callout> | ||
| - | == Guidelines == | + | * The abrupt withdrawal of clozapine has been associated with cholinergic rebound symptoms and rapid onset of psychosis.[([[https://www.ncbi.nlm.nih.gov/pubmed/8938913|Shiovitz, T. M., Welke, T. L., Tigel, P. D., Anand, R., Hartman, R. D., Sramek, J. J., ... & Cutler, N. R. (1996). Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophrenia bulletin, 22(4), 591.]])] |
| - | * [[https://safetyandquality.gov.au/wp-content/uploads/2013/01/National-Adult-Clozapine-Titration-Chart.pdf|Australian Monitoring Guidelines]] | + | * Discontinuation-induced supersensitivity of dopamine receptors may lead to worsening and the appearance of new and more complex symptoms, and there have been case reports of suicide.[([[https://www.ncbi.nlm.nih.gov/pubmed/8938913|Shiovitz, T. M., Welke, T. L., Tigel, P. D., Anand, R., Hartman, R. D., Sramek, J. J., ... & Cutler, N. R. (1996). Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophrenia bulletin, 22(4), 591.]])][([[https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5470314/|Patchan, K. M., Richardson, C., Vyas, G., & Kelly, D. L. (2015). The risk of suicide after clozapine discontinuation: Cause for concern. Annals of clinical psychiatry: official journal of the American Academy of Clinical Psychiatrists, 27(4), 253.]])] |
| - | * [[https://www.pharmaceutical-journal.com/learning/learning-article/how-clozapine-patients-can-be-monitored-safely-and-effectively/11138788.article|UK Guidelines]] | + | * Therefore, clozapine should always be gradually and slowly tapered over time. |
| - | * [[https://www.aaspire.ca/resources/HealthCareProfessional/English/17-AA004_AAC0070E_Dose%20Card%2017162_EN_Print_Layout_V11_LR_Client-Friendly.pdf|Canadian Guidelines]] | + | ===== Contraindications ===== |
| + | ==== Absolute ==== | ||
| + | * Clozapine is contraindicated in patients with a previous hypersensitivity to clozapine | ||
| + | * Myeloproliferative disorders[([[https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019758s054lbl.pdf|FDA Monograph Clozaril]])] | ||
| + | * Uncontrolled epilepsy | ||
| + | * Paralytic ileus | ||
| - | ==== Missed Doses ==== | + | ==== Relative ==== |
| - | http://www.ggcprescribing.org.uk/media/uploads/postscript_acute/psacute_06.pdf | + | * A history of clozapine-induced severe neutropenia or agranulocytosis is a relative contraindication for restarting clozapine. |
| + | * A history of clozapine-induced myocarditis | ||
| + | * Controlled seizures or epilepsy | ||
| + | ===== Drug-Drug Interactions ===== | ||
| + | * Fluvoxamine increases clozapine levels by inhibiting CYP 1A2 metabolism | ||
| + | * Clinically, sometimes fluvoxamine is added to clozapine to increase levels of clozapine, and reduce the conversion of clozapine to norclozapine, as there is evidence to suggest that a clozapine:norclozapine ratio of 2 or more will increase efficacy and tolerability of clozapine treatment (i.e. - more clozapine than norclozapine).[([[https://pubmed.ncbi.nlm.nih.gov/23490199/|Légaré, N., Grégoire, C. A., De Benedictis, L., & Dumais, A. (2013). Increasing the clozapine: norclozapine ratio with co-administration of fluvoxamine to enhance efficacy and minimize side effects of clozapine therapy. Medical hypotheses, 80(6), 689-691.]])] | ||
| + | * [[meds:supplements:st-johns-wort|St. John's wort]] induces CYP3A4 and CYP1A2 and reduces clozapine levels | ||
| + | * Caffiene can inhibit CYP1A2, and can increase clozapine levels (mild-moderate) | ||
| - | ==== Tapering or Discontinuation ==== | + | ==== Smoking ==== |
| - | The abrupt withdrawal of clozapine has been associated with cholinergic rebound symptoms and rapid onset of psychosis.[([[https://www.ncbi.nlm.nih.gov/pubmed/8938913|Shiovitz, T. M., Welke, T. L., Tigel, P. D., Anand, R., Hartman, R. D., Sramek, J. J., ... & Cutler, N. R. (1996). Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophrenia bulletin, 22(4), 591.]])] Discontinuation-induced supersensitivity of dopamine receptors can lead to worsening and the appearance of new and more complex symptoms.[([[https://www.ncbi.nlm.nih.gov/pubmed/8938913|Shiovitz, T. M., Welke, T. L., Tigel, P. D., Anand, R., Hartman, R. D., Sramek, J. J., ... & Cutler, N. R. (1996). Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophrenia bulletin, 22(4), 591.]])] Therefore, clozapine should always be gradually and slowly tapered over time. | + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success">See main article: **[[meds:cytochrome-p450|]]**</alert> |
| - | ===== Benefits ===== | + | |
| - | ==== Low EPS ==== | + | |
| - | Clozapine has the same incidence of [[meds:antipsychotics:eps|extrapyramidal symptoms]] as placebo.[([[https://www.ncbi.nlm.nih.gov/pubmed/12839431|Iqbal, M. M., Rahman, A., Husain, Z., Mahmud, S. Z., Ryan, W. G., & Feldman, J. M. (2003). Clozapine: a clinical review of adverse effects and management. Annals of Clinical Psychiatry, 15(1), 33-48.]])] This makes it a particularly useful switch antipsychotic for patients who are experiencing significant EPS from other antipsychotics. | + | |
| - | ==== Suicide Prevention ==== | + | Cigarette smoking induces the CYP1A2 isoenzyme which can lead to lower levels of clozapine. It can reduce clozapine plasma levels by up to 50% and higher doses may be required in smokers than in nonsmokers. The polycyclic aromatic hydrocarbons in cigarettes induce CYP1A2 activity, which increases the metabolism of clozapine.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736902/|Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.]])] Nicotine replacement products (patches, lozenges, nasal spray, inhalers, and gum) on the other hand, do not induce CYP1A2. The impact of electronic cigarettes and vaping is less clear, and there may be a potential to induce CYP1A2 as well (though less than cigarettes).[([[https://pubmed.ncbi.nlm.nih.gov/28515485/|Canistro, D., Vivarelli, F., Cirillo, S., Marquillas, C. B., Buschini, A., Lazzaretti, M., ... & Paolini, M. (2017). E-cigarettes induce toxicological effects that can raise the cancer risk. Scientific reports, 7(1), 1-9.]])] |
| - | Clozapine is only one of two psychotropics (the other is [[meds:mood-stabilizers-anticonvulsants:1-lithium|lithium]]) that has been clinically shown to reduce the risk of suicide.[([[https://www.ncbi.nlm.nih.gov/pubmed/12511175|Meltzer, H. Y., Alphs, L., Green, A. I., Altamura, A. C., Anand, R., Bertoldi, A., ... & Krishnan, R. (2003). Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial (InterSePT). Archives of general psychiatry, 60(1), 82-91.]])] | + | |
| + | <callout icon="true" type="tip" title="Quitting, Stopping, or Starting Smoking?"> | ||
| + | Patients who are smokers and on clozapine and decide to quit smoking face a higher risk of seizures (due to sudden increases in plasma clozapine)! These individuals may need up to a 50% reduction of their dose of clozapine. A patient who smokes at least 7-12 cigarettes a day and on a stable dose of clozapine may need a lower daily clozapine dosage when admitted to a smoke-free facility. Clozapine should be lowered by 30% to 40% over 4 to 7 days to reduce the risk of clozapine toxicity. If the patient starts smoking again, clozapine may need to be increased by as much as 1.5 times over a period of 2 to 4 weeks. | ||
| + | </callout> | ||
| ===== Side Effects ===== | ===== Side Effects ===== | ||
| Sedation, hypotension and seizure activity are most commonly correlated with higher plasma levels of clozapine.[([[https://www.ncbi.nlm.nih.gov/pubmed/22327098|Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.]])] | Sedation, hypotension and seizure activity are most commonly correlated with higher plasma levels of clozapine.[([[https://www.ncbi.nlm.nih.gov/pubmed/22327098|Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.]])] | ||
| + | |||
| + | ==== Fever ==== | ||
| + | **Clozapine-induced fever** is a benign but common side-effect that can occur in up to half of all patients on treatment.[([[https://pubmed.ncbi.nlm.nih.gov/12416597/|Tham, J. C., & Dickson, R. A. (2002). Clozapine-induced fevers and 1-year clozapine discontinuation rate. The Journal of clinical psychiatry, 63(10), 880-884.]])] Fevers typically last for up to 2-3 days, and occur in the first month of treatment. Other differential diagnoses to consider include [[meds:antipsychotics:nms-neuroleptic-malignant-syndrome|neuroleptic malignant syndrome]] and clozapine-induced myocarditis. | ||
| + | |||
| + | ==== Cardiovascular ==== | ||
| + | * Orthostatic hypotension can occur during the titration of clozapine. If hypotension occurs, the titration should be held while the blood pressure stabilizes. | ||
| + | * Asymptomatic tachycardia, which occurs in approximately 25% of patients | ||
| + | ==== Salivation (Hypersialorrhea) ==== | ||
| + | <alert type="info" icon="fa fa-book fa-lg fa-fw"> | ||
| + | See also: **[[https://pubmed.ncbi.nlm.nih.gov/17696024/|Sockalingam, S. et al. (2007). Clozapine-induced hypersalivation: a review of treatment strategies. The Canadian Journal of Psychiatry, 52(6), 377-384.]]** | ||
| + | </alert> | ||
| + | |||
| + | **Hypersialorrhea** (hypersalivation) is the excessive production of saliva. **Clozapine-induced hypersalivation/sialorrhea (CIH, or CIS)** is a common side effect related to clozapine use (but can also occur in other antipsychotics).[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127750/|Stroup, T. S., & Gray, N. (2018). Management of common adverse effects of antipsychotic medications. World Psychiatry, 17(3), 341-356.]])] Sialorrhea can range from being mildly uncomfortable drooling and excessive saliva, to potentially life-threatening conditions, such as parotitis, choking, and aspiration. Sialorrhea is //not// dose-related and can occur at any point during treatment. Although clozapine has many anticholinergic properties, the cause of CIS is thought to be due to clozapine //agonism// at the muscarinic (M4) receptors and blockade of a-2 adrenergic receptors, which increases salivary production and flow.[([[https://www.ncbi.nlm.nih.gov/pubmed/7895765|Zorn, S. H., Jones, S. B., Ward, K. M., & Liston, D. R. (1994). Clozapine is a potent and selective muscarinic M4 receptor agonist. European Journal of Pharmacology: Molecular Pharmacology, 269(3), R1-R2.]])] | ||
| + | |||
| + | CIS can be treated with an muscarinic receptor antagonist (i.e. - an antimuscarinic/anticholinergic) such as atropine or ipratropium, which can administered sublingually at night time.[([[https://www.ncbi.nlm.nih.gov/pubmed/12839431|Iqbal, M. M., Rahman, A., Husain, Z., Mahmud, S. Z., Ryan, W. G., & Feldman, J. M. (2003). Clozapine: a clinical review of adverse effects and management. Annals of Clinical Psychiatry, 15(1), 33-48.]])][([[https://www.ncbi.nlm.nih.gov/pubmed/21540404|Bird, A. M., Smith, T. L., & Walton, A. E. (2011). Current treatment strategies for clozapine-induced sialorrhea. Annals of Pharmacotherapy, 45(5), 667-675.]])] Common treatment regimens include: | ||
| + | * Atropine sulfate, 1 to 2 drops of the 1% ophthalmic solution sublingually 2 to 3 times daily[([[http://www.pharmacytimes.com/publications/health-system-edition/2012/august2012/psychiatry-clozapine-induced-sialorrhea|Mitchell, J. C. Pharmacist Rounds: Psychiatry: Clozapine-Induced Sialorrhea.]])] | ||
| + | * Ipratropium bromide, 1 to 2 sprays of 0.03% nasal spray sublingually at bedtime | ||
| + | * Clonidine up to 0.025 mg TID | ||
| + | |||
| + | ==== Constipation ==== | ||
| + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success">See main article: **[[meds:antipsychotics:constipation|]]**</alert> | ||
| + | <WRAP group> | ||
| + | <WRAP half column> | ||
| + | **Constipation** is very common and can affect up to 50% of patients.[([[http://mhc.cpnp.org/doi/full/10.9740/mhc.n87491?code=cpnp-site|Jill A. Fowler (2011) Clozapine-induced gastrointestinal hypomotility: More than just constipation. Mental Health Clinician: November 2011, Vol. 1, No. 5, pp. 92-93.]])] It is critical for every patient on clozapine to have bowel monitoring for constipation. Clozapine has the potential to decrease GI motility, and is associated with risk of paralytic ileus, bowel obstruction, fecal impaction, bowel perforation, and in rare cases, death.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816835/|Every-Palmer, S., Nowitz, M., Stanley, J., Grant, E., Huthwaite, M., Dunn, H., & Ellis, P. M. (2016). Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine, 5, 125-134.]])] If other anticholingerics are also being used, then the prescribing clinician needs to be even more vigilant about bowel monitoring, since anticholingeric effects are additive. In addition, the risk of medication-related constipation also increases with age. Other conditions like diabetes mellitus can also further worsen constipation due to autonomic neuropathy. | ||
| + | |||
| + | </WRAP> | ||
| + | <WRAP half column> | ||
| + | <callout type="danger" title="Don't Forget About Constipation!" icon="true"> | ||
| + | Constipation can be **life-threatening**. Severe constipation can cause bowel obstruction, sepsis and death. More deaths are caused by clozapine-induced ileus/megacolon than by agranulocytosis.[([[https://www.ncbi.nlm.nih.gov/pubmed/23842012|Nielsen, J., Correll, C. U., Manu, P., & Kane, J. M. (2013). Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?. The Journal of clinical psychiatry, 74(6), 603-13.]])] | ||
| + | </callout> | ||
| + | <callout type="tip" title="Before Starting Clozapine" icon="true"> | ||
| + | * Obtain a baseline bowel movement history | ||
| + | * Counsel patients on recognition and reporting of constipation. | ||
| + | * Review all current medications and anticholinergic medications and stop other constipating medications wherever possible. | ||
| + | * If baseline constipation exists, begin laxative treatment immediately. | ||
| + | </callout> | ||
| + | </WRAP> | ||
| + | </WRAP> | ||
| + | |||
| + | <panel type="info" title="Constipation Management" subtitle="" no-body="true" footer=""> | ||
| + | ^ 1st line | Osmostic agents: \\ • Polyethylene glycol (PEG): start 17 grams daily, and increase to 17 grams BID as needed (this is\\ beyond manufacturers’ recommended dose).\\ • Lactulose: start 15-30 mL daily, and increase to 30 mL BID \\ //Note: Combining lactulose and PEG 3350 combined is not a rational pharmacotherapy due to overlapping mechanisms.// | | ||
| + | ^ 2nd line | Stimulant laxatives: \\ • Sennosides \\ • Bisacodyl | | ||
| + | ^ 3rd line | Fibre and bulk-forming products //may// be helpful, but can also worsen constipation in underlying dehydration and should be used **cautiously**. | | ||
| + | ^ Adjunctive | Dietary and exercise interventions should be considered as adjunct to laxative therapy as they are not likely to improve clozapine-induced constipation alone. | | ||
| + | ^ Not recommended | There is no evidence for the use of surfactant agents ("stool softeners") like docusate sodium for chronic constipation. These agents only lower the surface tension of stool, but are not effective at preventing and treating medication-induced constipation.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794454/|Paré, P., Bridges, R., Champion, M. C., Ganguli, S. C., Gray, J. R., Irvine, E. J., ... & Flook, N. (2007). Recommendations on chronic constipation (including constipation associated with irritable bowel syndrome) treatment. Canadian Journal of Gastroenterology and Hepatology, 21(Suppl B), 3B-22B.]])] | | ||
| + | </panel> | ||
| + | ===== Adverse Events ===== | ||
| + | * [[meds:antipsychotics:nms-neuroleptic-malignant-syndrome|Neuroleptic malignant syndrome]] | ||
| ==== Agranulocytosis and Neutropenia ==== | ==== Agranulocytosis and Neutropenia ==== | ||
| - | **Agranulocytosis** (absolute neutrophil count, or ANC, less than 500/µL) is the most serious adverse reaction to clozapine. To prevent this from occurring, regular hematological monitoring is required, which reduces the risk of agranulocytosis by 20-fold. Agranulocytosis tends to develop during the first 6 months of treatment, whereas neutropenia (ANC between 0.5-1.5 x 10<sup>9</sup>/L) can occur at any time. | + | * **Agranulocytosis** (absolute neutrophil count, or ANC, less than 500/µL) is the most serious adverse reaction to clozapine. |
| + | * To prevent this from occurring, regular hematological monitoring is required, which reduces the risk of agranulocytosis by 20-fold. | ||
| + | * Agranulocytosis tends to develop during the first 4 to 6 months of treatment, whereas neutropenia (ANC between 0.5-1.5 x 10<sup>9</sup>/L) can occur at any time.[([[https://pubmed.ncbi.nlm.nih.gov/38040009/|Northwood, K., Myles, N., Clark, S. R., Every-Palmer, S., Myles, H., Kisely, S., ... & Siskind, D. (2024). Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study. The Lancet Psychiatry, 11(1), 27-35.]])] | ||
| + | * The risk for agranulocytosis become negligible after 2 years of clozapine exposure.[([[https://pubmed.ncbi.nlm.nih.gov/38040009/|Northwood, K., Myles, N., Clark, S. R., Every-Palmer, S., Myles, H., Kisely, S., ... & Siskind, D. (2024). Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study. The Lancet Psychiatry, 11(1), 27-35.]])] | ||
| - | ==== Smoking ==== | + | ==== Myocarditis and Cardiomyopathy ==== |
| - | Cigarette smoking reduces clozapine plasma levels by up to 50% and higher doses may be required in smokers than in nonsmokers. The polycyclic aromatic hydrocarbons in cigarettes induce CYP1A2 activity, which increases the metabolism of clozapine.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736902/|Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.]])] | + | **Myocarditis** and **cardiomyopathy** are the two serious cardiac-related adverse events to monitor for, both during initiation of treatment and throughout the course of treatment.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213891/|Sackey, B. K., Moore, T. A., Cupples, N. L., & Gutierrez, C. A. (2018). Clozapine-induced myocarditis: Two case reports and review of clinical presentation and recognition. Mental Health Clinician, 8(6), 303-308.]])] |
| - | <callout icon="true" type="tip" title="Find out if your patients are smoking or not!"> | + | |
| - | Patients who are smokers and on clozapine and decide to quit smoking face a higher risk of seizures (due to sudden increases in plasma clozapine)! These individuals may need up to a 50% reduction of their dose of clozapine. Conversely, for inpatients who are admitted into hospital and //stop// smoking during the hospitalization, ensure you discuss with them the risks of resuming smoking. If they start smoking again after discharge, this can lead to subtherapeutic levels of clozapine due to increased clozapine metabolism. | + | <panel type="info" title="Clozapine-induced Myocarditis and Cardiomyopathy " subtitle="" no-body="true" footer="* = CRP elevation is one of earliest signs of myocarditis and can appear up to 5 days prior to troponin elevation."> |
| + | <mobiletable 1> | ||
| + | ^ ^ Onset ^ % of patients ^ Signs and Symptoms ^ Pathophysiology ^ Bloodwork ^ Investigations and Treatment ^ | ||
| + | ^ Myocarditis | Generally occurs within first few weeks (14-21 days) of clozapine initiation. Mortality rates as high as 50% have been reported, when undetected. | 0.2% | Myocarditis has non-specific symptoms, including fever, tachycardia and chest pain. There may be signs of heart failure such as dyspnea (especially while supine) or dry cough. Other symptoms include diarrhoea, vomiting, dysuria or rashes. | The pathophysiology of clozapine-associated myocarditis not well understood but is not dose-dependent. | • CBC (↑ WBC, ↑ eosinophils)\\ • CRP (↑)*\\ • Troponin, BNP, CK, ESR | Echocardiogram, CXR. Treatment includes stopping clozapine, and usual treatment for myocarditis. Diagnosis is not straightforward, and suspected cases should be referred urgently for a cardiology opinion. | | ||
| + | ^ Cardiomyopathy | Usually occurs later in clozapine treatment compared to myocarditis. Clinicians need to maintain a high index of suspicion for cardiomyopathy throughout clozapine treatment, regardless of how long a patient has been on clozapine. | 0.02–0.1%[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531006/|Longhi, S., & Heres, S. (2017). Clozapine-induced, dilated cardiomyopathy: a case report. BMC research notes, 10(1), 338. https://doi.org/10.1186/s13104-017-2679-5]])] | Signs of heart failure, flu-like symptoms, cough, fever, sinus tachycardia/ palpitations, fatigue, hypotension and chest discomfort.[([[https://www.ncbi.nlm.nih.gov/pubmed/21524186|Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., Topliss, D. J., & McNeil, J. J. (2011). A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Australian and New Zealand Journal of Psychiatry, 45(6), 458-465.]])] | Poorly understood, may be secondary to untreated, acute clozapine-induced myocarditis.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531006/|Longhi, S., & Heres, S. (2017). Clozapine-induced, dilated cardiomyopathy: a case report. BMC research notes, 10(1), 338.]])] | • CBC (↑ WBC, ↑ eosinophils)\\ • CRP (↑)*\\ • Troponin, BNP, CK, ESR | Echocardiogram (reduced ejection fraction), ECG. Treatment includes stopping clozapine and usual treatment for heart failure. | | ||
| + | </mobiletable> | ||
| + | </panel> | ||
| + | <callout type="warning" title="Bloodwork and monitoring for the first month" icon="true"> | ||
| + | When doing clozapine monitoring, remember that elevated CRP means //general// inflammation, and when there is also elevated troponin this means there is //localization// of that inflammation (to the heart). | ||
| + | </callout> | ||
| + | |||
| + | <callout type="warning" title="Bloodwork and monitoring for the first month" icon="true"> | ||
| + | Although there are no universal guidelines, some monitoring protocols suggest monitoring troponin and CRP every week for the first month, plus vital signs every other day.[([[https://doi.org/10.9740/mhc.2015.03.082|Miller, L. J., & Grande, R. E. (2015). Clozapine-induced myocarditis may warrant cardiac monitoring protocol. Mental Health Clinician, 5(2), 82-87.]])] Symptoms suggestive of myocarditis, plus elevated troponin (>2 times the upper limit of normal) and CRP (>100 mg/L) is highly sensitive for the diagnosis of clozapine-induced myocarditis.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213891/|Sackey, B. K., Moore, T. A., Cupples, N. L., & Gutierrez, C. A. (2018). Clozapine-induced myocarditis: Two case reports and review of clinical presentation and recognition. Mental Health Clinician, 8(6), 303-308.]])] | ||
| </callout> | </callout> | ||
| ==== Seizures ==== | ==== Seizures ==== | ||
| - | Seizures occur more frequently in patients with serum levels above 1000 μg/L, or at doses more than 500mg per day. Clozapine-induced seizures can be treated and prevented with either valproate or lamotrigine. Valproate has the most data to support its use and it is widely regarded as the drug of choice. Adjunctive antiepileptic treatment is recommended as prophylaxis against seizures and myoclonus when plasma levels are above 600 μg/L. There is also a relationship between clozapine dose, plasma level, and the likelihood of an abnormal EEG.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736902/|Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.]])] | + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> |
| + | See main article: **[[neurology:approach-seizures|]]** | ||
| + | </alert> | ||
| - | Multiple factors can affect the true plasma level of clozapine. Plasma levels are generally lower in smokers, younger ages, and males. Conversely, plasma levels are generally higher in Asian patients, and they may have a higher risk of seizures even at low doses of clozapine.[([[https://www.ncbi.nlm.nih.gov/pubmed/8783895/|Matsuda, K. T., Cho, M. C., Lin, K. M., Smith, M. W., Young, A. S., & Adams, J. A. (1996). Clozapine dosage, serum levels, efficacy, and side-effect profiles: A comparison of Korean-American and Caucasian patients. Psychopharmacology bulletin.]])] Overall, clozapine plasma levels have a dose-dependent relationship with seizure occurrence. | + | **Seizure** risk increases in a dose-dependent manner with clozapine, and is most frequent in patients with serum levels above 1000 μg/L, or at doses more than 500 mg per day. Clozapine-induced seizures can be managed and prevented with either valproate or lamotrigine. Valproate has the most data to support its use and it is widely regarded as the drug of choice. Adjunctive antiepileptic treatment is recommended as prophylaxis against seizures and myoclonus when plasma levels are above 600 μg/L. There is also a relationship between clozapine dose, plasma level, and the likelihood of an abnormal EEG.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736902/|Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.]])] |
| + | Multiple factors can affect the true plasma level of clozapine. Plasma levels are generally lower in smokers, younger ages, and males. Conversely, plasma levels are generally higher in Asian patients, and they may have a higher risk of seizures even at low doses of clozapine.[([[https://www.ncbi.nlm.nih.gov/pubmed/8783895/|Matsuda, K. T., Cho, M. C., Lin, K. M., Smith, M. W., Young, A. S., & Adams, J. A. (1996). Clozapine dosage, serum levels, efficacy, and side-effect profiles: A comparison of Korean-American and Caucasian patients. Psychopharmacology bulletin.]])] | ||
| + | ===== Clinical Pearls ===== | ||
| - | ==== Cardiovascular ==== | + | ===== Special Populations ===== |
| - | **Cardiomyopathy** and **myocarditis** are the two serious cardiac-related side effects to monitor for. | + | ==== Geriatric ==== |
| + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> | ||
| + | See main article: **[[meds:pharmacology:geri|]]** | ||
| + | </alert> | ||
| - | **Myocarditis** generally occurs within the first few weeks after clozapine initiation. The absolute risk has been estimated at less than 0.2% of patients, however, mortality rates as high as 50% have been reported. Myocarditis has non-specific symptoms, including fever, tachycardia and chest pain. Other symptoms include shortness of breath, dry cough, elevated white cell count, peripheral eosinophilia, diarrhoea, vomiting, dysuria and rash. The pathophysiology of clozapine-associated myocarditis not well understood but is not dose-dependent. Diagnosis is not straightforward, and suspected cases should be referred urgently for a cardiology opinion. Elevated C-reactive protein (CRP) is one of the earliest signs of myocarditis, usually 5 days prior to any troponin elevation. An echocardiogram is recommended as an initial diagnostic step. | + | ==== Pediatric ==== |
| + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> | ||
| + | See main article: **[[meds:pharmacology:pediatric|]]** | ||
| + | </alert> | ||
| - | **Cardiomyopathy** usually occurs later in clozapine treatment than myocarditis. Symptoms include signs of heart failure, flu-like symptoms, cough, fever, sinus tachycardia/ palpitations, fatigue, hypotension and chest discomfort.[([[https://www.ncbi.nlm.nih.gov/pubmed/21524186|Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., Topliss, D. J., & McNeil, J. J. (2011). A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Australian and New Zealand Journal of Psychiatry, 45(6), 458-465.]])] Clinicians need to maintain a high index of suspicion for cardiomyopathy throughout clozapine treatment. Diagnosis of clozapine-associated cardiomyopathy is made through a finding of reduced ejection fraction on echocardiogram. Electrocardiograms (ECGs) and blood tests, including raised B-type natriuretic peptide (BNP) is also used. Treatment includes cessation of clozapine and usual treatment for heart failure. | + | ==== Obstetric and Fetal ==== |
| + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> | ||
| + | See main article: **[[meds:pharmacology:obstetric-and-fetal|]]** | ||
| + | </alert> | ||
| - | ==== Hypotension ==== | + | ==== Medically Ill ==== |
| - | Orthostatic hypotension can occur during the titration of clozapine. If hypotension occurs, the titration should be held while the blood pressure stabilizes. Other non-fatal symptoms include asymptomatic tachycardia, which occurs in approximately 25% of patients. | + | <alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success"> |
| - | ==== Sialorrhea === | + | See main article: **[[meds:pharmacology:psychotropic-rx-medically-ill|]]** |
| - | Clozapine-induced sialorrhea (CIS), is a common side effect related to clozapine use. Sialorrhea can range from being mildly uncomfortable drooling and excessive saliva, to potentially life-threatening conditions, such as parotiditis, choking, and aspiration. Sialorrhea is not dose-related and can occur at any point during treatment. It is due to clozapine agonism at muscarinic (M4) receptors and blockade of a-2 adrenergic receptors, which increases salivary production and flow.[([[https://www.ncbi.nlm.nih.gov/pubmed/7895765|Zorn, S. H., Jones, S. B., Ward, K. M., & Liston, D. R. (1994). Clozapine is a potent and selective muscarinic M4 receptor agonist. European Journal of Pharmacology: Molecular Pharmacology, 269(3), R1-R2.]])] | + | </alert> |
| - | CIS is treated with an muscarinic receptor antagonist (antimuscarinic) such as atropine or ipratropium, which can administered sublingually at night time.[([[https://www.ncbi.nlm.nih.gov/pubmed/12839431|Iqbal, M. M., Rahman, A., Husain, Z., Mahmud, S. Z., Ryan, W. G., & Feldman, J. M. (2003). Clozapine: a clinical review of adverse effects and management. Annals of Clinical Psychiatry, 15(1), 33-48.]])][([[https://www.ncbi.nlm.nih.gov/pubmed/21540404|Bird, A. M., Smith, T. L., & Walton, A. E. (2011). Current treatment strategies for clozapine-induced sialorrhea. Annals of Pharmacotherapy, 45(5), 667-675.]])] Common treatments include: | + | ===== Guidelines ===== |
| - | * Atropine sulfate, 1 to 2 drops of the 1% ophthalmic solution sublingually 2 to 3 times daily[([[http://www.pharmacytimes.com/publications/health-system-edition/2012/august2012/psychiatry-clozapine-induced-sialorrhea|Mitchell, J. C. Pharmacist Rounds: Psychiatry: Clozapine-Induced Sialorrhea.]])] | + | * [[https://safetyandquality.gov.au/wp-content/uploads/2013/01/National-Adult-Clozapine-Titration-Chart.pdf|Australian Monitoring Guidelines]] |
| - | * Ipratropium bromide, 1 to 2 sprays of 0.03% nasal spray sublingually at bedtime | + | * [[https://www.pharmaceutical-journal.com/learning/learning-article/how-clozapine-patients-can-be-monitored-safely-and-effectively/11138788.article|UK Guidelines]] |
| - | ==== Constipation ==== | ||
| - | <callout type="danger" title="Don't Forget About Constipation!" icon="true"> | ||
| - | Constipation can be **life-threatening**. Severe constipation can cause bowel obstruction, sepsis and death. More deaths are caused by clozapine-induced ileus/megacolon than by agranulocytosis.[([[https://www.ncbi.nlm.nih.gov/pubmed/23842012|Nielsen, J., Correll, C. U., Manu, P., & Kane, J. M. (2013). Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?. The Journal of clinical psychiatry, 74(6), 603-13.]])] | ||
| - | </callout> | ||
| - | Constipation is common and can affect up to 50% of patients.[([[http://mhc.cpnp.org/doi/full/10.9740/mhc.n87491?code=cpnp-site|Jill A. Fowler (2011) Clozapine-induced gastrointestinal hypomotility: More than just constipation. Mental Health Clinician: November 2011, Vol. 1, No. 5, pp. 92-93.]])] It is critical for every patient on clozapine to have bowel monitoring for constipation. Clozapine has the potential to decrease GI motility, and is associated with risk of paralytic ileus, bowel obstruction, fecal impaction, bowel perforation, and in rare cases, death.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816835/|Every-Palmer, S., Nowitz, M., Stanley, J., Grant, E., Huthwaite, M., Dunn, H., & Ellis, P. M. (2016). Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine, 5, 125-134.]])] If other anticholingerics are also being used, then the prescribing clinician needs to be even more vigilant about bowel monitoring, since anticholingeric effects are additive. In addition, the risk of medication-related constipation also increases with age. Other conditions like diabetes mellitus can also further worsen constipation due to autonomic neuropathy. | ||
| - | First-line management and treatment includes the use of an osmotic agent, such as polyethylene glycol (PEG), and/or a stimulant laxative such as senna. There is limited evidence for the use of surfactant agents ("stool softeners") like docusate sodium for chronic constipation. These agents only lower the surface tension of stool, but are not effective at preventing and treating medication-induced constipation.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794454/|Paré, P., Bridges, R., Champion, M. C., Ganguli, S. C., Gray, J. R., Irvine, E. J., ... & Flook, N. (2007). Recommendations on chronic constipation (including constipation associated with irritable bowel syndrome) treatment. Canadian Journal of Gastroenterology and Hepatology, 21(Suppl B), 3B-22B.]])] | ||
| ===== Resources ===== | ===== Resources ===== | ||
| + | == For Clinicians == | ||
| * [[http://www.bcpharmacists.org/readlinks/what-went-wrong-clozapine|BC College of Pharmacists: What Went Wrong? Clozapine]] | * [[http://www.bcpharmacists.org/readlinks/what-went-wrong-clozapine|BC College of Pharmacists: What Went Wrong? Clozapine]] | ||
| + | * [[http://aaclozapine.ca/|AA Clozapine - Product Page]] | ||
| + | * [[https://www.aaspire.ca/resources/HealthCareProfessional/English/17-AA004_AAC0070E_Dose%20Card%2017162_EN_Print_Layout_V11_LR_Client-Friendly.pdf|Healthcare Provider Card]] | ||
| + | * [[https://education.bccfe.ca/courses/treatment-optimization-of-psychosis/|BC Centre for Excellence - Treatment Optimization of Psychosis]] | ||
| + | |||
| + | == Readings == | ||
| + | * [[https://rationalpsychiatry.substack.com/p/all-the-lives-we-cannot-see|Rational Psychiatry: All the lives we cannot see -- the truth about clozapine - 'Britain's most dangerous drug']] | ||
| + | |||
| + | == Documentation == | ||
| + | <code> | ||
| + | We reviewed the common side effects of clozapine: elevated heart rate, ECG abnormalities, orthostatic hypotension, hyperlipidemia, hyperglycemia, drowsiness, dizziness, falls, insomnia, akathisia, excess saliva production, dry mouth, weight gain, constipation, nausea, vomiting, abdominal discomfort and heartburn, enuresis, EPS. Potentially rare, but more serious risks: agranulocytosis, tardive dyskinesia, neuroleptic malignant syndrome (muscle stiffness, fever, sudden rise in blood pressure, agitation and confusion), myocarditis, pericarditis, cardiomyopathy, stroke, blood clots, lowered blood cells (such as platelets and eosinophils), aspiration pneumonia, dysregulation of body temperature, arrhythmias, suicidal thinking, bowel obstruction and seizures. We also reiterated that sudden cardiac death is possible with patients who are prone to arrhythmias and QTc prolongation. Reviewed that patients with dementia have a known risk for death and stroke like events with use of neuroleptics. | ||
| + | </code> | ||