Drug Interactions between Clozapine Synthon and glycopyrronium topical

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

Caffeine may increase clozapine serum concentrations and exacerbate psychotic symptoms. The mechanism is unknown but may be related to competition for the same metabolic pathway. No specific intervention is necessary; however, if an interaction is suspected it is recommended that caffeine intake be avoided.

The use of neuroleptic agents is contraindicated in patients with acute alcohol intoxication exhibiting depressed vital signs. The central nervous system depressant effects of neuroleptic agents may be additive with those of alcohol. Severe respiratory depression and respiratory arrest may occur. Therapy with neuroleptic agents should be administered cautiously in patients who might be prone to acute alcohol intake.

The use of neuroleptic agents is contraindicated in comatose patients and patients with severe central nervous system depression. Neuroleptic agents may potentiate the CNS and respiratory depression in these patients.

Antipsychotic drugs are not approved for the treatment of patients with dementia-related psychosis. Older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; although the causes were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. A causal relationship with antipsychotic use has not been established. In controlled trials in older patients with dementia-related psychosis, patients randomized to risperidone, aripiprazole, and olanzapine had higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, compared to patients treated with placebo.

Neuroleptic agents have anticholinergic activity, to which elderly patients are particularly sensitive. Clozapine and low-potency agents such as chlorpromazine and thioridazine tend to exhibit greater anticholinergic effects than other agents in the class. Clozapine use has been associated with impairment of intestinal peristalsis ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus. Therapy with neuroleptic agents should be administered cautiously in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders.

Neuroleptic agents have anticholinergic activity, to which elderly patients are particularly sensitive. Clozapine and low-potency agents such as chlorpromazine and thioridazine tend to exhibit greater anticholinergic effects than other agents in the class. Clozapine use has been associated with impairment of intestinal peristalsis ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus. Therapy with neuroleptic agents should be administered cautiously in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders.

Hepatitis has been reported in association with the use of clozapine, both in patients with and without underlying liver function abnormalities. Therapy with clozapine should be administered cautiously in patients with preexisting liver disease. The drug should be discontinued if clinically significant elevations of liver function tests or symptoms of jaundice occur.

The central dopaminergic blocking effects of neuroleptic agents may precipitate or aggravate a potentially fatal symptom complex known as neuroleptic malignant syndrome (NMS). NMS is observed most frequently when high-potency agents like haloperidol are administered intramuscularly, but may occur with any neuroleptic agent given for any length of time. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria, and acute renal failure. Neuroleptic agents should not be given to patients with active NMS and should be immediately discontinued if currently being administered in such patients. In patients with a history of NMS, introduction or reintroduction of neuroleptic agents should be carefully considered, since NMS may recur.

The use of clozapine is contraindicated in patients with myeloproliferative disorders, preexisting bone marrow depression, or a history of clozapine-induced agranulocytosis or severe granulocytopenia. Clozapine therapy is associated with the development of agranulocytosis, defined as an absolute neutrophil count (ANC) below 500/mm3. The cumulative incidence is estimated at 1% to 2% after one year of use. The onset is generally between 4 to 16 weeks following initiation of therapy, and it is usually reversible if detected early and the drug discontinued promptly. All patients should have a white blood cell (WBC) count prior to initiating therapy, and clozapine should not be administered if baseline WBC count is less than 3500/mm3. WBC counts and differential should be monitored closely during therapy and for 4 weeks after end of therapy according to product labeling. Also, patients should be advised to immediately report signs of infection such as fever, sore throat, malaise, lethargy, and flu-like symptoms. Individuals who develop clozapine-induced agranulocytosis or severe granulocytopenia (WBC count < 2000/mm3 or ANC < 1000/mm3) should not be rechallenged following recovery, since the condition may recur, often with a shorter latency on reexposure. If continued neuroleptic therapy is necessary, other agents may be used with little apparent risk of cross-sensitivity.

The use of neuroleptic agents is contraindicated in comatose patients and patients with severe central nervous system depression. Neuroleptic agents may potentiate the CNS and respiratory depression in these patients.

Neuroleptic agents have anticholinergic activity, to which elderly patients are particularly sensitive. Clozapine and low-potency agents such as chlorpromazine and thioridazine tend to exhibit greater anticholinergic effects than other agents in the class. Clozapine use has been associated with impairment of intestinal peristalsis ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus. Therapy with neuroleptic agents should be administered cautiously in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders.

Severe hyperglycemia, sometimes resulting in ketoacidosis, has been reported during clozapine treatment in patients with no prior history of hyperglycemia. Glucose levels normalized in most cases following discontinuation of clozapine, and a rechallenge in one patient produced a recurrence of hyperglycemia. While a causal relationship has not been established, patients with or predisposed to hyperglycemia should be monitored during clozapine therapy. Dosage adjustments in insulin or oral hypoglycemic medications may be necessary in patients with diabetes.

Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

The chronic use of neuroleptic agents can cause persistent elevations in prolactin levels due to antagonism of dopamine D2 receptors. Based on in vitro data, approximately one-third of human breast cancers are thought to be prolactin-dependent. The clinical significance of this observation with respect to long-term neuroleptic therapy is unknown. Chronic administration of neuroleptic drugs has been associated with mammary tumorigenesis in rodent studies but not in human clinical or epidemiologic studies. Until further data are available, therapy with neuroleptic agents should be administered cautiously in patients with a previously detected breast cancer. Caution is also advised in patients with preexisting hyperprolactinemia. Hyperprolactinemia may suppress hypothalamic gonadotrophin releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds; however, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

Severe hyperglycemia, sometimes resulting in ketoacidosis, has been reported during clozapine treatment in patients with no prior history of hyperglycemia. Glucose levels normalized in most cases following discontinuation of clozapine, and a rechallenge in one patient produced a recurrence of hyperglycemia. While a causal relationship has not been established, patients with or predisposed to hyperglycemia should be monitored during clozapine therapy. Dosage adjustments in insulin or oral hypoglycemic medications may be necessary in patients with diabetes.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported with the use of atypical antipsychotic agents. Patients with diabetes should be monitored for worsening control of blood glucose when treated with these agents. It is recommended that patients with risk factors for diabetes mellitus starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment, and periodically thereafter. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when treatment with these agents was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic drugs. These drugs should be administered cautiously in patients at risk for aspiration pneumonia.

Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

Atypical antipsychotic drugs have been associated with undesirable alterations in lipid levels. While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile. Before or soon after initiation of antipsychotic medications, a fasting lipid profile should be obtained at baseline and monitored periodically during treatment.

The chronic use of neuroleptic agents can cause persistent elevations in prolactin levels due to antagonism of dopamine D2 receptors. Based on in vitro data, approximately one-third of human breast cancers are thought to be prolactin-dependent. The clinical significance of this observation with respect to long-term neuroleptic therapy is unknown. Chronic administration of neuroleptic drugs has been associated with mammary tumorigenesis in rodent studies but not in human clinical or epidemiologic studies. Until further data are available, therapy with neuroleptic agents should be administered cautiously in patients with a previously detected breast cancer. Caution is also advised in patients with preexisting hyperprolactinemia. Hyperprolactinemia may suppress hypothalamic gonadotrophin releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds; however, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

Most neuroleptic agents are extensively metabolized by the liver. The plasma concentrations of these agents may be increased and the half-lives prolonged in patients with impaired hepatic function. Therapy with neuroleptic agents should be administered cautiously in patients with significant liver disease. Lower initial dosages and slower titration may be appropriate.

Weight gain has been observed with atypical antipsychotic use. While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile. When treating pediatric patients with atypical antipsychotic agents, weight gain should be monitored and assessed against that expected for normal growth. Monitor weight at baseline and frequently thereafter.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported with the use of atypical antipsychotic agents. Patients with diabetes should be monitored for worsening control of blood glucose when treated with these agents. It is recommended that patients with risk factors for diabetes mellitus starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment, and periodically thereafter. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when treatment with these agents was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug.

The use of neuroleptic agents is associated with pseudo-parkinsonian symptoms such as akinesia, bradykinesia, tremors, pill-rolling motion, cogwheel rigidity, and postural abnormalities including stooped posture and shuffling gait. The onset is usually 1 to 2 weeks following initiation of therapy or an increase in dosage. Older neuroleptic agents such as haloperidol are more likely to induce these effects, and their use may be contraindicated in patients with Parkinson's disease or parkinsonian symptoms.

Thromboembolic events such as deep-vein thrombosis and pulmonary embolism have been noted during clozapine therapy. Therapy with clozapine should be administered cautiously in patients with an active or past history of thromboembolic events.

Clozapine is extensively metabolized by the liver and subsequently excreted in the urine (50%) and feces (35%), primarily as metabolites. One of the metabolites appears to have only limited pharmacologic activity, while the others are inactive. However, the effects of possible metabolite accumulation have not been studied. The manufacturer recommends that therapy with clozapine be administered cautiously in patients with impaired renal function.

Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs; the syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk appears highest in older patients (particularly older women) but it is not possible to predict which patients are likely to develop TD; whether antipsychotic drugs differ in their potential to cause TD is unknown. The risk of TD and the likelihood that it will become irreversible increase with the duration of therapy and the total cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low dosages; it may also occur after discontinuation of therapy. TD may remit (partially or completely) upon discontinuation of antipsychotic therapy, although antipsychotic therapy itself may suppress (or partially suppress) signs/symptoms of TD, possibly masking the underlying process; the effect of symptomatic suppression on the long-term course of TD is unknown. In patients with preexisting drug-induced TD, initiating or increasing the dosage of antipsychotic therapy may temporarily mask the symptoms of TD but could eventually worsen the condition. In patients requiring chronic therapy, the lowest dose and shortest duration of therapy producing a satisfactory clinical response are recommended; the need for continued therapy should be reassessed periodically. If signs/symptoms of TD occur during antipsychotic therapy, discontinuation of the offending agent should be considered; however, some patients may require treatment despite the presence of TD.

Thromboembolic events such as deep-vein thrombosis and pulmonary embolism have been noted during clozapine therapy. Therapy with clozapine should be administered cautiously in patients with an active or past history of thromboembolic events.

The use of atypical antipsychotic agents has been associated with orthostatic hypotension and syncope. Therapy with atypical antipsychotics should be administered cautiously in patients with hypotension or conditions that could be exacerbated by hypotension, such as a history of myocardial infarction, angina, or ischemic stroke. Patients with dehydration (e.g., due to severe diarrhea or vomiting) may be predisposed to hypotension and should also be managed carefully during therapy with atypical antipsychotics. Blood pressure should be monitored at regular intervals, particularly during dosage escalation or whenever dosage has been altered, and patients should be advised not to rise abruptly from a sitting or recumbent position.