Source: Health Products and Food Branch (CA) Revision Year: 2014
LOXAPAC IM is contraindicated in:
LOXAPAC IM like other antipsychotics, may impair mental and/or physical abilities, especially during the first few days of therapy. Therefore, ambulatory patients should be warned about activities requiring alertness (e.g. operating vehicles or machinery) and about concomitant use of alcohol and other CNS depressants.
LOXAPAC IM has an antiemetic effect in animals. Since this effect may also occur in man, loxapine may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumour.
LOXAPAC IM should be used with caution in patients with cardiovascular disease. Increased pulse rate and transient hypotension have both been reported in patients receiving antipsychotic doses. In the presence of severe hypotension requiring vasopressor therapy, the preferred drugs would be levarterenol or phenylephrine. The use of epinephrine in these cases should be avoided.
Hyperprolactinemia: Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in-vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer.
Although disturbances such as galactorrhea, amenorrhea, gynecomastia and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies, nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorogenesis; the available evidence is considered too limited to be conclusive at this time.
Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects.
Hyperglycemia: Diabetic ketoacidosis (DKA) has occurred in patients with no reported history of hyperglycemia. Patients should have baseline and periodic monitoring of blood glucose and body weight.
Rare cases of priapism have been reported with antipsychotic use, such as loxapine. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment.
Neutropenia, granulocytopenia and agranulocytosis have been reported during antipsychotic use. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting LOXAPINE IM and then periodically throughout treatment.
Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including loxapine, in case reports and/or observational studies. When prescribing LOXAPAC IM all potential risk factors for VTE should be identified and preventative measures undertaken. This drug is not recommended for use in patients with blood dyscrasias.
This drug should not be used in patients with liver disorders of significant severity (see CONTRAINDICATIONS).
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although the prevalence of tardive dyskinesia with conventional antipsychotics appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the beginning of treatment, which patients are likely to develop the syndrome.
Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment itself, however, may suppress (or partially suppress) the signs and symptoms of tardive dyskinesia and thereby may possibly mask the underlying process. The effect that symptom suppression has upon the long-term course of the syndrome is unknown.
Given this consideration, LOXAPAC IM should be prescribed in a manner that is most likely to minimize the risk of the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic LOXAPAC IM use should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on LOXAPAC IM, drug discontinuation should be considered. However, some patients may require treatment with LOXAPAC IM despite the presence of the syndrome.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring and 3) treatment of any concomitant serious medical problems for which specific treatment is available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
LOXAPAC IM should be used with extreme caution in patients with a history of convulsive disorders, since it lowers the convulsive threshold. Seizures have been reported in epileptic patients receiving LOXAPAC IM at antipsychotic dose levels, and may occur even with maintenance of routine anticonvulsant drug therapy.
Abrupt withdrawal after short-term administration of antipsychotic drugs does not generally pose problems. However, transient dyskinetic signs are experienced by some patients on maintenance therapy after abrupt withdrawal. The signs are very similar to those described under Tardive Dyskinesia, except for duration. Although it is not known whether gradual withdrawal of antipsychotic drugs will decrease the incidence of withdrawal-emergent neurological signs, gradual withdrawal would appear to be advisable.
Although clinical experience has not demonstrated ocular toxicity, careful observation should be made for pigmentary retinopathy and lenticular pigmentation, since these have been observed in some patients receiving certain other antipsychotic drugs for prolonged periods.
Because of possible anticholinergic action, the drug should be used with caution in patients with glaucoma, particularly with concomitant administration of an anticholinergic type of antiParkinson medication.
LOXAPAC IM has not been evaluated for the management of behavioural complications in patients with mental retardation, and therefore cannot be recommended in these patients.
Because of possible anticholinergic action, the drug should be used with caution in patients with a tendency to urinary retention, particularly with concomitant administration of anticholinergic type of anti-Parkinson medication. The drug should not be used in patients with renal insufficiency (see CONTRAINDICATIONS).
There is a possibility of photosensitivity and/or phototoxicity; skin rashes of uncertain etiology have been observed in a few patients during the hot summer months.
Pregnant Women: Safe use of LOXAPAC IM during pregnancy has not been established; therefore, its use in pregnancy or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.
Neonates exposed to antipsychotic drugs (including LOXAPAC IM) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Nursing Women: Safe use of LOXAPAC IM during lactation has not been studied in nursing women. Although no human data are available, animal studies indicate that loxapine crosses the placenta and distributes into milk. Therefore, LOXAPAC IM should not be used in nursing women unless the expected benefits to the mother markedly outweigh the potential risks to the baby.
Pediatrics (<18 years of age): Studies have not been performed in children; therefore this drug is not recommended for use in children below the age of 18.
Geriatrics (>65 years of age): The safety and efficacy of LOXAPAC IM in patients 65 years of age or older have not been studied. Caution should be exercised with the use of LOXAPAC IM in the elderly patient, recognizing the more frequent hepatic, renal, central nervous system, and cardiovascular dysfunctions, and more frequent use of concomitant medication in this population (see DOSAGE AND ADMINISTRATION).
LOXAPAC IM is not indicated in elderly patients with dementia. Elderly patients with dementia treated with atypical antipsychotic drugs showed increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs.
The incidence of sedation following LOXAPAC IM (loxapine hydrochloride injection) administration has been less than that of certain aliphatic phenothiazines and slightly more than the piperazine phenothiazines. Drowsiness, usually mild, may occur at the beginning of therapy or when dosage is increased. It usually subsides with continued LOXAPAC IM therapy. Dizziness, faintness, headache, staggering gait, shuffling gait, muscle twitching, weakness, insomnia, agitation, tension, seizures, akinesia, slurred speech, numbness, paresthesia, and confusional states have been reported. Neuroleptic malignant syndrome has been reported (see WARNINGS AND PRECAUTIONS, Neurologic).
Neuromuscular (extrapyramidal) reactions during the administration of LOXAPAC IM have been reported frequently, often during the first few days of treatment. In most patients, these reactions involved Parkinson-like symptoms such as tremor, rigidity, excessive salivation, and masked facies. Akathisia (motor restlessness) also has been reported relatively frequently. These symptoms are usually not severe and can be controlled by reduction of LOXAPAC IM dosage or by administration of anti-Parkinson drugs in usual dosage.
Dystonic and dyskinetic reactions have occurred less frequently, but may be more severe and may occur during the first few days of treatment. Dystonias include spasms of muscles of the neck and face, tongue protrusion and oculogyric movement. Dyskinetic reaction has been described in the form of choreoathetoid movements. These reactions sometimes require reduction or temporary withdrawal of LOXAPAC IM dosage in addition to appropriate counteractive drugs.
As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and, in some patients, appear to be irreversible. The syndrome is characterized by rhythmical involuntary movement of the tongue, face, mouth, or jaw (e.g. protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities.
There is no known effective treatment for tardive dyskinesia; anti-Parkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. The physician may be able to reduce the risk of this syndrome by minimizing the unnecessary use of neuroleptic drugs and reducing the dose or discontinuing the drug, if possible, when manifestations of this syndrome are recognized, particularly in patients over the age of 50. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome and if the medication is stopped at that time the syndrome may not develop.
Dry mouth, nasal congestion, constipation, blurred vision, urinary retention, and paralytic ileus have occurred.
Tachycardia, hypotension, hypertension, lightheadedness, and syncope have been reported. A few cases of ECG changes similar to those seen with phenothiazines have been reported. It is not known whether these were related to LOXAPAC IM administration.
Rarely, thrombocytopenia and leukopenia have been observed. In addition, neutropenia, granulocytopenia and agranulocytosis have been reported during antipsychotic use. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting LOXAPAC IM and then periodically throughout treatment.
Nausea and vomiting have been reported in some patients. Hepatocellular injury (i.e. SGOT/SGPT elevation) has been reported in association with loxapine administration and rarely, jaundice and/or hepatitis questionably related to LOXAPAC IM treatment.
Patients should be advised of the risk of severe constipation during LOXAPAC IM treatment, and that they should tell their doctor if constipation occurs or worsens, as they may need laxatives.
Dermatitis, edema (puffiness of face), pruritus and seborrhea have been reported with LOXAPAC IM. There is also the possibility of photosensitivity and/or phototoxicity; skin rashes of uncertain etiology have been observed in a few patients during the hot summer months.
Rarely, galactorrhea, amenorrhea, gynecomastia, and menstrual irregularity of uncertain etiology have been reported.
Weight gain, weight loss, dyspnea, ptosis, hyperpyrexia, flushed facies, polydipsia and hyperprolactinemia have been reported in some patients.
The following serious and unexpected adverse events not listed in the Adverse Drug Reaction Overview section have been reported. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: disseminated intravascular coagulation, eosinophilia
Cardiac disorders: cardiogenic shock Congenital, familial and genetic disorders: cleft uvula
Eye disorders: mydriasis
Gastrointestinal disorders: abdominal compartment syndrome, abdominal distension, abdominal pain, colonic pseudo-obstruction, dysphagia, gastritis, gastrointestinal hypomotility, regurgitation.
General disorders and administration site conditions: drug ineffective, drug interaction, hyperthermia, malaise, pain, pyrexia.
Injury, poisoning and procedural complications: gun shot wound, joint dislocation, overdose, toxicity to various agents.
Investigations: blood creatine phosphokinase increased, blood creatinine increased, blood glucose abnormal, blood glucose increased, blood pressure decreased, pulse absent, respiratory rate decreased, respiratory rate increased, transaminases increased.
Musculoskeletal and connective tissue disorders: periostitis, rhabdomyolysis.
Nervous system disorders: convulsion, disturbance in attention, loss of consciousness, unresponsive to stimuli.
Psychiatric disorders: aggression, anger, mental status changes, obsessive thoughts, personality change, schizophrenia paranoid type, thinking abnormal.
Renal and urinary disorders: renal failure acute
Reproductive system and breast disorders: amenorrhoea
Respiratory, thoracic and mediastinal disorders: aspiration, hypopnoea, pulmonary embolism, respiratory arrest.
Skin and subcutaneous tissue disorders: hyperhidrosis
Surgical and medical procedures: intestinal resection, surgery
Vascular disorders: extremity necrosis, hypotension, shock.
Loxapine may be additive with or may potentiate the action of other CNS depressants (including barbiturates and alcohol) or anticholinergic agents. If LOXAPAC IM is used concomitantly with other depressant drugs, including alcohol, caution should be used to avoid overdosage.
Loxapine inhibits the vasopressor effect of epinephrine. If patients receiving LOXAPAC IM require a vasopressor agent, norepinephrine, levarterenol or phenylephrine should be used; epinephrine should not be used.
The drug interactions listed below (Table 1) are based on either case reports or studies (C), or potential interactions (T) due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Table 1. Established or Potential Drug-Drug Interactions:
| Proper name | Ref | Effect | Clinical comment |
|---|---|---|---|
| Carbamazepine | C | An increased risk of carbamazepine toxicity (ataxia, nystagmus, diplopia, headache, vomiting, apnea, seizures, coma) | The concurrent use of carbamazepine and loxapine has resulted in neurotoxicity in one case report. For patients receiving concurrent carbamazepine and loxapine therapy, monitor for signs of carbamazepine toxicity and adjust doses accordingly. |
| Dehydroepiandrosterone (DHEA) | T | Reduced effectiveness of loxapine | In case reports, patients have been resistant to antipsychotics when DHEA levels were elevated. Patients being treated with loxapine should avoid DHEA supplementation. |
| Hydromorphone | T | An increase in CNS or respiratory depression | The concomitant use of hydromorphone and other CNS depressants, such as antipsychotics, may result in additive CNS depressant effects, including respiratory depression, hypotension, profound sedation, and coma. When administering hydromorphone and an antipsychotic together, dose reduction of one or both of the medications should be considered. |
| Lithium | T | Weakness, dyskinesias, increased extrapyramidal symptoms, encephalopathy, and brain damage | Coadministration of lithium and a number |
| Metoclopramide | T | An increased risk of extrapyramidal reactions or neuroleptic malignant syndrome | Concomitant use of metoclopramide with antipsychotic agents may increase the risk of extrapyramidal symptoms, such as tardive dyskinesia or neuroleptic malignant syndrome, and is contraindicated. If concurrent therapy is required, monitor patients for signs and symptoms of extrapyramidal reactions or neuroleptic malignant syndrome (fever, sweating, confusion, muscle stiffness). Discontinue metoclopramide if patient develops signs and symptoms of extrapyramidal reactions. |
| Milnacipran | T | Increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes) | Concomitant use of milnacipran and an antipsychotic may result in hypertension, coronary artery vasoconstriction or serotonin syndrome, which may be lifethreatening. When concomitant use of milnacipran and an antipsychotic is required, caution should be used. If symptoms of serotonin syndrome develop (e.g., restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased body temperature, over-reactive reflexes, nausea, vomiting, and diarrhea), treatment should be immediately discontinued and the appropriate supportive therapy initiated. |
| Tramadol | T | An increased risk of seizures | Seizures have been reported in patients using tramadol. Caution should be used if tramadol is to be administered to patients receiving neuroleptic therapy. If possible, avoid this combination, especially in patients with underlying conditions that might predispose to seizures. |
| Zotepine | T | Increased risk of seizures | Zotepine used concurrently with neuroleptics may increase the risk of seizures. Caution should be used in those patients who: (1) are taking large doses of zotepine; (2) have a history of seizure disorders; (3) are of young age; or (4) have a past history of brain injury. |
Legend: C = Case Report/Study; T = Theoretical
Interactions with food have not been studied or reported in human.
Belladonna: The anticholinergic activity of the active alkaloids present in belladonna may predispose the patient to excessive anticholinergic activity if taken with loxapine. Excessive anticholinergic activity may be manifested by dry mouth, constipation, urinary retention, tachycardia, decreased sweating, mydriasis, blurred vision, elevated temperature, muscular weakness, and sedation. If such effects are noted, belladonna should be discontinued immediately.
Because belladonna is typically available as a homeopathic preparation, the clinical severity of the interaction with loxapine is unknown. Caution is advised.
Betel Nut: Case reports have described increased extrapyramidal side effects when betel nut was chewed by patients taking fluphenazine and fluphenthixol for schizophrenia. The extrapyramidal effects were not improved with anticholinergic therapy with procyclidine, and resolved with betel nut discontinuation. Case reports suggest the onset of betel nut activity to be within 2 weeks with resolution within 4 to 7 days after discontinuation.
It is unclear to what extent the cholinergic effect of betel nut may increase the incidence of extrapyramidal side effects of loxapine, especially if patients are treated with anticholinergic agents to control these side effects.
Deterioration in symptoms of patients with Parkinson’s disease or other extrapyramidal movement disorders may be expected.
Interactions with laboratory tests have not been studied.
Loxapine, like other antipsychotics, may impair mental and/or physical abilities, especially during the first few days of therapy. Therefore, ambulatory patients should be warned about activities requiring alertness (e.g. operating vehicles or machinery) and about concomitant use of alcohol and other CNS depressants (see WARNINGS AND PRECAUTIONS, General).
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