Action And Clinical Pharmacology: Loxapine, a tricyclic dibenzoxazepine antipsychotic agent, which is chemically distinct from the phenothiazines, thioxanthenes and butyrophenones, produces pharmacological responses in various animal species which are characteristic of those seen with the majority of antipsychotic drugs.
Loxapine is an antipsychotic drug which exhibits many of the actions common to this broad class of drugs. Loxapine has proven to be of value in the management of both acute and chronic schizophrenia. As in the case of other antipsychotics, the mode of action has not been clearly established, but is postulated to involve changes in synaptic transmission at the subcortical level of the brain, resulting in strong inhibition of spontaneous motor activity.
Absorption of orally administered loxapine tablets, oral concentrate, and i.m. injection in man is rapid and virtually complete following a single 25 mg dose. After administration of the oral concentrate somewhat higher and earlier peak serum levels may be expected initially than after tablet administration. When the i.m. administration was compared to the oral administration, the mean serum concentrations of unmetabolized loxapine were approximately twice as high after i.m. injection of 25 mg as they were after equivalent oral dosage during the period of 1 to 4 hours. Signs of sedation in normal volunteers appear generally within 30 minutes for oral and parenteral administration. Duration of sedation is essentially the same with either the tablets or the oral concentrate and may last through a 12-hour period. The duration and intensity of sedation produced by the i.m. formulation in normal volunteers have been less than those observed following oral administration. (Average: 1 hour with the i.m. solution and close to 3 hours with the oral administration.) When multiple doses were given by the oral or i.m. route, the onset and duration of sedative effects were generally comparable. Initially, sedation occurred within 1.5 hours of the dose and lasted 8 hours: thereafter the duration was shortened to 1 to 2.5 hours. Loxapine is metabolized extensively, essentially no unchanged parent drug being excreted in urine or feces. The serum half-life of loxapine is approximately 3 hours. The serum concentration time curve of total drug related materials (loxapine plus metabolites), as shown by studies with radio-labelled drug, is biphasic in nature and shows larger half-lives, i.e., 5 hours for the alpha-phase and 19 hours for the beta-phase.
Five metabolites have been identified in the urine – loxapine N-oxide, 8-hydroxyloxapine, 7-hydroxyloxapine, 8-hydroxyamoxapine and 7-hydroxyamoxapine. The phenolic metabolites are excreted in the urine largely in the form of conjugates and in the feces primarily in the free form. In man, the greater proportion of the dose (56 to 70%) is excreted in the urine.
Indications And Clinical Uses: The management of the manifestations of schizophrenia.
Contra-Indications: Comatose or severe drug induced depressed states (alcohol, barbiturates, narcotics, etc.), individuals with known hypersensitivity to the drug, patients with circulatory collapse.
Manufacturers’ Warnings In Clinical States: Tardive Dyskinesia: 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, loxapine 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 loxapine 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 loxapine, drug discontinuation should be considered. However, some patients may require treatment with loxapine despite the presence of the syndrome.
Neuroleptic Malignant 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).
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 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.
Pregnancy and Lactation: Safe use of loxapine during pregnancy or lactation has not been established; therefore, its use in pregnancy, in nursing mothers or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.
Children: Studies have not been performed in children; therefore, this drug is not recommended for use in children below the age of 16.
Occupational Hazards: 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.
This drug is not recommended for use in cases suffering from blood dyscrasias or liver disease of significant severity.
Loxapine has not been evaluated for the management of behavioral complications in patients with mental retardation and therefore cannot be recommended in these patients.
Precautions: Loxapine 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 loxapine at antipsychotic dose levels and may occur even with maintenance of routine anticonvulsant drug therapy.
Loxapine 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 tumor.
Use loxapine 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.
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 or a tendency to urinary retention, particularly with concomitant administration of anticholinergic type of antiparkinson medication.
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 tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
There have been reports of excessive stupor, significant reduction in respiratory rate, and, in one patient, hypotension when loxapine and lorazepam were given concomitantly.
Withdrawal Emergent Neurological Signs: 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.
Adverse Reactions: CNS: The incidence of sedation following loxapine 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 loxapine 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).
Extrapyramidal Reactions: Neuromuscular (extrapyramidal) reactions during loxapine administration 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 not usually severe and can be controlled by reduction of loxapine dosage or by administration of antiparkinson 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 loxapine dosage in addition to appropriate counteractive drugs.
Tardive Dyskinesia: 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; antiparkinson 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.
Autonomic: Dry mouth, nasal congestion, constipation, blurred vision, urinary retention and paralytic ileus have occurred.
Cardiovascular: Tachycardia, hypotension, hypertension, light-headedness 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 loxapine administration.
Hematologic: Rarely, agranulocytosis, thrombocytopenia and leukopenia.
Gastrointestinal: Nausea and vomiting have been reported in some patients. Hepatocellular injury (i.e., AST/ALT elevation) has been reported in association with loxapine administration and rarely, jaundice and/or hepatitis questionably related to loxapine treatment.
Dermatological: Dermatitis, edema (puffiness of face), pruritus and seborrhea have been reported with loxapine. The possibility of photosensitivity and/or phototoxicity occurring has not been excluded; skin rashes of uncertain etiology have been observed in a few patients during hot summer months.
Endocrine: Rarely, galactorrhea, amenorrhea, gynecomastia and menstrual irregularity of uncertain etiology have been reported.
Other Adverse Reactions: Weight gain, weight loss, dyspnea, ptosis, hyperpyrexia, flushed facies, and polydipsia have been reported in some patients.
Symptoms And Treatment Of Overdose: Symptoms: Would be expected to range from mild depression of the CNS and cardiovascular systems to profound hypotension, respiratory depression and unconsciousness. The possibility of occurrence of extrapyramidal symptoms and/or convulsive seizures should be kept in mind. tag_Treatment
Treatment: No specific antidote is known. The treatment of overdosage would be essentially symptomatic and supportive. Early gastric lavage might be expected to be beneficial as might be extended dialysis. Additional supportive measures include the administration of oxygen and i.v. fluids. Centrally acting emetics may have little effect because of loxapine’s antiemetic action. In addition, emesis should be avoided because of the possibility of aspiration of vomitus. Avoid analeptics, which may cause convulsions.
Severe hypotension might be expected to respond to the administration of levarterenol or phenylephrine. Epinephrine should not be used since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Severe extrapyramidal reactions should be treated with anticholinergic antiparkinson agents or diphenhydramine HCl, and anticonvulsant therapy should be initiated as indicated.
Renal failure following loxapine overdosage has also been reported.
Dosage And Administration: Loxapine is administered orally, usually in divided doses 2 to 4 times a day. Daily dosage should be adjusted to the individual patient’s needs, as assessed by the severity of symptoms and previous history of response to antipsychotic drugs. Initial dosage of 10 mg twice daily is recommended, although in severely disturbed patients, initial dosage up to a total of 50 mg daily may be desirable. Based on initial response to the drug, dosage may then be increased fairly rapidly over the first 7 to 10 days until there is effective control of psychotic symptoms. The usual therapeutic range is 60 to 100 mg daily. However, as with other antipsychotic drugs, some patients respond to lower dosage and others require higher dosage for optimal benefit. Daily dosage higher than 250 mg is not recommended. For maintenance therapy, dosage should be reduced to the lowest level compatible with symptom control; many patients have been maintained satisfactorily at dosages in the range of 20 to 60 mg daily.
I.M. Administration: Loxapine i.m. is utilized in patients whose symptoms render oral medication temporarily impractical. During clinical trials, there were no reports of significant local tissue reaction.
Loxapine is administered by i.m. (not i.v.) injection in doses of 12.5 mg (1/4 mL) to 50 mg (1 mL) at intervals of 4 to 6 hours or longer, both dose and interval depending on patient response. Many patients have responded satisfactorily to twice-daily dosage. As described above for oral administration, attention is directed to the necessity for dosage adjustment on an individual basis over the early days of loxapine administration.
Once the desired symptomatic control is achieved and the patient is able to take medication orally, loxapine should be administered in tablet or oral concentrate form.
Availability And Storage: Oral Concentrate: Each mL of clear, colorless solution (pH: 5.0 to 6.5) contains: loxapine 25 mg as loxapine HCl. Nonmedicinal ingredients: hydrochloric acid, propylene glycol and purified water. Should be mixed with orange or grapefruit juice shortly before administration. Bottles with a dropper calibrated to deliver 10, 15, 20 and 25 mg and a syringe calibrated to deliver 2.5, 5.0, 7.5, 10.0, 12.5 or 15.0 mg. Expiration date: 2 years following date of manufacture. Bottles of 100 mL.
Injectable: For i.m. use only. Not for i.v. use. Each 1 mL ampul contains: loxapine HCl equivalent to loxapine 50 mg for i.m. injection. Nonmedicinal ingredients: polysorbate 80, polypropylene glycol and Water for Injection with hydrochloric acid or sodium hydroxide to adjust the pH to approximately 6.0. Tartrazine-free. Boxes of 10.
Tablets: 5 mg: Each yellow, scored, round, convex, film-coated tablet, engraved “LL” in script over “5” on one side and “x” above and “1” below the score on the other contains: loxapine 5 mg as the succinate salt. Nonmedicinal ingredients: alginic acid, calcium phosphate dibasic dihydrate, D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hydroxypropyl methylcellulose, magnesium stearate, mineral oil, mineral oil light, sodium lauryl sulfate, starch, starch pregelatinized, stearic acid and titanium dioxide. Tartrazine-free. Bottles of 100 and 500.
10 mg: Each light green, scored, round, convex, film-coated tablet, engraved “LL” in script over “10” on one side and “x” to the left and “2” to the right of the score on the other contains: loxapine 10 mg as the succinate salt. Nonmedicinal ingredients: calcium phosphate dibasic dihydrate, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hydroxypropyl methylcellulose, magnesium stearate, methylcellulose, mineral oil, mineral oil light, sodium lauryl sulfate, starch, starch pregelatinized, stearic acid and titanium dioxide. Tartrazine-free. Bottles of 100 and 500.
25 mg: Each pink, scored, round, convex, film-coated tablet, engraved “LL” in script over “25” on one side and “x” to the left and “3” to the right of the score on the other contains: loxapine 25 mg as the succinate salt. Nonmedicinal ingredients: calcium phosphate dibasic dihydrate, D&C Red No. 30 Aluminum Lake, hydroxypropyl methylcellulose, magnesium stearate, methylcellulose, mineral oil, mineral oil light, sodium lauryl sulfate, starch, starch pregelatinized, stearic acid and titanium dioxide. Tartrazine-free. Bottles of 100 and 500.
50 mg: Each white, scored, round, convex, film-coated tablet, engraved “LL” in script over “50” and “x” to the left and “4” to the right of the score on the other contains: loxapine 50 mg as the succinate salt. Nonmedicinal ingredients: calcium phosphate dibasic dihydrate, hydroxypropyl methylcellulose, magnesium stearate, methylcellulose, mineral oil light, sodium lauryl sulfate, starch, starch pregelatinized, stearic acid and titanium dioxide. Tartrazine-free. Bottles of 100 and 500.
Store all preparations at room temperature (15 to 30°C).
LOXAPAC® Wyeth-Ayerst Loxapine Antipsychotic Agent