LOXAPAC

Loxapine, a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines.

Chemically, it is 2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[ b,f ]oxazepine.

It is present as the succinate salt.

Each capsule for oral administration, contains loxapine succinate, USP 6.8, 13.6, 34.0 or 68.1 mg equivalent to 5, 10, 25 or 50 mg of loxapine base respectively.

It also contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, gelatin, magnesium stearate, polacrilin potassium, sodium lauryl sulfate, talc, titanium dioxide, D&C Yellow #10 and FD&C Blue #1.

Additionally, the 5 mg capsule contains D&C Red #33, the 10 mg capsule contains D&C Red #33 and D&C Red #28, and the 25 mg capsule contains FD&C Yellow #6.

In addition, the black imprinting ink contains shellac glace in ethanol, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue #2/indigo carmine aluminum lake, FD&C Red #40/Allurea Red AC aluminum lake, FD&C Blue #1/brilliant Blue FCF aluminum lake, D&C Yellow #10 aluminum lake, SDA 3A alcohol, and methanol.

The white imprinting ink contains pharmaceutical glaze in SD-45, titanium dioxide, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol and simethicone.

For the management of the manifestations of psychotic disorders such as schizophrenia

Loxapine, a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines.

Pharmacologically, Loxapine is a tranquilizer for which the exact mode of action has not been established, however, it is believed that by antagonising dopamine and serotonin receptors, there is a marked cortical inhibition which can manifest as tranquilization and suppression of aggression.

5-hydroxytryptamine receptor 2A Antagonist D dopamine receptor Antagonist.

Systemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers.

Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated.

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Signs and symptoms of overdosage will depend on the amount ingested and individual patient tolerance.

As would be expected from the pharmacologic actions of the drug, the clinical findings may 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.

Renal failure following loxapine overdosage has also been reported.

The treatment of overdosage is essentially symptomatic and supportive.

Early gastric lavage and extended dialysis might be expected to be beneficial.

Centrally-acting emetics may have little effect because of the antiemetic action of loxapine.

In addition, emesis should be avoided because of the possibility of aspiration of vomitus.

Avoid analeptics, such as pentylenetetrazol, which may cause convulsions.

Severe hypotension might be expected to respond to the administration of norepinephrine 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 hydrochloride, and anticonvulsant therapy should be initiated as indicated.

Additional measures include oxygen and intravenous fluids.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Loxapine is not approved for the treatment of patients with dementia-related psychosis.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome 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 treatment is withdrawn.

Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered.

However, some patients may require treatment despite the presence of the syndrome. See ADVERSE REACTIONS and Information for Patients sections.

Syndrome (NMS) 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 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 treatments are 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.

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.

Loxapine has not been evaluated for the management of behavioral complications in patients with mental retardation, and therefore, it cannot be recommended.

Loxapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Loxapine is contraindicated in comatose or severe drug-induced depressed states (alcohol, barbiturates, narcotics, etc).

Loxapine is contraindicated in individuals with known hypersensitivity to dibenzoxazepines.

Capsules, USP are administered, usually in divided doses, two to four times a day. Daily dosage (in terms of base equivalents) 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.

Dosage should then be increased fairly rapidly over the first seven to ten days until there is effective control of symptoms of schizophrenia.

The usual therapeutic and maintenance range is 60 mg to 100 mg daily.

However, as with other drugs used to treat schizophrenia, 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 to 60 mg daily.

Capsules, USP are available in the following strengths: Loxapine Succinate, USP 6.8 mg equivalent to 5 mg loxapine, opaque, with a dark green body and cap, imprinted with logo "LANNETT" on the cap and "1394" on the body are supplied as follows: NDC 0527-1394-01 –Bottle of 100s NDC 0527-1394-10 –Bottle of 1000s Loxapine Succinate, USP 13.6 mg equivalent to 10 mg loxapine, yellow opaque body and dark green opaque cap, imprinted with logo "LANNETT" on the cap and "1395" on the body are supplied as follows: NDC 0527-1395-01 –Bottle of 100s NDC 0527-1395-10 –Bottle of 1000s Loxapine Succinate, USP 34.0 mg equivalent to 25 mg loxapine, light green opaque body and dark green opaque cap, imprinted with logo "LANNETT" on the cap and "1396" on the body are supplied as follows: NDC 0527-1396-01 –Bottle of 100s NDC 0527-1396-10 –Bottle of 1000s Loxapine Succinate, USP 68.1 mg equivalent to 50 mg loxapine, light blue opaque body and dark green opaque cap, imprinted with logo "LANNETT" on the cap and "1397" on the body are supplied as follows: NDC 0527-1397-01 –Bottle of 100s NDC 0527-1397-10 –Bottle of 1000s Store at 20°-25°C (68°-77°F).

Dispense in a tight, child-resistant container.

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Philadelphia, PA 19136 CIB70541F Rev. 11/24.

Neonates exposed to antipsychotic drugs, 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.

Succinate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

No embryotoxicity or teratogenicity was observed in studies in rats, rabbits, or dogs although, with the exception of one rabbit study, the highest dosage was only two times the maximum recommended human dose and in some studies it was below this dose.

Perinatal studies have shown renal papillary abnormalities in offspring of rats treated from mid-pregnancy with doses of 0.6 and 1.8 mg/kg, doses which approximate the usual human dose but which are considerably below the maximum recommended human dose.

The extent of the excretion of loxapine or its metabolites in human milk is not known.

However, loxapine and its metabolites have been shown to be transported into the milk of lactating dogs.

Loxapine administration to nursing women should be avoided if clinically possible.

Safety and effectiveness of loxapine in pediatric patients have not been established.