The P-I-E-N-O Parkinsn's List Drug Database
loxapine /LoxitaneTM
HIGH RISK
Description: Loxapine is a typical antipsychotic drug that is structurally similar to the antidepressant amoxapine. Loxapine is used in the treatment of psychotic disorders and schizophrenia. It most often is used in patients who have not responded to other antipsychotic drugs. A 10 mg loxapine dose would be equivalent to 100 mg chlorpromazine, the prototype antipsychotic. Loxapine was approved by the FDA in 1975.
Mechanism of Action: Loxapine blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the DA somatodendritic autoreceptor. After approximately 12 weeks of chronic therapy, depolarization blockade of dopamine tracts occurs. The decrease in dopamine neurotransmission has been found to correlate with the antipsychotic effects. DA-receptor blockade is also responsible for the potent extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Loxapine possesses moderate anticholinergic and strong ›-adrenergic receptor blocking effects. Blockade of ›A-adrenergic receptors produces sedation; muscle relaxation; and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns. Pharmacokinetics: Following oral administration, loxapine is rapidly and completely absorbed from the GI tract. Intramuscular administration, used for agitated patients or patients unable to take oral preparations, is also rapidly absorbed. First-pass hepatic metabolism reduces bioavailability to roughly 30% compared with intramuscular doses. Peak serum concentrations are attained more slowly following IM administration but are similar at steady state to those attained after oral administration. After oral doses, sedative effects are seen in about 20-30 minutes, with peak effects in about 1.5-3 hours and a duration of about 12 hours. Several days of therapy are required to produce steady-state serum levels, and maximum antipsychotic effect may require weeks.
There is wide distribution of loxapine, mainly into brain, lungs, heart, liver, and pancreas. The drug appears in the CSF, crosses the placenta, and is distributed into breast milk. Half-life of loxapine depends on the route of administration. Half-life is roughly 4 hours after oral administration and about 12 hours after IM administration, possibly due to slow absorption from muscle tissue. Metabolism is extensive. Loxapine has several active metabolites, 8-hydroxyloxapine, 7-hydroxyloxapine, and undergoes demethylation to amoxapine and its hydroxy metabolites. Insignificant amounts of unchanged drug are found in the urine and feces; most excretion of metabolites is as glucuronide or sulfate conjugates. About 50% of an oral dose is excreted in urine and feces within 24 hours.
CONTRAINDICATIONS/PRECAUTIONS: Loxapine should be used with extreme caution in patients with thyroid disease such as thyrotoxicosis or hyperthyroidism. Antipsychotic agents can cause extremely severe extrapyramidal symptoms such as dystonias or rigidity. Laryngospasm can prevent breathing and could be life-threatening.
Patients with hypocalcemia may be at an increased risk for having dystonic reactions, so loxapine should be used with caution in this patient population.
Severe adverse CNS reactions induced by loxapine may appear similar to neurologic symptoms of CNS disorders such as encephalitis, Reye's syndrome, encephalopathy, meningitis, and tetanus. In addition, loxapine can suppress the symptoms of these disorders, if they are present. Loxapine is contraindicated in patients who are in a coma, who have a brain tumor, or who exhibit severe toxic CNS depression.
Loxapine also should be used with caution in patients with cardiovascular disorders or cardiac disease. Severe hypotension, myocardial depression, arrhythmias, and changes in ECG patterns occur. While these effects are generally reversible, they can lead to cardiac arrest.
Patients receiving anticonvulsant agents or who have a history of a seizure disorder, epilepsy, or EEG abnormalities should be carefully monitored during therapy with loxapine due to its potent lowering of seizure threshold, particularly at very high doses. Adequate anticonvulsant therapy should prevent an increase in seizure frequency during treatment with loxapine. High doses and large changes in loxapine doses should be avoided in patients with a known history of seizures.
Loxapine should be used with caution in patients with hepatic disease because the drug's metabolism can be decreased, increasing toxicity.
Loxapine should be used with caution in patients with renal impairment, or in elderly or debilitated patients. Reduction in dosage may be required.
Loxapine should be used with caution in patients with glaucoma. Other antipsychotics have caused lenticular opacity, resulting in visual impairment. Patients on prolonged therapy should undergo periodic ophthamological examination.
Loxapine should be used with caution in patients with prostatic hypertrophy because the drug's potent anticholinergic effects can increase urinary retention. Rarely, loxapine can cause blood dyscrasias, such as agranulocytosis and leukopenia, as well as other adverse hematologic effects, so it should be used cautiously in patients with preexisting blood dyscrasias. Leukopenia normally resolves upon discontinuation of the drug, but other disorders can progress to a fatal stage, so periodic blood counts should be undertaken, especially for patients on long-term therapy. Loxapine should be used cautiously in patients with preexisting hematological disease. Therapy should be discontinued if signs and symptoms of possible hematologic disorder develop such as sore throat, fever, or unusual tiredness and weakness.
Loxapine is contraindicated in patients with Parkinson's disease. The dopamine blockade from loxapine will dramatically worsen the preexisting Parkinson's disease, possibly incapacitating the patient.
Loxapine should be used with caution in patients with peptic ulcer disease because its anticholinergic effects can mask symptoms of the disease.
Loxapine should be used with caution in patients with active alcoholism because they can have an increased risk of toxicity from potentially serious adverse CNS effects.
Loxapine has not been studied in children under the age of 16. Use in this population should be avoided, if possible.
Loxapine is contraindicated in patients known to have sensitivity to amoxapine.
Loxapine can disrupt the hypothalamic mechanism for temperature regulation. Patients therefore should avoid exposure to extreme temperature variations to prevent hyperthermia or hypothermia.
Loxapine is classified as pregnancy category C. Rats and mice have been observed to experience increased fetal reabsorptions and decreased fetal weight when exposed to loxapine. Loxapine should be used during pregnancy only when the benefits outweigh the potential risks to the fetus. Loxapine and metabolites are excreted into the breast milk of dogs. Adverse effects on human infants are unknown, so loxapine should be used during breastfeeding only when a benefit-to-risk assessment shows that it is clearly needed.
Antipsychotics stimulate the release of prolactin and should be used extremely cautiously in patients who have a history of breast cancer.
Tobacco smoking can reduce plasma concentrations of loxapine. Plasma concentrations of loxapine should be monitored and linear dosage adjustments made in patients that start or stop smoking.
DRUG INTERACTIONS: Loxapine can potentiate the actions of other CNS depressants such as opiate agonists, barbiturates, ethanol, or general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Carbamazepine is a potent inducer of the cytochrome P-450 mixedfunction oxidase system. Concomitant use of carbamazepine can reduce the plasma concentrations of loxapine. Plasma concentrations of loxapine should be monitored and linear dosage adjustments made in patients receiving carbamazepine. Additive CNS depression can occur and the seizure threshold lowered if loxapine is used concomitantly with carbamazepine. If loxapine therapy is necessary for a patient taking anticonvulsants, dosage adjustment of the anticonvulsant may be required because loxapine lowers the seizure threshold. In a single patient, loxapine was reported to reduce serum phenytoin concentrations.
Ototoxic symptoms, such as tinnitus, dizziness, or vertigo, can be masked if loxapine is used concurrently with ototoxic medications, especially antibiotics such as aminoglycosides, vancomycin, or erythromycin. Erythromycin can inhibit metabolism of many drugs. Plasma concentrations of loxapine should be monitored and linear dosage adjustments made in patients receiving erythromycin or other macrolide antibiotics.
Although a causal relationship has not been established, an encephalopathic syndrome can occur when loxapine is administered to patients whose lithium serum concentrations are "1.2 mEq/L. This syndrome is characterized by weakness, lethargy, fever, confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood glucose. Additive extrapyramidal effects also have been noted in patients receiving both agents at normal concentrations concurrently. Lithium levels should be monitored closely during concomitant therapy with loxapine.
The absorption of loxapine from the GI tract can be reduced if the drug is given concomitantly with antacids or antidiarrheals.
The anticholinergic effects of tricyclic antidepressants, benztropine, or other anticholinergic antiparkinsonian drugs will be increased if used concomitantly with loxapine. Such drug combinations can cause severe constipation, increased intraocular pressure, or paralytic ileus. Patients should be asked about any GI problems or changes in vision.
Concurrent administration of loxapine and methyldopa has been reported to cause dementia in some cases. The clinical importance of this interaction has not been established, but caution is advised during simultaneous use of methyldopa and antipsychotics. In addition, antipsychotics can inhibit the antihypertensive effects of guanethidine.
The vasoconstrictive properties of dopamine infusion can be decreased by the ›-adrenergic blocking capability of loxapine. Dopamine infusions intended to improve renal perfusion can be ineffective due to loxapine's dopamine receptor blockade.
Loxapine, a dopamine receptor antagonist, is a pharmacologic antagonist to drugs such as levodopa, bromocriptine, or pergolide, which are dopamine agonists. Loxapine can antagonize the actions of these drugs. Limited research data suggest that there could be therapeutic benefits from the addition of levodopa in a small number of refractory schizophrenic patients.
The hypotensive effects of guanadrel and guanethidine can be reduced by concurrent use with loxapine.
The pressor effect of methoxamine can be blocked by the ›adrenergic blocking action of loxapine when used prior to administration of methoxamine, possibly resulting in severe hypotension. Patients taking loxapine can have reduced pressor response to ephedrine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The ›-adrenergic effects of epinephrine can be blocked during concurrent administration of loxapine. This reaction can result in an apparently paradoxical condition called "epinephrine reversal." Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction.
The combination of loxapine and lorazepam has been associated with acute respiratory depression in several patients. Lorazepam, and possibly other benzodiazepines, should be used cautiously in patients receiving loxapine.
ADVERSE REACTIONS: Extrapyramidal symptoms (EPS) occur occasionally during treatment with loxapine and appear to be the result of blockade of the DAreceptor. These symptoms occur with greater severity and frequency during high-dose therapy. Extrapyramidal symptoms are categorized as dystonia, akathisia (subjective and objective motor restlessness), and parkinsonism. Parkinsonian symptoms are more common in the elderly, whereas children most often develop dystonic reactions, which can be worsened by acute infections or severe dehydration. Dystonic reactions are seen during the first week of treatment. Akathisia and parkinsonian symptoms usually develop several days to weeks into therapy. Dystonia and pseudoparkinsonism usually are easily treated with concomitant benztropine, diphenhydramine, lorazepam, or amantadine. Akathisia can respond to dosage reduction or concomitant administration of a benzodiazepine (usually lorazepam) or propranolol. However, patients should be monitored carefully for excessive sedation and respiratory depression (see Drug Interactions). Loxapine is less likely to cause EPS than are high-potency antipsychotics such as haloperidol.
Neuroleptic malignant syndrome (NMS) can occur in patients receiving loxapine. NMS is characterized by hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability. Increased serum creatine phosphokinase (CPK), acute renal failure, and leukocytosis also have occurred. NMS does not appear to be doserelated. Severe cases have resulted in death occurring 3-30 days after onset of the syndrome. Several predisposing factors can contribute to the development of NMS, including heat stress, physical exhaustion, dehydration, and organic brain disease. NMS occurs more frequently in young men. Loxapine should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered.
Tardive dyskinesia (TD) is characterized by involuntary movements of the perioral region (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities. It can develop during long-term therapy or following discontinuation of loxapine, and it occurs more frequently in elderly women. The incidence may be higher in patients with bipolar disorder than with schizophrenia. Some cases can be irreversible. While contradictory evidence exists, it has been suggested that the likelihood of developing TD increases with prolonged treatment and cumulative doses. Although this complication often occurs following prolonged treatment or with administration of high dosages, it also has been reported to occur after short periods of time and with low dosages. Routine monitoring (at 3to 6month intervals) of movement disorders is considered the standard practice when using loxapine. If signs or symptoms of TD develop, loxapine use should be reevaluated and possibly discontinued.
Drowsiness is a CNS effect that frequently occurs during initial treatment with loxapine. Tolerance usually develops with continued therapy. Other CNS effects reported less frequently include restlessness, insomnia, depression, headache, and cerebral edema. Seizures can occur and are of special significance in patients who have preexisting seizure disorders or EEG abnormalities.
Anticholinergic effects related to loxapine administration include blurred vision, mydriasis, nausea, adynamic ileus, urinary retention, impotence, sinus tachycardia, and constipation. These effects can be enhanced by the concomitant administration of anticholinergic antiparkinsonian drugs, antidepressants, or other anticholinergic agents.
Cardiac arrhythmias, such as sinus tachycardia, can occur during therapy with loxapine. More serious ventricular arrhythmias, (eg. ventricular tachycardia) including those that can produce hypotension, can occur but are relatively rare unless large doses are used.
Hypothermia and hyperthermia have been reported and may result from loxapine's effect on the hypothalamic control of temperature regulation. Hyperpyrexia and heat stroke unrelated to NMS also have occurred.
Hematologic disturbances that have been reported following loxapine administration include leukopenia, leukocytosis, thrombocytopenia, pancytopenia, aplastic anemia, and anemia. Agranulocytosis has occurred rarely and has been associated with combination treatment with other agents.
Skin hyperpigmentation secondary to loxapine administration is more likely to occur following prolonged therapy. Changes in skin pigmentation generally are restricted to areas of the body exposed to sunlight. Severe photosensitivity can result, so patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body. Withdrawal of the drug can reverse the effects, and the clinician must decide whether therapy should be continued if pigmentary changes occur. Contact dermatitis has occurred when some antipsychotic liquids remain on the skin. Precautions to avoid contact should be taken, and any inadvertent spillage should be washed off immediately.
Pigmentary retinopathy due to loxapine can occur with or without pigmentary changes in the skin. Symptoms of blurred vision, difficulty with nighttime vision, or defective color vision should be investigated promptly. Wearing protective dark glasses can reduce the possibility of developing this reaction. The drug has been associated with frequent ocular changes including deposition of fine particles in the lens and cornea, which can cause visual impairment.
Pneumonia has occurred with other antipsychotics. This condition can result from dehydration, hemoconcentration, and reduced pulmonary ventilation, which are secondary to decreased thirst and lethargy from central inhibition.
Liver impairment manifest as cholestasis with jaundice has been reported rarely with administration of antipsychotics.
Priapism has been reported during therapy with loxapine.
PATIENT INFORMATION:
What do loxapine capsules do?
Loxapine (LoxitaneTM ) helps to treat schizophrenia. Loxapine can help you to keep in touch with reality and reduce your mental problems. It is for patients that have not been helped by other medicines. Generic loxapine capsules are not yet available.
What should my doctor, dentist, or pharmacist know before I take loxapine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take loxapine capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. If loxapine upsets your stomach you can take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 16 years old.
Elderly patients over age 65 years may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is less than 1 hour to your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with loxapine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking loxapine?
Serious side effects with loxapine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with loxapine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take loxapine?
Visit your doctor for regular checks on your progress. It may be several weeks before you see the full effects of loxapine. Do not suddenly stop taking loxapine. You may need to gradually reduce the dose. Only stop taking loxapine on your doctor's advice.
You may get dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how loxapine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase dizziness and drowsiness. Avoid alcoholic drinks. You can get a hangover effect the morning after a bedtime dose.
Do not treat yourself for colds, diarrhea or allergies. Ask your doctor or pharmacist for advice, some nonprescription medicines may increase possible side effects.
Loxapine may make your mouth dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help. Be careful when brushing and flossing your teeth to avoid mouth infections or damage to your gums. See your dentist regularly.
If you are going to have surgery tell your doctor or dentist that you are taking loxapine.
Do not take antacids or medicine for diarrhea within 2 hours of taking loxapine.
Loxapine may make you more sensitive to sun or ultraviolet light. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen (at least SPF 15). Do not use sun lamps, or sun tanning beds or booths. To protect your eyes wear sunglasses even on cloudy days.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Throw away any unused medicine after the expiration date.
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