Odan-Prochlorperazine Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

Prochlorperazine is a piperazine phenothiazine derivative with antipsychotic, antiemetic and weak sedative activity.

Prochlorperazine has actions similar to those of other phenothiazine derivatives but appears to be less sedating and to have a weak propensity for causing hypotension or potentiating the effects of Central Nervous System (CNS) depressants and anesthetics. However, it produces a high incidence of extrapyramidal reactions.

Prochlorperazine is well absorbed from the gastrointestinal tract.

The onset of action is 60 minutes following rectal administration of suppositories. Duration of action for rectal administration is 3 to 4 hours. Prochlorperazine distributes to most body tissues with high concentrations being distributed into the liver and spleen. Prochlorperazine enters the enterohepatic circulation and is excreted chiefly in the feces.

INDICATIONS AND CLINICAL USE

In the management of manifestations of psychotic disorders such as agitation, confusion, delusion, tension and anxiety.

Prochlorperazine is also effective in controlling nausea and vomiting due to stimulation of the chemoreceptor trigger zone (CTZ).

In selected patients, prochlorperazine may be of value for the relief of excessive anxiety, accompanied by severe tension and agitation, associated with psychoneurotic or somatic conditions.

CONTRAINDICATIONS

Prochlorperazine should not be administered in the presence of circulatory collapse, altered states of consciousness or comatose states, particularly when these are due to intoxication with central depressant drugs (alcohol, hypnotics, narcotics). It is contraindicated in severely depressed patients, in the presence of blood dyscrasias, liver disease, renal insufficiency, pheochromocytoma, or in patients with severe cardiovascular disorders or a history of hypersensitivity to phenothiazine derivatives.

As with other phenothiazines, prochlorperazine is contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures above 40^oC may occur, sometimes not until 14 to 16 hours after drug administration.

Phenothiazine compounds should not be used in patients receiving large doses of hypnotics, due to the possibility of potentiation.

Odan-Prochlorperazine is contraindicated in children undergoing surgery.

WARNINGS

General

The antiemetic action of prochlorperazine may mask the signs and symptoms of overdosage of other drugs and may obscure the diagnosis and treatment of other conditions such as brain tumour or intestinal obstruction. Therefore the etiology of nausea and vomiting should be established before using the drug.

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 Odan-Prochlorperazine and then periodically throughout treatment.

Occupational Hazards: The use of this drug may impair the mental and physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery.

Potentiation of the effects of alcohol may also occur.

Special Populations

Pregnant Women:

Teratogenic Effects

Safety during pregnancy has not been established. Therefore, it is recommended that the drug be given to pregnant patients only when, in the judgement of the physician, the potential benefit to the patient outweighs the possible risk to the fetus.

Non-Teratogenic Effects

Neonates exposed to antipsychotic drugs (including prochlorperazine) 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.

Prochlorperazine should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.

Pediatrics: The drug should not be used in children under 2 years unless potentially life-saving.

The extrapyramidal symptoms which can occur secondary to prochlorperazine may be confused with the CNS signs of an undiagnosed primary disease responsible for the vomiting, e.g. Reye's syndrome or other encephalopathy. The use of Odan-Prochlorperazine should be avoided in children and adolescents whose signs and symptoms suggest Reye's syndrome.

PRECAUTIONS

The increased incidence of seizures, which occasionally occur in epileptics started on antipsychotic medication, may be controlled by increasing the dosage of their anticonvulsant. Patients with a familial history of seizures or febrile convulsions are more likely to develop seizures than those who have no such history.

Phenothiazines may increase the effects of general anesthetics, opiates, barbiturates, and other CNS depressants and the doses of these drugs should be reduced if administered concomitantly with prochlorperazine.

On long-term therapy, particularly during the first 2 or 3 months, it is advisable to perform periodic liver function tests and blood counts as cholestatic jaundice and blood dyscrasias may occur necessitating discontinuation of treatment. Renal function should be monitored and, if BUN becomes abnormal, treatment should be discontinued.

To lessen the likelihood of adverse reactions related to drug accumulation, patients on long-term therapy, particularly on high doses, should be evaluated periodically to decide whether the maintenance dosage could be lowered or drug therapy discontinued.

Because of its anticholinergic action, prochlorperazine should be used with great caution in patients with glaucoma or prostatic hypertrophy.

The effects of anticholinergic drugs may be potentiated by prochlorperazine. Paralytic ileus, even resulting in death, may occur, especially in the elderly. Caution should be observed if constipation develops.

Retinal changes, lenticular and corneal deposits and abnormal skin pigmentation have been observed with other phenothiazines and may occur after prolonged therapy. The possibility of persistent tardive dyskinesia should also be borne in mind when patients are under long-term treatment.

Patients receiving Odan-Prochlorperazine should be cautioned against exposure to extreme heat or organophosphorous insecticides.

Hypotension and ECG changes, particularly non-specific and usually reversible Q and T wave distortions, have been associated with the administration of phenothiazines. Therefore, Odan-Prochlorperazine should be used with caution in patients with compensated cardiovascular and cerebrovascular disorders.

Unexpected, sudden deaths have occurred in hospitalized patients treated with phenothiazines. Previous brain damage or seizures may predispose. High doses should be avoided in known seizure patients. Sudden exacerbations of psychotic behaviour patterns occurred in several patients shortly before death. Acute fulminating pneumonia or pneumonitis and aspiration of gastric contents were also observed. Therefore, the physician should also keep in mind the possible development of silent pneumonia.

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.

Hematologic

Venous Thromboembolism: Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including prochlorperazine, in case reports and/or observational studies. When prescribing Odan-Prochlorperazine all potential risk factors for VTE should be identified and preventative measures undertaken.

Endocrine and Metabolism

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.

Hyperprolactinemia: Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects.

Genitourinary: Rare cases of priapism have been reported with antipsychotic use, such as prochlorperazine. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment.

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.

Older Patients: The incidence of adverse reactions may be greater in patients over 55 years of age, since the half-lives of antipsychotic drugs are often prolonged. To minimize this possibility, the maintenance dosage should be reduced to the lowest effective level as soon as possible after initial titration and periodically reviewed.

Since psychiatric syndromes in the elderly can be caused by drugs or organic disease, withdrawal of the precipitating drug or treatment of the medical condition should supersede initiation of antipsychotic medication. These agents should not be used for non-psychiatric conditions for which other drugs are available, since the elderly are especially prone to develop adverse effects from antipsychotic drugs.

Pediatrics: Children with an acute febrile illness or suffering from dehydration seem to be much more susceptible than adults to neuromuscular reactions, particularly dystonias. In such patients, the drug should be used under close supervision and at low doses.

ADVERSE REACTIONS

Adverse reactions with different phenothiazines vary in type, frequency, and mechanism of occurrence, i.e. some are dose-related, while others involve individual patient sensitivity. Some adverse reactions may be more likely to occur with greater intensity in patients with special medical problems.

Not all of the following adverse reactions have been observed with every phenothiazine derivative, but they have been reported with one or more and should be borne in mind when drugs of this class are administered.

Patients should be advised of the risk of severe constipation during prochlorperazine treatment, and that they should tell their doctor if constipation occurs or worsens, as they may need laxatives.

Neurological: Extrapyramidal reactions including tremor, rigidity, akathisia, dystonia, dyskinesia, oculogyric crises, opisthotonos, hyperreflexia and sialorrhea. EEG changes, disturbed temperature regulation and seizures have also been encountered.

Persistent Tardive Dyskinesia: As with other antipsychotic agents, tardive dyskinesia may occur in patients on long-term therapy or may be observed after drug therapy has been discontinued. The risk seems to be greater in elderly patients on high doses, especially females. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements 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; antiparkinsonian 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. 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. 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.

Behavioral: Sleep disturbances, drowsiness, fatigue, insomnia, and depression have been reported and may, in severe cases, necessitate reduction in dosage. As with other phenothiazine derivatives, reactivation or aggravation of psychotic processes may be encountered. Paradoxical effects such as agitation, anxiety, restlessness, excitement and bizarre dreams, have been observed.

Autonomic Nervous System: Dry mouth, nasal congestion, headache, nausea, constipation, tachycardia, hypotension, syncope, dizziness, blurred vision, vomiting, sweating, and urinary incontinence have been observed.

Patients with pheochromocytoma, cerebral vascular or renal insufficiency, or a severe cardiac reserve deficiency such as mitral insufficiency appear to be particularly prone to hypotensive reactions with phenothiazine compounds, and should therefore be observed closely when the drug is administered. Should hypotension occur in patients receiving prochlorperazine and a vasopressor agent be required, i.v. levarterenol or phenylephrine should be used, and not epinephrine, since phenothiazine derivatives can reverse the pressor effect of the latter drug.

Other autonomic reactions which have occurred with phenothiazines are salivation, polyuria, glaucoma, bladder paralysis, adynamic ileus, and fecal compaction.

Metabolic and Endocrine: Anorexia, menstrual irregularities, impotence, increased thirst, weight changes, increased appetite, peripheral edema, galactorrhea, gynecomastia, false positive pregnancy tests, and changes in libido have also occurred in patients receiving phenothiazine therapy.

Allergic or Toxic: Pruritus, dermatitis, rash, erythema, urticaria, seborrhea, eczema, exfoliative dermatitis, and photosensitivity. The possibility of an anaphylactoid reaction should be borne in mind.

Blood dyscrasias including leukopenia, agranulocytosis, pancytopenia, thrombocytopenic or non-thrombocytopenic purpura, eosinophilia, and anemia, have been associated with phenothiazine therapy. Routine blood counts are therefore advisable during prolonged therapy. If any soreness of the mouth, gums or throat or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.

Cholestatic jaundice and biliary stasis may be encountered, particularly during the first months of therapy, and require immediate discontinuation of treatment.

Miscellaneous: The following adverse reactions have been reported in patients receiving phenothiazine derivatives: headache, asthma, laryngeal, cerebral and angioneurotic edema, altered cerebrospinal fluid proteins, systemic lupus erythematosus-like syndrome, hyperpyrexia, ECG and EEG changes and hypotension severe enough to cause fatal cardiac arrest. Skin pigmentation, epithelial keratopathy, lenticular and corneal deposits have been associated with long-term administration.

Sudden, unexpected and unexplained deaths have been reported in hospitalized psychotic patients receiving phenothiazines. Previous brain damage or seizures may be predisposing factors; high doses should be avoided in known seizure patients. Several patients have shown flare-ups of psychotic behaviour patterns shortly before deaths. Autopsy findings have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents or intramyocardial lesions.

Potentiation of CNS depressants (barbiturates, narcotics, analgesics, alcohol, antihistamines) may occur.

Neuroleptic Malignant Syndrome: As with other neuroleptic drugs, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) may occur. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure). Additional signs may include elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. NMS is potentially fatal and requires symptomatic treatment and immediate discontinuation of neuroleptic treatment.

OVERDOSAGE

Symptoms: Primarily extrapyramidal reactions, CNS depression which may vary from simple lethargy to coma. Agitation and restlessness may also occur. Other possible manifestations include convulsions, fever and autonomic reactions such as hypotension, dry mouth and ileus.

Treatment: The treatment is essentially symptomatic and supportive. Early gastric lavage may be helpful.

Maintain an open airway. If hypotension occurs, the standard measures for managing circulatory shock should be initiated; if a pressor agent is required, give levarterenol or phenylephrine and not epinephrine as it may further depress the blood pressure. Extrapyramidal reactions should be treated with an antiparkinsonian agent.

Centrally acting emetics will be ineffective because of prochlorperazine's antiemetic action. Limited experience indicates that phenothiazines are not dialysable.

DOSAGE AND ADMINISTRATION

Dosage of prochlorperazine and its salts is expressed in terms of prochlorperazine base.

Begin with the lowest recommended dosage. Adjust to response of the individual.

Adults

To control nausea, vomiting or excessive anxiety: usually 1 suppository 1 to 3 times a day, or as directed by a physician. In mild cases, a single suppository is often adequate.

In psychiatry for moderate to severe conditions, the usual starting dosage is 10 mg, 3 or 4 times a day; increase dosage gradually by 10 mg every 2 or 3 days until symptoms are controlled or adverse reactions intervene.

Some patients respond satisfactorily on 50 to 75 mg per day. In more severe disturbances it may reach 100 to 150 mg a day. For maintenance therapy, the dosage should be reduced to the minimum effective dose.

STORAGE AND STABILITY

Store below 25^oC. Protect unwrapped suppository from light.

Keep out of reach and sight of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition:

Each rectal Odan-Prochlorperazine suppository contains 10 mg of prochlorperazine base. Also contains the following non-medicinal ingredients: Hard Fat, Mixed Tocopherols.

Packaging:

Odan-Prochlorperazine suppository is available in boxes of 10.