Piportil L4 (Pipotiazine Palmitate)

PIPORTIL L4®

Rh´ne-Poulenc Rorer

Pipotiazine Palmitate

Antipsychotic

Action And Clinical Pharmacology: Pipotiazine palmitate is the palmitic ester of pipotiazine, a piperidine phenothiazine with antipsychotic properties and weak sedative activity with prolonged duration of action. The onset of action appears usually within the first 2 to 3 days after injection and the effects of the drug on psychotic symptoms are significant within 1 week. Improvement in symptomatology lasts from 3 to 6 weeks, but adequate control may frequently be maintained with one injection every 4 weeks. However, in view of the variations in individual response, careful supervision is required throughout treatment.

Pipotiazine has actions similar to those of other phenothiazines. Among the different phenothiazine derivatives, it appears to be less sedating and to have a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. However, it produces a high incidence of extra pyramidal reactions.

Indications And Clinical Uses: The maintenance treatment of chronic non-agitated schizophrenic patients.

Contra-Indications: 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 e.g., alcohol, hypnotics, narcotics. 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.

It is not indicated for the management of psychoneurotic patients or geriatric patients with confusion and/or agitation.

As with other phenothiazines, pipotiazine is contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures above 40°C 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.

Children: The safety and efficacy of pipotiazine in children have not been established. Therefore, it is not indicated for use in children.

Manufacturers’ Warnings In Clinical States: Severe adverse reactions requiring immediate medical attention may occur and are difficult to predict. Therefore, pipotiazine should be administered under the supervision of physicians experienced in the use of psychotropic drugs and facilities should be readily available to cope with any emergency situation.

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.

Pregnancy: Safety during pregnancy has not been established, and the drug should not be used in women of childbearing potential unless, in the opinion of the physician, the expected benefit to the patient outweighs the possible risk to the fetus.

Precautions: Phenothiazines, particularly those which are long acting, should be used with caution in patients with a history of convulsive disorders; treatment should not be initiated unless such patients are receiving appropriate anticonvulsive medication.

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.

Hypotensive phenomena may develop in phenothiazine treated patients who are undergoing surgery. Careful observation is necessary and dosages of anesthetics or CNS depressants may have to be reduced. Antipsychotic agents should be temporarily discontinued in patients receiving spinal or epidural anesthesia, if possible, to allow time for the residual drug to be metabolized.

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

The effects of anticholinergic drugs may be potentiated by pipotiazine. 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 be considered with long-term treatment.

Patients receiving pipotiazine should be cautioned against exposure to extreme heat or organophosporus insecticides.

Hypotension and ECG changes, particularly nonspecific and usually reversible Q and T wave distortions, have been associated with the administration of phenothiazines. Use with caution in patients with compensated cardiovascular and cerebrovascular disorders.

The antiemetic effects of most phenothiazines can obscure toxic signs due to overdosage of other drugs or they may mask the symptoms of diseases such as brain tumors or intestinal obstruction.

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 behavior patterns occurred in several patients shortly before death. Acute fulminating pneumonia or pneumonitis and aspiration of gastric contents also were observed. Therefore, the physician also should keep in mind the possible development of “silent pneumonias”.

Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately 33% 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.

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.

Geriatrics: 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.

Adverse Reactions: Neurological: The side effects most frequently reported are extrapyramidal reactions including tremor, rigidity, akathisia, dystonia, dyskinesia, oculogyric crises, opisthotonos, hyperreflexia and sialorrhea which tend to occur in the first few days after an injection. Pipotiazine tends to produce a higher incidence of extrapyramidal reactions than some other phenothiazine derivatives. Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These reactions may tend to subside as treatment is continued but are often dose related and may respond to a reduction of the dose. Antiparkinsonian medication may be required to control serious reactions or, if intractable, the drug may have to be withdrawn. The information available tends to indicate that persistent tardive dyskinesia results from heavy drug overloading of the extrapyramidal system. Therefore, caution should be exercised to avoid overdosing and the optimum dosage should not be exceeded since this will tend to elicit marked extrapyramidal reactions.

Persistent 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. 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. 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 in some patients.

Autonomic Nervous System: Dry mouth, nausea and constipation were most frequently seen during pipotiazine therapy. Tachycardia, hypotension, syncope, dizziness, blurred vision, vomiting, sweating, nasal congestion, and urinary incontinence have also 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 pipotiazine 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, and increased thirst have been reported with pipotiazine.

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 and rash have been observed with pipotiazine. Other allergic reactions reported with phenothiazine derivatives are 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 nonthrombocytopenic 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 death. 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.

Local tolerance to pipotiazine is good and reactions at the site of injection are seldom seen.

Symptoms And Treatment Of Overdose: Symptoms: Severe extrapyramidal manifestations, hypotension, lethargy and sedation are most likely to be observed. Initial hospitalization may be required and close medical supervision should be maintained until symptoms are well under control. tag_Treatment

Treatment: Symptomatic and supportive. Severe extrapyramidal reactions may be treated with an appropriate antiparkinsonian agent. Maintain an adequate airway and, in cases of severe hypotension, administer i.v. levarterenol or phenylephrine (not epinephrine as it may further depress the blood pressure).

When a sufficient amount of time has elapsed or when the patient shows signs of relapse, treatment may be resumed at a lower dosage.

Dosage And Administration: Pipotiazine palmitate is to be administered as an i.m. injection only. As a long acting depot phenothiazine, it has been found useful in the maintenance therapy of non-agitated, chronic schizophrenic patients stabilized with shorter acting neuroleptics who might benefit from a transfer to a long acting injectable drug.

The changeover to pipotiazine palmitate should aim at maintaining a clinical outcome similar to or better than that obtained with the previously used antipsychotic agent in patients who cannot be relied upon to take oral medication regularly. In those patients who might benefit from a long acting neuroleptic, it is suggested to discontinue the previous antipsychotic medication prior to the changeover of drugs. The initial dose and the interval between injections should be selected on an individual basis, considering such factors as age, physical condition, symptoms and severity of illness, and previous drug history. Depending on the previous drug history or other individual factors, an initial dose of 50 to 100 mg may be administered. If necessary, further symptom control can usually be obtained by increasing the dose by increments of 25 mg every 2 or 3 weeks. The optimal dose and the interval between injections must be determined in accordance with the patient’s response. A single injection of pipotiazine palmitate may effectively control the schizophrenic symptoms for 3 to 6 weeks. However, it is frequently possible to achieve adequate control with a dosage between 75 and 150 mg administered every 4 weeks. Some patients may not require more than 25 to 50 mg every 4 weeks, while in others, doses of up to 250 mg may be needed.

Lower doses should be used in patients over the age of 50 when initiating therapy.

The dosage should not be increased in order to prolong the interval between injections. Some patients may benefit from the use of lower doses administered every 3 weeks. Regular and continuous supervision is considered essential in order to maintain the patient on the lowest effective individual dose and to make any additional adjustments in the dosage which may be required to avoid overdosage and troublesome adverse effects.

Although the incidence of extrapyramidal reactions is high, antiparkinsonian medication should be prescribed only to treat emergent symptoms that may occur. They should not be used prophylactically against such reactions.

A dry syringe and a needle of at least 21 gauge should be used. Use of a wet needle or syringe may cause the solution to become cloudy.

Availability And Storage: 25 mg/mL: Each mL contains: pipotiazine palmitate 25 mg. Nonmedicinal ingredients: sesame oil. Ampuls of 1 mL, boxes of 3.

50 mg/mL: Each mL contains: pipotiazine palmitate 50 mg. Nonmedicinal ingredients: sesame oil. Ampuls of 1 mL, boxes of 3. Ampuls of 2 mL, boxes of 1.

Store at room temperature and protect from light.

PIPORTIL L4® Rh´ne-Poulenc Rorer Pipotiazine Palmitate Antipsychotic

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