Class: Central Nervous System
Dosage Form: Tablets
Description: Antidepressant and anxiolytic
Manufacturer: Bristol-Myers Squibb
Flurphenazine HCl………….0.5 mg
Nortriptyline HCl……………..10 mg
The mechanism of antidepressant action of nortriptyline is not fully understood. It inhibits the activity of histamine, serotonin, and acetylcholine, but its effects on norepinephrine and serotonin are regarded as the most clinically important. Fluphenazine has activity at all levels of the central nervous system as well as on multiple organ systems. The mechanism of therapeutic action is unknown, but may be related to antidopaminergic effects of the drug.
The pharmacokinetics and dose-response of both nortriptyline and fluphenazine are characterized by inter-individual variability. Inter-patient variations may be influenced by age and genetics as well as by interaction with other drugs.
After oral administration, both nortriptyline andfluphenazine are well absorbed from the GI tract and extensively metabolized during “first pass” metabolism in the liver. Both agents are widely distributed in the brain and other organs and highly bound to plasma proteins (nortriptyline: 87% to 93%; fluphenazine: greater than 90%). The apparent volume of distribution of nortriptyline is 15-23 L/kg. Both fluphenazine and nortriptyline cross the placenta. Nortriptyline is excreted in small amounts in breast milk. It is not known whether fluphenazine is present in breast milk; however, other phenothiazines have been shown to be excreted in human breast milk.
The plasma half-life of nortriptyline ranges from approximately 18 to 93 hours. The serum half-life of fluphenazine HCl is approximately 15 hours. Steady-state for nortriptyline is reached in approximately 4 to 19 days. A relationship between serum concentration and therapeutic response has been demonstrated for nortriptyline, with the best antidepressant effect in the concentration range of 50-150 ng/ml.
Nortriptyline and fluphenazine and their metabolites are excreted both in urine and faeces. Neither fluphenazine nor nortriptyline are considered dialyzable.
Motival is indicated for the short-term treatment of patients suffering from mild-to-severe symptoms of mixed anxiety and depression.
Motival in contraindicated:
- In patients with a history of hypersensitivity to fluphenazine, nortriptyline, any component of the preparation, any other phenothiazine or dibenzazapine
- During the acute recovery period after myocardial infarction
- In patients with suspected or established subcortical brain damage
- In patients receiving large doses of CNS depressants (alcohol, barbiturates, narcotics, hypnotics, etc…)
- In comatose or severel depressent states
- In patients with blood dyscriasis or liver damage
Concurrent treatment with tricylcic antidepressants and monomaine oxidase inhibitors (MAOIs) should be avodied. This combination can cause a serious symptom complex that may include hyperreflexia, hyperpyretic crisis, and severe convulsions, and has resulted in deaths.
Clinical evaluation of Motival has not revealed any drug interactions peculiar to the combination. The interactions that occurred were limited to those that have been reported previously for nortriptyline and fluphenazine.
- Amphetamine/Anorectic Agents: Concurrent administration may produce antagonistic pharmacologic effects.
- Antacids/Antidiarrheal Agents: Concurrent administration may interfere with Motival absorption. Administration of antacids should be spaced at least 1 hour before or 2-3 hours after Motival dose.
- Antiarrhythmics (Class I): Concurrent administration of Motival with quinidine, procainamide or similar agents may alter the metabolism of nortriptyline, resulting in decreased total body clearance of nortriotyline, and may cause dose-related additive effects on cardiac conduction.
- Anticholinergic/Antimuscarinic Agents: Cholinergic blockade may be exaggerated when Motival is administered with anticholinergic agents, expecially in older patients.
Antimuscarinic effects may be potentiated or prolonged. Close supervision and careful dosage adjustment are requried when Motival is used with other anticholinergic or antimuscarinic drugs.
- Anticonvulsants: Anticonvulsant action may be impaired by Motival.
- Antidiabetic: Phenothiazines have been associated rarely with loss of blood glucose control in diabetics, and nortriptyline may increase the hypoglycemic effects of oral sulfonylurea or insulin.
- Anticoagulants: Patients on tricyclic antidepressants and anticoagulants should be monitored for altered anticoagulant response; animal studies indicate that phenothiazines may alter the effects of anticoagulants.
- Antihypertensives: The antihypertensives action of guanethidine, clonidine and possibly other adrenergic-blocking antihypertensive agents may be blocked by Motival. Clonidine may decrease the antipsychotic activity of phenothiazines.
- Levodopa: Phenothiazines may impair the anti-parkinson effect of L-Dopa.
- ACE Inhibitors/Thiazide Diuretics: Hypotension may result via additive or synergestic pharmacologic activity.
- Beta Blockers: Plasma levels of fluphenazine and the beta blocker may be increased. Dosage reduction of both drugs is recommended.
- CNS Depressants/Alcohol/Analgesics: The patient’s response to alcohol and other CNS depressants such as hypnotics, sedatives or strong analgesics may be exaggerated while taking Motival. Combined use with narcotic analgesics may cause hypotension as well as CNS or respiratory depression.
- Cimetidine: Steady-state serum concentrations of tricyclic antidepressants, including nortriptyline, are reported to be significantly elevated by the addition of cimetidine to a patient’s drug regimen. Conversely, nortriptyline levels can be significantly reduced if cimetidine is deleted from the patient’s regimen. Cimetidine may also reduce plasma concentrations of phenothiazines.
- Fluoxetine: Greater than two-fold increases in previously stable plasma levels of nortriptyline have occurred when fluoxetine was administered.
- Lithium: Rarely, neurotoxicity has been reported when lithium is used concomitantly with fluphenazine.
- Methylphenidate: Concurrent administration of tricyclic antidepressants with methlyphenidate may cause paranoid ideation.
- Metrizamide: Phenothiazines may predispose patients to metrizamide-induced seizures. Also, there is a known reaction between metrizamide and nortriptyline. Discontinue Motival for 48 hours prior to and for at least 24 hours after myelography.
- Monoamine Oxidase Inhibitors (MAOIs): Avoid concurrent administration of MAOIs and tricyclic antidepressants; it is advisable to disctontinue the MAOI for at least 2 weeks before starting treatment with Motival.
- Sympathomimetic (direct or indirect) Amines: Cocurrent administration should be avoided, as Motival can both enhance the pressor response to adrenergic agents, as well as, antagonize the action of adrenaline and other sympathomimetics causing severe hypotension.
Included in the following list are a few adverse events that have been reported with tricyclic antidepressants other than nortriptyline. They have been included here because of the pharmacologic similarities among the tricyclic antidepressant drugs. Many of the events have been reported with fluphenazine use at higher doses than those in Motival.
- Central Nervous System: Confusion (especially in the elderly) with hallucinations, drowsiness, lethargy, delirium, disorientation, delusions, anxiety, restlesness, agitiation, excitement, insomnia, panic, nightmares, bizarre dreams, hypomania, excerbation of psychosis, hostility, numbness, tingling, paresthesia of extremities, incoordination, ataxia, tremors, prephiral neuropathy, extrapyramidal symptoms, seizures, alteration in EEG patterns, alterations in CSF proteins, tinnitus and cerebral edema.
The adverse events most frequently reported with phenothiazine compounds such as fluphenazine are extrapyramidal symptoms, including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crisis, opisthotonos, and hyperreflexia. Most often these extrapyramidal symptoms are reversible, however, they have persisted after long-term use in some patients.
Occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on fluphenazine. Leukocytosis, fever, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS.
- Autonomic Nervous System: Dry mouth and rarely, associated sublingual adenitis or gingivitis, blurred vision, disturbance of accomodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition, hypertension, fluctuation in blood pressure, nausea, loss of appetite, salivation, polyuria, perspiration, headache, glaucoma, bladder paralysis, fecal impaction tachycardia, nasal congestion. Autonomic effects can usuallybe controlled by reducing or temporarily discontinuing dosage.
- Allergic: Drug fever, cross-sensitivity with other tricylic drugs, skin disorders such as itching, skin rash, petechia, erythem, urticaria, seborrhea, photosensitivity (avoid excessive exposure to sunlight), eczema and even exfoliative dermatitis have been reported with phenothiazine derivatives. The possibility of anaphylactic reactions occurring in some patients should be borne in mind. Asthama, edema (general laryngeal, facial or of the tongue), and angioneurotic edema may rarely occur.
- Cardiovascular: Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, and stroke. Patients with prexisting cardiac disease appear to be more susceptible to antidepressant-induced cardiotoxicity.
- Hematologic: Agranulocytosis, aplastic anemia, leukopenia, eosinophilis, purpura, thrombocytopenia, and pancytopenia. If any soreness of the mouth, gums or throat, or indicates bone marrow depression, therapy should be discontinued and other appropriate measures instituted immediately.
- Hepatic: Cholestatic jaundice has been encountered with fluphenazine treatment, particularly during the first months of therapy. Treamtent should be discotinued if jaundice occurs.
Alterations in other liver function tests, hepatitis and liver necrosis has been reported.
- Gastroinestinal: Nausea and vomiting, anorexia, epogastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue.
- Endocrine/Metabolic: Gynecomastia in the male, breast enlargement and galactorrhea in the female, testicular swelling, hyper- or hypoglycemia, hyponatremia, syndrome of inappropriate secretion of ADH (antidiuretic hormone), weight change, peripheral edema, abnormal lactation, menstrual irregularitis, false results on pregnancy tests, impotency and libido changes have all been known to occur in some patients on phenothiazine therapy.
- Other Adverse Events: Fever, prespiration, flushing, urinary frequency, nocturia, drowsiness, dizziness, weakness, fatigue, headache, parotid swelling, alopecia, cutaneous vasculitis, a systemic lupus erythematosus-like syndrome and altered ECG tracings, and – at higher doses of phenothiazines – sudden death.
Dosage and Administration:
Antidepressant effects may not occur before 2 or more weeks after the initiation of Motival therapy. Increasing the dose will not shorten this period but rather increase the incidence of adverse reactions.
- Adults: The usual adult dose of Motival is one 10/0.5 mg tablet tid; as an alternative regimen, the total daily dose may be given once a day, usually at bedtime. If the patient does not respond after four weeks, an alternative treatment should be given.
- A course of treatment with Motival should be limited to three months.
- Elderly Patients: When administering Motival, close attention should be paid to the potential anticholinergic, neurological, or cardiovascular complications, to which the elderly are especially vulnerable. In general, lower doses should be given to elderly patients than to younger adults. Response should be monitored. If necessary, dosage should be gradually increased.
- Pediatric Patients: Motival is not recommended for use in patients under 12 years of age.
Overdose causes serious toxicity. The severity of the patient’s response to overdose is conditioned by such factors as age, amount ingested, amount absorbed, and interval between ingestion and start of treatment. However, regardless of age, overdose should be regarded as serious and potentially fatal, and treated as medical emergency.
The major signs and symptoms of toxic overdose with tricylcic antidpressants are primarily extensions of common adverse reactions. Symptoms of overdose may begin within several hours of ingestion.
Symptoms associated with overdose may include the following:
CNS symptoms: Restlessness, drowsiness, sedation, confusion, excitement, agitation, muscle rigidity, ataxia, hyperactive reflexes, choreoathetoid movements, abnormal eye movements.
These may progress to severe extrapyramidal reactions, stupor, convulsions, or coma with areflexia.
Cardiac abnormalities may include arrhythmia, tachycardia, signs of congestive heart failure, and ECG evidence of impaired conduction. Prolongationof the QRS duration to more than 100 millisecond is predictive of more severe toxicity. Other symptoms may include respiratory depression, cyanosis, hypotension, shock vomiting, hyper- or hypothermia, mydriasis, diaphoresis and abnormal vision.
The drug should be withdrawn and symptoms treated supportively. In managing overdose, consideration should be given to the possibility of multiple overdoses, interaction among drugs, and unusual drug pharmacokinetics.
Blood and urine levels of tricyclic antidepressants are unreliable predictors of clinical management and outcomes and are primarily useful for diagnosing overdose.
Depending on need, the following measures can be considered:
- Hospitalize and closely observe the patient, even when the amount ingested or initial intoxication appears slight because CNS involvement, respiratory depression, or cardiac arrhythmia can occur suddenly. Patients with any alteration of ECG should have continous cardiac monitoring for at least 72 hours and be observed until well after the cardiac status has returned to normal; relapses may occur after apparently recovery.
- In the alert patient, empty the stomach rapidly by inducing emesis, followed by lavage, activated charcoal and then cathartics. In the obtunded patient, secure the airway with a cuffed endotracheal tube before beginning lavage; do not induce emesis. Instillation of activated-charcoal slurry may help to reduce absorption.
- Slow administration of IV physostigmine salicylate has been used to antagonize cardiac and CNS symptoms of tricylic antidepressant toxicity; however, its use is complicated by the possibility of physostigmine-induced convulsions and other serious adverse effects.
- Minimize external stimulation to reduce the tendecny to convulsions. Diazepam is generally considered the anticonvulsant of choice for tricyclic antidepressant overdose; phenytoin ca be used to prevent further seizures.
- Maintain adequate respiratory exchange. Do not use respiratory stimulants.
- Treat shock with supportive measures, such as intravenous fluids, oxygen, and corticosteroids.
- Cardiac glycosides and drugs such as quinidine, procainamide, disopyramide and atropine are contraindicated for treating arrhythmias in tricyclic antidepressants overdose. Arrhythmias, especially when accompanied by lengthened QRS intervals, may respond to alkalnization by administration of sodium bicarbonate. Refractory congestive haert failure necessitates rapid digitalization, particular care must be exercised. If severe hypotension should occur, supportive measures, including the use of intravenous vasopressor drugs should be instituted immediately. Levarterenol bitartarate is the most suitable drug for this purpose; epinephrine should not be used, since phenothiazine derivatives have been found to reverse its action, resulting in a further lowering of blood pressure.
- Hyperprexia should be controlled by whatever external means are available, including ice packs and cooling sponge baths, if necessary.
- In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks. Antiparkinson medication should be administered, and should be continued for several weeks. Antiparkinson medication should be withdrawn gradually to avoid the emergence of rebound extrapyramidal symptoms.
Limited experience indicates that neither fluphenazine nor nortriptyline is dialyzable. Hemodialysis, pertioneal dialysis, echange transfusions, and forced diuresis are generally reported to the be ineffective in both phenothiazine and tricyclic poisoning.
Pregnancy and Lactation:
Safe use of Motival during pregnancy and lactation has not been established.
Nortriptyline is excreted in small amounts in breast milk. It is not known whether fluphenazine is present in breast milk; however, other phenothiazines have been shown to be excreted in human breast milk. When the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be carefully weighed against the potential hazards.
Patients with cardiovascular disease should be closely supervised because Motival may prolong conduction time and produce sinus tachycardia. Myocardial infarction, arrhythmia, and strokes have occurred in associated with tricyclic antidepressant therapy.
Because of its anticholinergic activity, Motival should be used cautiously in patients with glaucoma, benign porstatic hypertrophy, or a history of urinary retention.
Patients with a history of seizures should be closely followed when Motival is administered, since nortriptyline is known to lower the seizure threshold.
In hyperthyroid patients or those receiving thyroid medication, caution is required with Motival administration, since cardiac arrhythmias may develop.
The depressant effects of alcohol and other CNS depressants may be potentiated by Motival.
Tardive dyskinesia, a syndrome consisting of potentially irreversibly, involuntary dyskinetic movements, may develop in patients treated with neuroleptic (antipsychotic) drugs, including fluphenazine, usually after prolonged courses given at doses adequate to treat psychotic illness.
Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict which patients are likely to develop the syndrome. Consequently, Motival treatment should be limited to three months.
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 neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment period at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn.
Neuroleptic treatment itself including fluphenazine, however, may suppress (or partially suppress) the signs and symptoms 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.
If signs and symptoms of tardrive dyskinesia appear in a patient taking Motival, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
Neuroleptic Malignant Syndrome (NMS). This rare but potentially fetal symptom complex has been reported in association with fluphenazine. CLinical manifestations of NMS are fever, hyperprexia, msucle rigidity, altered mental status, and evidence of autonomic instability (irregular: pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). If NMS, is suspected Motival should be discontinued. If NMS does occur, the reintroduction of therpay with Motival should be carefully monitored, since recurrences of NMS have been reported.
The management of NMS should include:
- Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy.
- Intesnive symptomatic treatment and medical monitoring.
- Treatmnet of any concomitant serious medical problems for which specific treatments are available. There is no general agreement abot 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.
Because improvement may not occur during the intial weeks of therapy, patients posing a high suicide risk should be closely monitored during this period. Motival should be dispensed in the least possible quantity at any given time.
Motival should be discontinued as long as possible prior to elective surgery, as the combination may increase the risk of hypotension and arrhythmia.
Avoid coadministration of Motival with guanethidin, class I antiarrhythmics, sympathomimetics, and any agnet that may decrease total body clearance of nortriptyline.
Liver or kidney damage, pigmentary retinopathy, lens and corneal deposits, and the development of irreversible dyskinesia may occur on prolonged therapy.
The development of silent pneumonias may occur with prolonged therapy.
Caution should be exercised when using Motival under the following circumstances:
- In patients receiving anticholinergics.
- In patients exposed to extreme heat or phosphorous insecticides.
- In patient with a history of convulsive disorders.
- In patients with special medical disorders, such as mitral insufficiency or other cardiovascular diseases, hepatic disease, or pheochromocytoma.
Motival can elevate blood prolactin levels; the elevation persists during chronic administration. An increase in mammary neoplasms has been found in rodenis after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic sutdies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis.
1. Dirving/Operating Machinery:
The use of Motival may impair the mental and physical abilities required for driving or operating heavy machinery, particularly during the first days of therapy. Potentiation of the effects of alcohol may occur with the use of this drug. The patient should be warned accordingly.
2. Pediatric Patients:
The safe use of Motival for the treatment of pediatric patients has not been established. Use of Motival is not recommended in patients under 12 years of age.
3. Elderly Patients:
When administering Motival, close attention should be paid to the potential anticholinergic, neurological or cardiovascular complications of Motival therapy, the elderly are especially vulnerable to these reactions.
In general, lower doses of Motival should be given to elderly patients than to younger adults. Response should be monitored and the dose adjusted. If an increase is necessary, doses should be gradually increased.
The patient should be advised that the response to alcohol is exaggerated and that skills in driving or operating machinery may be impaired. Patients should also be advised that Motival may not have antidepressant effects for 2 or more weeks.
Although not indicative of addiction, nausea, headache, and malaise have occurred following abrupt cessation of treatment after prolonged therapy with fluphenazine.
Pack of 2 strips of 10 tablets each.
Store at room temperature, below 25°C.