INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
MOTIVAL TABLETS

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

MOTIVAL TABLETS

COMPOSITION
MOTIVAL tablets each contain 0,5 mg fluphenazine hydrochloride and 10 mg nortriptyline base as the hydrochloride.

PHARMACOLOGICAL CLASSIFICATION
Category A 2.6 Tranquillizers.

PHARMACOLOGICAL ACTION
MOTIVAL contains fluphenazine, a trifluoromethyl phenothiazine derivative, intended for the management of anxiety and tension states and nortriptyline, a tricyclic antidepressant intended for the treatment of mental depression.
Pharmacokinetics:
The pharmacokinetics and dose-response of both nortriptyline and fluphenazine are characterized by inter-individual variability.
After oral administration, both nortriptyline and fluphenazine are well absorbed from the gastrointestinal tract and extensively metabolized during "first pass" metabolism in the liver. Both agents are widely distributed in the brain and other organs and are highly bound to plasma proteins.
The plasma half-life of nortriptyline ranges from approximately 18 to 93 hours. The serum half-life of fluphenazine HCl is approximately 15 hours.

INDICATIONS
Treatment of patients with mild to moderate mixed anxiety depression states.

CONTRA-INDICATIONS
MOTIVAL is contraindicated:

•	in patients with a history of hypersensitivity to fluphenazine, nortriptyline or any other phenothiazine or dibenzazapine.
•	during the acute recovery period after myocardial infarction, cardiac failure and ischaemic heart disease.
•	in patients with suspected or established brain damage.
•	in patients receiving large doses of central nervous system depressants (alcohol, barbiturates, narcotics, hypnotics, ets.)
•	in comatose or severely depressed states.
•	in patients with blood dyscrasia or liver damage
•	during pregnancy and lactation
•	in patients with glaucoma or urinary retention.
•	in children
•	epilepsy

Concurrent treatment with tricyclic antidepressants and monoamine oxidase inhibitors is generally contraindicated. This combination can cause a serious symptom complex that may include hyperreflexia, hyperpyretic crisis and severe convulsions and has resulted in deaths. MOTIVAL should not be given within two weeks after cessation of treatment with MAOIs.

WARNINGS
Nortriptyline: Patients with cardiovascular disease should be closely supervised when on nortriptyline because of the tendency of drugs in this class to produce sinus tachycardia and to prolong conduction time.
Because of its anticholinergic activity, nortriptyline should be used with great caution in patients who have glaucoma, benign prostatic hypertrophy, or a history of urinary retention.
Patients with a history of seizures should be followed closely when nortriptyline is administered, since nortriptyline is known to lower the seizure threshold.
In hyperthyroid patients or those receiving thyroid medication, great care is required with nortriptyline administration, since cardiac arrhythmias may develop.
Nortriptyline may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a car; therefore, the patient should be warned accordingly.
The central nervous system depressant effects of alcohol may be potentiated by nortriptyline.
Fluphenazine: Tardive dyskinesia, a syndrome consisting of potentially irreversible, 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. However, the syndrome can develop, after relatively brief treatment periods at low doses.
Therefore in continued long term use of the medicine consideration should be given to the medical benefit versus the side effects associated with its use.
Neuroleptic Malignant Syndrome (NMS): This rare but potentially fatal symptom complex has been reported in association with fluphenazine. Clinical manifestations of NMS are fever, hyperpyrexia, muscle 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 permanently.
The use of fluphenazine 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 medication.

DOSAGE AND DIRECTIONS FOR USE
One Motival tablet three times daily. The course of treatment should be limited to three months. If the patient does not respond after four weeks, an alternative treatment should be given.
A children's dose has not been established, therefore it is not recommended for children.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The following side effects may be observed:
Central Nervous System
Nortriptyline: Confusion (especially in the elderly) with hallucinations, delirium, disorientation, delusions; anxiety, restlessness, agitation, insomnia, panic, nightmares, hypomania, exacerbation of psychosis, hostility.
Numbness has occurred, as well as tingling, paraesthesia of extremities, incoordination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, alteration in EEG patterns, and tinnitus.
Fluphenazine: (see WARNINGS: Fluphenazine). The side effects most frequently reported with phenothiazine compounds such as fluphenazine are extrapyramidal symptoms, including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crisis, opisthotonos, and hyperreflexia. Respiratory complications may occur due to hypertonia of the respiratory muscles.
Occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on fluphenazine. Leucocytosis, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS.
Drowsiness or lethargy may occur. Phenothiazine derivatives have been known to cause restlessness, excitement, or bizarre dreams in some patients. Alterations in electroencephalographic tracings or cerebrospinal fluid proteins may occur; cerebral edema may rarely occur.
Autonomic Nervous System
Nortriptyline: Dry mouth and, rarely, associated sublingual adenitis or gingivitis, blurred vision, disturbance of accommodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition.
Fluphenazine: Hypertension and fluctuation in blood pressure have been reported with fluphenazine, as well as nausea, loss of appetite, salivation, polyuria, perspiration, dry mouth, headache, and constipation. Autonomic effects can usually be controlled by reducing or temporarily discontinuing dosage. In some patients, phenothiazine derivatives have caused blurred vision, glaucoma, bladder paralysis, fecal impaction, paralytic ileus, tachycardia, or nasal congestion.
Allergic
Nortriptyline: Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight), edema (general or of face and tongue), drug fever, cross-sensitivity with other tricyclic drugs.
Fluphenazine: Skin disorders such as itching, erythema, urticaria, seborrhoea, photosensitivity, 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. Asthma, laryngeal edema, and angioneurotic edema may rarely occur.
Cardiovascular
Nortriptyline: Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke. Patients with preexisting cardiac disease appear to be more susceptible to antidepressant-induced cardiotoxicity.
Hematologic
Nortriptyline: Bone-marrow depression, including agranulocytosis, aplastic anemia, leucopenia, eosinophilla, purpura, thrombocytopenia.
Fluphenazine: Routine blood counts are advisable during therapy since blood dyscrasias including leucopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia have been observed with phenothiazine derivatives. Furthermore, if any soreness of the mouth, gums, or throat, or any symptoms of upper respiratory infection occur and confirmatory leucocyte count indicates bone marrow depression, therapy should be discontinued and other appropriate measures instituted immediately.
Hepatic
Nortriptyline: Jaundice; altered liver function; hepatitis and liver necrosis.
Fluphenazine: Cholestatic jaundice has been encountered with fluphenazine treatment, particularly during the first months of therapy. Treatment should be discontinued if jaundice occurs. Alterations in other liver function tests have been reported in patients receiving fluphenazine who have had no clinical evidence of liver damage.
Gastrointestinal
Nortriptyline: Nausea and vomiting, anorexia, epigastric distress, diarrhoea, peculiar taste, stomatitis, abdominal cramps, black tongue.
Fluphenazine: Nausea, loss of appetite, salivation, dry mouth, (see Autonomic Nervous System above).
Endocrine/Metabolic
Nortriptyline: Gynecomastia in the male, breast enlargement and galactorrhea in the female; changes in libido, impotence; testicular swelling; hyper- or hypoglycemia; syndrome of inappropriate secretion of ADH (antidiuretic hormone).
Fluphenazine: Weight change, peripheral edema, abnormal lactation, gynecomastia, menstrual irregularities, false results on pregnancy tests, impotency in men and libido changes in women have all been known to occur in some patients on phenothiazine therapy.
Other Adverse Reactions
Nortriptyline: Fever, weight gain or loss; perspiration; flushing, urinary frequency, nocturia; drowsiness, dizziness, weakness, fatigue; headache; parotid swelling; alopecia; cutaneous vasculitis.
Fluphenazine: Lens and corneal deposits (at higher doses) sudden death, a systemic lupus erythematosus-like syndrome and altered ECG tracings.
The low dose of fluphenazine provided in MOTIVAL reduces the incidence of extrapyramidal reactions that may appear with fluphenazine. The anticholinergic activity of nortriptyline provides further protection against extrapyramidal reactions.
In contrast to the weak anticholinergic effects of the phenothiazines, the anticholinergic responses to therapeutic doses of the tricyclic antidepressants are prominent.

PRECAUTIONS
MOTIVAL should be administered cautiously under the following conditions:-
Nortriptyline: Because improvement may not occur during the initial 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.
Epileptiform seizures may accompany administration of tricyclic antidepressants (TCA's), including nortriptyline. Epilepsy may be aggravated.
Nortriptyline should be discontinued as long as possible prior to elective surgery, as the combination may increase the risk of hypotension and arrhythmia occurring with surgery.
In the presence of hepatic disease, nortriptyline should be administered cautiously.
Avoid coadministration of nortriptyline with guanethidine, Class I antiarrhythmics, central nervous system (CNS) depressants, sympathomimetics, anticholinergics, and any agent that may decrease total body clearance of nortriptyline (see Interactions, below).
In patients suffering from manic depressive psychosis, as mania may be precipitated.
In elderly male patients suffering from prostatism; urinary retention may be precipitated. (See WARNINGS).
In patients suffering from cardiac disease (See WARNINGS) because of the occasional problems of tachycardia, dysrhythmias, orthostatic hypotension and other unwanted effects on blood pressure.
Fluphenazine: Fluphenazine should be used with caution in patients who have developed allergic reactions to phenothiazine derivatives.

-	in patients undergoing surgery (hypotension can occur, and reduced amounts of anesthetics or central nervous system depressants may be necessary).
-	in patients receiving atropine, because of added anticholinergic effects.
-	in patients exposed to extreme heat or phosphorus insecticides;
-	in patients with a history of convulsive disorders, and
-	in patients with special medical disorders, such as mitral insufficiency or other cardiovascular diseases, or phaeochromocytoma.

Fluphenazine can elevate prolactin levels; the elevation persists during chronic administration. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs.
Use in Pregnancy and Lactation
Safe use of MOTIVAL during pregnancy and lactation has not been established. (See CONTRA-INDICATIONS).
Paediatric Patients
The safe use of MOTIVAL for the treatment of paediatric patients has not been established. (See contra-indications).
Use in the Elderly
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.
Interactions
Clinical evaluation of MOTIVAL has not revealed any 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 with phenothiazines impairs efficacy of both agents.
Antacids: Concurrent administration may interfere with MOTIVAL absorption.
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 nortriptyline, and may cause dose-related additive effects on cardiac conduction.
Anticholinergic Agents: Cholinergic blockade may be exaggerated when MOTIVAL is administered with anticholinergic agents, especially in older patients. Antimuscarinic effect may be potentiated or prolonged. Close supervision and careful adjustment of the dosage are required when MOTIVAL is used with other anticholinergic agents.
Anti-convulsants: The anticonvulsant action may be impaired by MOTIVAL.
Antidiabetics: Phenothiazines have been associated with loss of blood glucose control in diabetics, and nortriptyline may increase the hypoglycemic effects of oral sulfonylureas 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 antihypertensive action of guanethidine, clonidine and possibly other adrenergic-blocking antihypertensive agents may be blocked by MOTIVAL.
Clonidine may decrease the antipsychotic activity of fluphenazine.
Anti-Parkinsonian: The effect of levodopa may be impaired by fluphenazine.
Ace-inhibitors: Hypotension may be aggravated.
Beta Blockers: Plasma levels of fluphenazine and the beta blockers may be increased. Dosage reduction of both agents is recommended. The depression of myocardial contractility by nortriptyline may be potentiated by beta-blockers. Conversely, the cardiovascular effects of beta-blockers may be reduced by nortriptyline.
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 TCAs, 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 fluphenazine.
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 TCAs with methylphenidate may cause paranoid ideation.
Metrizamide: Phenothiazines reportedly predispose patients to metrizamide-induced seizures. Also, there is a known reaction between metrizamide and nortriptyline. Discontinue MOTIVAL for at least 48 hours prior to and for at least 24 hours after myelography.
Monoamine oxidase inhibitors (MAOI's): Avoid concurrent administration of MAOIs and TCAs, it is advisable to discontinue the MAOI for at least 2 weeks before starting treatment with MOTIVAL. (see CONTRA-INDICATIONS).
Sympathomimetic (direct or indirect) amines: Concurrent administration should be avoided, as MOTIVAL can both enhance the pressor response to adrenergic agents and antagonize the action of adrenaline and other sympathomimetics.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdose should be regarded as serious and potentially fatal, and treated as a medical emergency. Symptoms of overdose may begin within several hours of ingestion.
The major signs and symptoms of toxic overdose with TCAs are primarily extensions of common adverse reactions.
Overdosage and poisoning may be characterized by central nervous system depression or excitation, severe anticholinergic effects, cardiotoxicity and extrapyramidal reactions. The following symptoms and signs are characteristic of acute overdosage:
CNS Symptoms: Drowsiness, restlessness, ataxia, sedation, confusion, excitement, agitation, muscle rigidity, hyperactive reflexes, chorioathetoid movements, abnormal eye movement, These may progress to severe extrapyramidal reactions, stupor, convulsions or coma with araflexia.
Cardiac abnormalities: These may include arrhythmia, tachycardia, signs of congestive failure, and ECG evidence of impaired conduction. Prolongation of the QRS duration to more than 100 msec is predictive of more severe toxicity.
Other symptoms may include respiratory depression, cyanosis, hypotension, shock, vomiting, hyper-or hypotension, mydriasis, diaphoresis and abnormal vision.
Epileptiform seizures may occur. Mixed poisoning with other central nervous system depressants is not uncommon.
Overdosage should be treated symptomatically and supportively. If the patient is conscious, prompt gastric lavage, dilution of stomach contents to delay absorption, or stimulation of vomiting should be attempted. An open airway should be maintained. Extrapyramidal reactions are amenable to antiparkinsonian drugs.
In severe hypotension, all standard procedures for the management of circulatory shock should be instituted, e.g. vasoconstrictors, intravenous fluids, or both. Adrenaline should not be administered as this will further lower the blood pressure through interaction with phenothiazine.
Haemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis are generally reported to be ineffective in both phenothiazine and tricyclic poisoning.

IDENTIFICATION
Pink sugar-coated triangular tablets.

PRESENTATION
Amber glass bottles containing 90 tablets.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C. Avoid excessive heat.
THIS MEDICINE SHOULD AT ALL TIMES BE KEPT OUT OF REACH OF CHILDREN, AS EVEN SMALL DOSES MAY BE FATAL TO THEM.

REGISTRATION NUMBER
D/2.6/5.

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road
BEDFORDVIEW. 2008.

DATE OF PUBLICATION OF THIS PACKAGE INSERT
July 2001

*Registered user of the ™ MOTIVAL

Updated on this site: July 2005
Source: Pharmaceutical Industry
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