INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
XANOR™

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

XANOR^™

XANOR^™0,25 mg (TABLETS)
XANOR^™0,5 mg (TABLETS)
XANOR^™1,0 mg (TABLETS)
XANOR^™2,0 mg (TABLETS)
XANOR^™SR 0,5 mg (TABLETS)
XANOR^™SR 1 mg (TABLETS)
XANOR^™SR 2 mg (TABLETS)

COMPOSITION:
Each XANOR 0,25 mg tablet contains 0,25 mg Alprazolam and 0,1125 mg Sodium benzoate (preservative)
Each XANOR 0,5 mg tablet contains 0,5 mg Alprazolam and 0,1125 mg Sodium benzoate (preservative)
Each XANOR 1,0 mg tablet contains 1,0 mg Alprazolam and 0,1125 mg Sodium benzoate (preservative)
Each XANOR 2,0 mg tablet contains 2,0 mg Alprazolam and 0,225 Sodium benzoate (preservative)
Each XANOR SR tablet contains 0,5 mg; 1,0 mg; or 2,0 mg Alprazolam

PHARMACOLOGICAL CLASSIFICATION:
A 2.6. Tranquillisers

PHARMACOLOGICAL ACTION:
Alprazolam is an anxiolytic agent of the benzodiazepine group. Benzodiazepines, including alprazolam, are thought to bind to central nervous system benzodiazepine receptors, thereby increasing the affinity of the receptor for gamma-aminobutyric acid (GABA). GABA, an inhibitory neurotransmitter, modulates the activity of other neurotransmitter systems, including the noradrenergic system
Pharmacokinetics:
The pharmacokinetics of alprazolam are linear over the recommended dosage range, with plasma concentrations being proportional to dose given. Alprazolam is almost completely bioavailable following oral administration. The bioavailability and pharmacokinetic characteristics of XANOR Tablets or XANOR SR Tablets are comparable, except for a slower rate of absorption of alprazolam from XANOR SR Tablets. The slower absorption rate for XANOR SR Tablets results in peak plasma alprazolam concentrations that are approximately one-half that of an equivalent dose of XANOR Tablets; peak concentrations occur within one to two hours after a single dose of XANOR Tablets, and 5 to 11 hours after a single dose of XANOR SR Tablets.
Steady-state plasma concentrations are achieved within three to four days of continuous dosing with either dosage form. When equivalent daily doses are given, steady-state peak and trough plasma alprazolam concentrations for XANOR SR Tablets given once or twice a day are comparable to XANOR Tablets given three or four times a day.
Alprazolam and its metabolites are excreted primarily in the urine. The predominant metabolites are alpha-hydroxy-alprazolam, 4-hydroxy alprazolam, and a benzophenone derived from alprazolam. Although they possess some pharmacological activity, the plasma levels of these metabolites are extremely low during chronic dosing. In vitro, alprazolam is bound (80%) to human serum protein.
The plasma elimination half-life of alprazolam has been found to be about 11 to 15 hours in healthy adults. A comparable elimination half-life for XANOR SR Tablets indicates that the metabolism and elimination of alprazolam are the same for both dosage forms. Alprazolam clearance has been reported to be delayed in patients with impaired hepatic and renal function, alcoholism, in elderly or obese patients, and by the co-administration of certain medicines.

INDICATIONS:

•	SHORT-TERM RELIEF OF SYMPTOMS OF ANXIETY
•	TREATMENT OF ANXIETY DISORDERS

Anxiety disorder is a condition corresponding most closely to the latest APA Diagnostic and Statistical Manual [DSM] diagnosis of generalised anxiety disorder.
Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Diagnostic criteria for Generalised Anxiety Disorder

A.	Generalised, persistent anxiety is manifested by symptoms from three of the following four categories:
1.	Motor tension:
	Shakiness, jitteriness, jumpiness, trembling, muscle aches, tension, eyelid twitch, inability to relax, furrowed brow, strained face, restlessness and easily startled.
2.	Autonomic hyperactivity:
	Heart pounding or racing, sweating, cold clammy hands, dry mouth, light-headedness, dizziness, paresthesias, upset stomach, diarrhoea, discomfort in the pit of the stomach, hot or cold spells, lump in the throat, flushing, pallor, high resting pulse and respiration rate.
3.	Apprehensive expectation:
	Fear, anxiety, worry, rumination, and anticipation of misfortune to self and others.
4.	Vigilance and scanning:
	Hyper attentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling "on edge", impatience and irritability.
B.	The anxious mood has been continuous for at least one month.
C.	Not due to another mental disorder, such as Depressive Disorder or Schizophrenia.
D.	At least 18 years of age.

•	ANXIETY ASSOCIATED WITH DEPRESSION
•	MIXED ANXIETY-DEPRESSION
•	DEPRESSION
	Depression can be variously described as neurotic depression, reactive depression, major depressive disorder, etc., depending upon local psychiatric nosology. Usage has not been established in depression with psychiatric features, in bipolar disorders or in "endogenous" depression (i.e., severely depressed inpatients).
•	PANIC DISORDERS
	This includes panic disorder with or without agoraphobia. The essential feature of panic disorder is the unexpected panic attack, a sudden onset of intense apprehension, fear, or terror. Panic disorder is an illness characterised by recurrent panic attacks. Later in the course of this disturbance, certain issues, e.g. driving a car or being in a crowded place, may become associated with having a panic attack. These panic attacks are not triggered by situations in which the person is the focus of others' attention (as in social phobia).

Diagnostic criteria for Panic Disorder:

A.	At least three panic attacks within a three-week period in circumstances other than during marked exertion or in a life-threatening situation. The attacks are not precipitated by exposure to a circumscribed phobic stimulus.
B.	Panic attacks are manifested by discrete periods of apprehension or fear, and at least four of the following symptoms appear during each attack:
	Dyspnea
	Palpitations
	Chest pain or discomfort
	Choking or smothering sensations
	Dizziness, vertigo, or unsteady feelings
	Feelings of unreality
	Paresthesias (tingling in hands or feet)
	Hot and cold flushes
	Sweating
	Faintness
	Trembling or shaking
	Smothering sensations, dizziness

XANOR is indicated for use of up to six month's duration for anxiety and depression and for up to eight months in the treatment of panic disorder with or without some phobic avoidance. The effectiveness for long-term use, exceeding 6 months has not been established.       

CONTRA-INDICATIONS:
Alprazolam is contraindicated in patients with known hypersensitivity to benzodiazepines.
Alprazolam is not recommended for patients whose primary diagnosis is schizophrenia.
XANOR should not be administered during labour. Given during labour, it crosses the placenta and may cause the floppy-infant syndrome characterised by central respiratory depression, hypothermia and poor sucking.

WARNINGS:
XANOR usage has not been established in certain types of depression (See INDICATIONS)
XANOR must be used with caution in patients with impaired renal or hepatic function, pulmonary disease or limited pulmonary reserve.
The safety and efficacy of alprazolam has not been established in children under the age of 18 years.
The safety of alprazolam during pregnancy and lactation has not been established. The potential for congenital malformations in children of patients who have received benzodiazepines during pregnancy exists.
XANOR should not be administered to nursing mothers, since alprazolam is excreted in human breast milk.
Benzodiazepines produce additive CNS depressant effects when co-administered with alcohol or other drugs producing CNS depression.
Caution patients about using alprazolam while operating motor vehicles or other dangerous activities until it is established that they do not become drowsy or dizzy while taking the medicine.
Habituation and emotional/physical dependence may occur with benzodiazepines, including alprazolam. Caution should be particularly used when prescribing benzodiazepines to patients who are prone to abuse drugs (e.g., alcoholics and drug addicts) because of their predisposition to habituation and dependence.
Withdrawal symptoms have occurred following rapid decrease or abrupt discontinuance of benzodiazepines, including alprazolam. These can range from mild dysphoria and insomnia to a major syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor, and convulsions. In addition, withdrawal seizures have occurred upon rapid decrease or abrupt discontinuation of therapy with alprazolam and special care must be taken in the treatment of epileptic patients ( See “DOSAGE AND DIRECTIONS FOR USE”section for dose reduction during withdrawal period).
XANOR should be avoided in psychotic patients and patients suffering from mental depression unless there is a marked component of anxiety in their illness.
Panic disorders have been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Therefore, the same precaution must be exercised when using the higher doses of XANOR in treating patients with panic disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans.

DOSAGE AND DIRECTIONS OF USE:
Patients should be periodically re-assessed and dosage adjustments made, as appropriate.
The optimum dose of XANOR Tablets should be individualised based upon the severity of the symptoms and individual patient response. The usual dose (see table) will meet the needs of most patients. In patients who require higher doses, dosage should be increased cautiously to avoid adverse effects.
When higher dosage is required, the evening dose should be increased before the daytime dose. In general, patients who have not previously received psychotropic medications will require somewhat lower doses than those previously treated with minor tranquillisers, antidepressants or hypnotics or those with a history of chronic alcoholism. It is recommended that the general principle of using the lowest effective dose be followed in elderly or debilitated patients to preclude the development of ataxia or oversedation.

XANOR Tablets	Usual Starting Dose*	Usual Dose Range
Anxiety	0,25 to 0,5 mg given 3 times daily	0.5 to 4.0 mg daily, given in divided doses
Mixed anxiety/depression Anxiety associated with depression	0,5 mg given 3 times daily	1.5 to 4.5 mg daily, given in divided doses
Panic Disorders	0,5 –1,0 mg given at bedtime or 0.5 mg three times daily	The dose should be adjusted to patient response. Dosage adjustments should be in increments no greater than 1 mg every three to four days. With XANOR Tablets, additional doses can be added until a three times daily or four times daily schedule is achieved. The mean dose in a large multi-clinic study was 5.7 +2.27 mg with occasional patients requiring a maximum of 10 mg daily.
Geriatric Patients or in the presence of debilitating disease	0,25 mg given two or three times daily.	0.25 to 0.75 mg daily, given in divided doses; to be gradually increased if needed and tolerated.

XANOR SR	Usual Starting Dose*	Usual Dose Range
Anxiety	1 mg daily, in one or two doses	0,5 to 4,0 mg daily, in one or two doses
Mixed anxiety/depression Anxiety associated with depression	1 mg daily, in one or two doses	0,5 to 4,5 mg daily, in one or two doses
Panic Disorders	0,5-1,0 mg given at bedtime or 0,5 mg two times daily	In clinical trials the mean maintenance dose was between 5 and 6 mg per day given as a single daily dose or divided into two doses daily, with occasional patients needing up to 10 mg per day. The dose should be adjusted to patient response, with dose increments of no greater than 1 mg in the daily dose every three to four days.
Geriatrics Patients	0,5 to 1,0 mg daily, given in one or two doses	0,5 to 1 mg daily; may be gradually increased if needed and tolerated.

* If side effects occur, the dose should be lowered (See Warnings).

To discontinue treatment in patients taking XANOR Tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANOR be decreased by no more than 0,5 mg every three days. Some patients may require an even slower dosage reduction.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects are generally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage.
The most common adverse reactions to alprazolam reported by patients treated for anxiety, anxiety associated with depression and depression, were drowsiness and light-headedness/dizziness. Less common adverse reactions were blurred vision, headache, depression, insomnia, nervousness/anxiety, tremor, change in weight, memory impairment/amnesia, co-ordination disorders, various gastro-intestinal symptoms, and autonomic manifestations.
In addition, the following adverse events have been reported in association with the use of anxiolytic benzodiazepines including alprazolam: dystonia, irritability, anorexia, fatigue, slurred speech, jaundice, musculoskeletal weakness, changes in libido, menstrual irregularities, incontinence, urinary retention, and abnormal liver function. Increased intraocular pressure has been rarely reported.
The most common adverse reactions in patients with panic disorders evaluated during clinical trials which were more frequently seen than with placebo were sedation/ drowsiness/fatigue, ataxia/impaired co-ordination, and slurred speech. Less common adverse reactions were altered mood, GI symptoms, dermatitis, memory problems, sexual dysfunction, intellectual impairment and confusion.
Reactions such as concentration difficulties, confusion, hallucinations, stimulation, and adverse behavioural effects such as irritability, agitation, rage and aggressive or hostile behaviour have been reported rarely. Patients who have borderline personality disorder, a prior history of violent or aggressive behaviour, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility and intrusive thoughts have been reported during discontinuance of alprazolam in patients with post-traumatic stress disorder.
Interactions
The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of XANOR Tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.
Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450IIIA4) may increase the concentration of alprazolam and enhance its activity. Data from clinical and in vitro studies with alprazolam, and clinical studies with drugs metabolised similarly to alprazolam provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs. Based on the degree of interaction and the type of data available, the following recommendations are made: The co-administration of alprazolam with ketoconazole, itraconazole, or other azole-type antifungals is not recommended.
Caution and consideration of dose reduction is recommended when alprazolam is co-administered with nefazodone, fluvoxamine, and cimetidine. Caution is recommended when alprazolam is co-administered with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Manifestations of XANOR overdosage include extensions of its pharmacological activity, namely ataxia and somnolence, confusion, coma, respiratory and cardiovascular depression and hypotension.
Treatment is supportive and symptomatic.

IDENTIFICATION:
XANOR0.25 mg tablets are white, ovoid shaped, embossed with "Upjohn 29" on the one side and scored on the other side.
XANOR 0.5 mg tablets are pink, ovoid shaped, embossed with "Upjohn 55" on the one side and scored on the other side.
XANOR 1.0 mg tablets are lavender, ovoid shaped, embossed with "Upjohn 90" on the one side and scored on the other side.
XANOR 2.0 mg tablets are white capsule shaped, three scored tablets, embossed with "U94".
XANOR SR0.5 mg tablets are light blue, round deep oval shape, embossed with "Upjohn 57".
XANOR SR 1.0 mg tablets are white, round deep oval shape, embossed with "Upjohn 59".
XANOR SR2.0 mg tablets are light blue, pentagonal deep oval shape, embossed with "Upjohn 66".

PRESENTATION:
XANOR 0,25 mg and 1,0 mg are packed in blister packs of 30 and 100 tablets.
XANOR 0,5 mg is packed in blister packs of 30 and 100 tablets and in bottles containing 500 tablets.
XANOR 2,0 mg is packed in bottles containing 30 and 100 tablets.
XANOR SR tablets are packed in foil blisters of 60 tablets.

STORAGE INSTRUCTIONS:
Store below 30°C. Keep tablets packed in bottles tightly closed.
Keep tablets in the carton until use. Protect from light. Keep out of reach of children

REGISTRATION NUMBERS:
XANOR^TM 0,25 mg tablets: M/2.6/233
XANOR^TM 0,5 mg tablets: M/2.6/234
XANOR^TM 1,0 mg tablets: M/2.6/235
XANOR^TM 2,0 mg tablets: 27/2.6/0096
XANOR^TM SR 0,5 mg tablets: 29/2.6/0504
XANOR^TM SR 1,0 mg tablets: 29/2.6/0505
XANOR^TM SR 2,0 mg tablets: 29/2.6/0506

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
MIDRAND 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
February 1996

New addition to this site: January 2005
Source: Pharmaceutical Industry
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