Frixitas

FRIXITAS^®
Tablet

FRIXITAS^® 0.25 mg
Each tablet contains 0.25 mg of Alprazolam

FRIXITAS^® 0.5 mg
Each tablet contains 0.5 mg of Alprazolam

FRIXITAS^® 1.0 mg
Each tablet contains 1 mg of Alprazolam

Pharmacology
Anxiolytic, antidepressant and antipanic

Pharmacokinetics: Following oral administration, alprazolam is readily absorbed. Peak concentration in the plasma occur in 1-2 hours following administration. After single-dose-administration, plasma levels are proportionate to the dose given; over the dose range of 0.5-3 mg, peak levels of 8-37 ng/ml were observed.
The mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 - 26.9 hours), 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. The biological activity of alpha-hydroxy-alprazolam is approximately 1/2 that of alprazolam. The benzophenone metabolite is essentially inactive. Plasma levels of these metabolites are extremely low. However, their half-lives appear to be of the same order of magnitude as that of alprazolam. Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In vitro, alprazolam is bound (80%) to human serum protein. When alprazolam-¹⁴C was administered to pregnant mice, drug-related materials appeared uniformly distributed in the fetus with ¹⁴C concentration approximately the same as in the blood and skeletal muscle of the mother. Because of its similarity to other benzodiazepine, it is assumed that alprazolam undergoes transplacental passage and that is excreted in human milk. Changes have been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9 - 26.9 hours, n=16) compared to 11 hours (range: 6.3 - 15.8 hours, n=16) in healthy adult subjects. The co-administration of oral contraceptive to healthy women increased the half-life of alprazolam as compared to that in healthy control women (mean: 12.4 hours, n=11 versus 9.6 hours, n=9). There was a prolongation in the mean half-life alprazolam from 12.4 hours (range : 7.2-18.4 hours, n=9) to 16.6 hours (range: 10-24.3 hours, n=9) by the co-administration of cimetidine to the same healthy adults, In patients with alcoholic liver disease, the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (means = 11.4, n=17) in healthy subjects. In an obese group of subjects, the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean: 21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean: 10.6 hours, n=12) in healthy subjects.


Indications

• Treatment of anxiety including anxiety neurosis, anxiety disorder, symptoms of anxiety, etc.
• Mixed Anxiety-Depression: Including anxiety associated with depression.
• Panic Disorders: Including 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.

Contraindications
Patients with known sensitivity to the benzodiazepines and those with acute narrow-angle glaucoma.

Side Effects
Side effects of alprazolam tablets, if they occur, are gene rally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage. In patients treated for anxiety and anxiety associated with depression, the most common adverse reactions to alprazolam were drowsiness and lightheadedness/dizziness. Less common adverse reactions were blurred vision, headache, depression, insomnia, nervousness/anxiety, tremor, change in weight, memory impairment/amnesia, coordination disorders, various gastrointestinal symptoms and autonomic manifestations. As with other benzodiazepines, reactions, e.g. stimulation, agitation, concentration difficulties, confusion, hallucinations or other adverse behavioral effects have been reported with alprazolam. Increased intraocular pressure has been rarely reported.
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, change in libido, menstrual irregularities, incontinence, urinary retention and abnormal liver function. The most common adverse reactions in patients with panic-related disorders were sedation/drowsiness, fatigue, ataxia/impaired coordination and slurred speech. Less common adverse reactions were altered mood, GI symptoms, dermatitis, memory problems, sexual dysfunction, intellectual impairment and confusion.

Precautions and Warnings
Usage has not been established in depression with psychiatric features, in bipolar disorders or in "endogenous" depression (i.e., severely depressed in patients). Habituation and emotional/physical dependence may occur with benzodiazepine, 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. Alprazolam tablets are not recommended for use in patients whose primary diagnosis is schizophrenia.
Withdrawal symptoms have occurred following rapid decrease or abrupt discontinuance of benzodiazepine including alprazolam. Therefore, dosage must be gradually tapered to preclude sequelae of rapid withdrawal. These can range from mild dysphoria and insomnia to a major syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor and convulsions. These signs and symptoms, especially the more serious ones, are generally more common in those patients who have received excessive doses over an extended period of time. However, withdrawal symptoms have also been reported following abrupt discontinuance of benzodiazepines taken at therapeutic levels. Consequently, abrupt discontinuation should be avoided and a gradual tapering in dosage followed (see Dosage and Administration). When therapy is discontinued in patients with panic related disorders, the symptoms associated with recurrence of panic attacks often mimic these of withdrawal. Administration to severely depressed or suicidal patients should be done with appropriate precaution and appropriate size of prescription. Panic related 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 alprazolam tablets in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or over-sedation which may be a particular problem in elderly or debilitated patients. The usual precautions for treating patients with impaired renal or hepatic function should be observed. Alprazolarn may be used in patients with open-angle glaucoma who are receiving appropriate therapy.
Effects on the ability to drive or operate machineries: As with other CNS active drugs, patients receiving alprazolam should be advised not to operate motor vehicles or dangerous machinery until it is established that they do not become drowsy or dizzy while receiving medication.

Carcinogenicity, Mutagenicity and Impairment of Fertility: No evidence of carcinogenic potential was observed during 2-year bio-assay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose). Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay. Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose.

Use in pregnancy and lactation: An increased risk of congenital malformations associated with minor tranquilizer (chlordiazepoxide, diazepam and meprobamate) during the 1^st trimester of pregnancy has been suggested in several studies. Because the use of these drug is rarely a matter of urgency, the use of alprazolam during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the start of therapy should be considered. Patients should be advised that if they become pregnant, they should communicate with their physician about the desirability of discontinuing the drug. As a general rule, nursing should not be undertaken while a patient taking Alprazolam, since many drugs are excreted in human milk. Use in children: Safety and efficacy of Alprazolam in children ‹ 18 years has not been established.

Drug Interactions
The benzodiazepines, including alprazolam, produce additive CNS depressant effect when co-administered with other psychotropic medications, anticonvulsants, antihistamines, ethanol and other drugs which themselves produce CNS depression. The steady state plasma concentration of imipramine and desipramine have been reported to be increased an average of 31 % and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/dav. The clinical significance of these changes is unknown. Pharmacokinetic interactions of benzodiazepines with other drugs have been reported. For example, the clearance of alprazolam and certain other benzodiazepines can be delayed by the co-administration of cimetidine or macrolide antibiotics. The clinical significance of this is unclear.

Dosage and Administrations
The optimum dosage should be individualized based upon the severity of the symptoms and individual patient response. The daily dosage (see table) will meet the needs of most patients.

Indication	Usual Starting Dose	Usual Dose Range
Anxiety	0.75 - 1.5 mg daily, given in divided doses	0.5 - 4 mg daily, given in divided doses
Panic disorder	0.5 - 1 mg given at bed time or 0.5 mg 3 times daily	The dose should be adjusted to patient response. Dosage adjustment should be in increments not greater than 1 mg every 3 - 4 days. Additional doses can be added until 3 or 4 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 Patient	0.5 - 0.75 mg daily, given in divided dose	0.5 - 0.75 mg daily, given in divided doses; to be gradually increased if needed and tolerated.

In a few patients who require higher doses, dosage should be increased cautiously to avoid adverse effects. When higher dosage required, the evening dose should be increased before the daytime doses. In general, patients who have not previously received psychotropic medications will require lower doses than those previously treated with minor tranquilizers, antidepressants or hypnotics or those with a history of chronic alcoholism. Patients should be periodically reassessed and dosage adjustments made as appropriate.

Discontinuation of therapy: The dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of Alprazolam tablets be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction,

Over dosage
Manifestation of alprazolam over dosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzoadiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
Experiments in animals have indicated that cardiopulmonary collapse can occur following massive IV doses of alprazolam (› 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the IV infusion of norepinephrine bitartrate. Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating over dosage. As with the management of any over dosage, the physician should bear in mind that multiple agents may have been ingested.

Presentations
FRIXITAS^® 0.25 mg
Box of 6 strips @ 10 tablets Reg. No.: DPL0033501110A1

FRIXITAS^® 0.5 mg
Box of 6 strips @ 10 tablets Reg. No. : DPL0033501110B1

FRIXITAS^® 1.0 mg
Box of 6 strips @ 10 tablets Reg. No. : DPL0033501110C1

Store at room temperature (below 30°C).

ON MEDICAL PRESCRIPTION ONLY

Manufactured by :
NOVELL
PHARMACEUTICAL LABORATORIES
BOGOR-INDONESIA

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