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0.125mg tablets: Oval, flat, bevel-edged, light violet coloured, single-scored compressed tablets embossed NOVO .125.
0.25mg tablets: Oval, flat, bevel-edged, light blue coloured, single-scored compressed tablets embossed NOVO .25.
Triazolam is a benzodiazepine with short-acting, hypnotic properties, reducing sleep latency, increasing the duration of sleep and decreasing the number of nocturnal awakenings.
Triazolam administered orally to man has a mean absorption of 85% and reaches a peak plasma level between 1 - 1.5 hours. After 0.25mg doses peak concentrations between 4 - 5ng/mL can be expected. Measured half-lives range from 2.6 - 3.2 hours and this is consistent with the absence of accumulated triazolam in the plasma 24 hours after each dose for seven consecutive daily 1mg doses.
Studies of blood and plasma indicated no accumulation of triazolam-related material in the formed elements of the blood.
Triazolam was 89% bound in human serum. Binding to albumin accounted for only a portion of the total binding observed, since binding in a physiological concentration of human serum albumin amounted to only 49%.
Urine from humans dosed orally with triazolam contained small amounts of unmetabolised triazolam as well as 6 metabolites. The two metabolites found in highest concentration in human urine were 1'-hydroxytriazolam and 4-hydroxytriazolam, which accounted for 69% and 11% of the urinary radioactivity respectively. These metabolites are relatively inactive.
In man, following oral administration of triazolam, approximately 85% of the dose is excreted in the urine as unchanged triazolam and metabolites. Approximately 8% is excreted in the faeces. Biliary excretion appeared relatively unimportant in man. Urinary excretion of triazolam and metabolites was quite rapid in man and could be described by two exponentials.
The initial excretion rate was equivalent to a mean excretion half-time of about 6 hours and the mean excretion half-time for the terminal excretion phase was about 36 hours.
Tissue distribution of triazolam -14C radioactivity was studied in the mouse by whole-body section autoradiography. Following oral or intravenous administration, triazolam and/or its metabolites were rapidly and widely distributed throughout the body. The concentration of triazolam-related material in most organs and tissues had reached a maximum within 1 hour of dosing and decreased rapidly thereafter.
The 14C concentration in the brain was reasonably well reflected by the blood 14C concentration.
When triazolam was given to pregnant mice two days before term, triazolam-related material was found uniformly distributed in the foetus with concentrations approximately the same as in the brain of the mother.
Animal studies have indicated that triazolam and its metabolites are secreted in milk.
In lactating rats, an oral dose of triazolam 14C produced peak triazolam concentrations in milk after 4 hours, which were 70% of the maternal plasma concentration.
Triazolam is indicated as a hypnotic agent in the short-term management of severe or disabling insomnia.
TRYCAM (triazolam) tablets are for oral administration. The dosage of TRYCAM should be individualised to obtain the desired hypnotic effect while avoiding oversedation and other side effects.
The lowest effective dose of TRYCAM (triazolam) should be used. Treatment with triazolam should usually not exceed 7 - 10 consecutive days. Use for more than 2 - 3 consecutive weeks requires complete re-evaluation of the patient.
The starting dose in all patients should be 0.125mg; for many patients this dose immediately before retiring should be sufficient. In most adults, a dose of 0.25mg should not be exceeded.
For elderly, or debilitated patients and patients with disturbed liver/kidney function, the dose should not exceed 0.125mg before retiring. The 0.25mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose.
In all patients the risk of severe adverse reactions increases with the size of the dose administered.
Triazolam is contraindicated in patients with known hypersensitivity to the medicine. Patients with myasthenia gravis or a history of glaucoma should not receive benzodiazepines. The safety and effectiveness in patients under the age of eighteen has not been established.
Caution is required in patients receiving triazolam concerning the possible combined effects of alcohol and other central nervous system depressants and consideration should be given to potential additive effects. Alcohol combined with therapeutic doses of triazolam has caused severe central nervous system depression.
Varying severity of anterograde amnesia has been reported following therapeutic doses of triazolam. Anterograde amnesia has also been shown to occur following the administration of other benzodiazepines.
Rebound effects may occur with triazolam while tolerance can develop with chronic use.
Dependence and withdrawal effects can occur even with therapeutic doses of triazolam given on a short term basis. Withdrawal symptoms are likely to occur a few days after abrupt discontinuation of triazolam. Withdrawal symptoms range from mild to severe, and may include anxiety, sleep disorders, hypersensitivity to light, sound and touch, metallic taste, gastrointestinal complaints, tremor, seizures, depression or psychoses. The withdrawal syndrome may last for days, weeks or even months. Triazolam therapy should be tapered off gradually, the length of time required depending on dose and duration of therapy.
Elderly Patients: In elderly and/or debilitated patients, or in patients with organic brain disorders there is a possibility of the development of oversedation, dizziness or impaired co-ordination. Therefore, it is recommended that treatment with TRYCAM be initiated at the lowest possible dose and increased gradually if necessary.
Exacerbation of depression by triazolam in depressed patients has not been demonstrated in clinical trials. Caution should be exercised, however, if the patient exhibits symptoms of depression or reveals evidence of latent depression, particularly when suicidal tendencies may be present and protective measures may be required.
TRYCAM should be given with caution to patients with impaired renal or hepatic function.
Use in Pregnancy: The safety of triazolam in pregnancy has not been established and, therefore, triazolam is not recommended for use in pregnant women. An increased risk of congenital malformations associated with the use of benzodiazepines, chlordiazepoxide and diazepam, and meprobamate during the first trimester of pregnancy has been suggested. Therefore, since triazolam is also a benzodiazepine derivative, its administration is rarely justified in women of childbearing potential. If a women of childbearing potential is receiving triazolam and intends to become or suspects that she is pregnant, she should contact her physician regarding the discontinuation of the medicine.
Use in Lactation: The safety and use of triazolam in nursing mothers has not been established. Since animal studies indicate that triazolam appears in milk ( see pharmacokinetics ) it is recommended that nursing mothers requiring triazolam therapy use a different method of infant feeding.
Reproduction and Teratology Studies: Oral pretreatment of rats with 2 and 5mg/kg/day of triazolam resulted in a slightly longer gestation period, slightly decreased fertility and a slight increase in the number of dead pups at birth. Postnatal survival also appeared to be decreased. No medicine-related malformations were noted by gross examination of stillborn, visceral examination of surplus 5-day old pups or by necropsy of weanlings at 21 days post-parturition.
Triazolam given orally to pregnant rats from day 6 through day 15 at dosage levels of 0, 10 and 30mg/kg/day showed a slight increase in the average number of resorption sites per litter at the 30mg level. At the 30mg/kg level there was a higher incidence of metacarpals absent and minor sternbrae variations.
Triazolam administered orally to pregnant rabbits at 10 and 30mg/kg/day revealed alterations in rib numbers and the presence of fused ribs. Higher incidences of extra or asymmetric sternbrae and missing first metacarpals and phalanges were also observed in the treated foetuses suggesting teratogenic activity in this species.
Treatment of pregnant rabbits with orally administered triazolam (0, 0.2, 0.5, 2.0 and 5.0mg/kg/day) was compared with orally administered diazepam (8, 20, 25 and 50mg/kg/day). No difference in teratogenicity was observed between the two compounds.
The incidence and severity of adverse reactions of triazolam are dose related. The adverse effects most frequently reported with the single-dose and multiple-dose use of triazolam were morning drowsiness (8.3-18.7%), grogginess (7.5%), dizziness (3.5-10.6%), lightheadedness (2.6-8%), impaired co-ordination (2.3-6%), headache and nausea. Severe drowsiness and impaired co-ordination are indicative of medicine intolerance or overdosage.
Less frequently reported adverse reactions include: restlessness, taste alterations, depression, blurred vision, irritability, anterograde amnesia ( see warnings and precautions ), constipation, rash, diarrhoea, epigastric discomfort, nervousness, weakness, confusion, burning eyes, dry mouth, tinnitus, palpitations, tiredness, hiccups, hallucinations, visual disturbances, elevation of SGOT, total and direct bilirubin and alkaline phosphatase. Paradoxical reactions related to stimulation, excitement and hyperactivity may occur.
As for most CNS medicines, alcohol can potentiate the effects of triazolam and should be avoided. Twice the triazolam concentration has been seen on concomitant administration of cimetidine and erythromycin. When both of these medicines are co-administered there is an increase in elimination half-life and a reduction in triazolam clearance. Other macrolide antibiotics may have similar effects and patients' blood plasma triazolam levels should be monitored.
Ingestion of grapefruit has been shown to increase the oral availability of triazolam as a result of inhibition of gut wall metabolism of triazolam during absorption. An increased sedation has been found clinically. It is recommended that ingestion of grapefruit or grapefruit juice be avoided, or at least do not take grapefruit/grapefruit juice within 10 hours before or two hours after taking triazolam.
Manifestations of overdosage include extensions of triazolam's pharmacological activity, namely somnolence and hypnosis. Respiration, pulse and blood pressure should be monitored and supported by general measures when necessary. Gastric lavage should be performed as soon as possible. Institute general supportive therapy as necessary including airway maintenance and intravenous fluids to maintain adequate circulation.
Animal experiments have indicated that cardiopulmonary collapse can occur with massive intravenous doses of triazolam. This could be reversed with positive mechanical respiration and the intravenous infusion of noradrenaline. Experiments in animals have suggested that haemodialysis and forced diuresis are probably of little value. As with the management of intentional overdosage with any medicine, the physician should bear in mind that multiple agents may have been ingested by the patient.
Protect from light and moisture. Keep out of reach of children. Store below 30°C.
Controlled Drug C5
Both strengths: 100 and 500 tablets.
Triazolam is a triazolo benzodiazepine with the chemical name 8-chloro-6(o-chloro-phenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine. Its molecular formula and weight are C17H12Cl2N4 and 343.21 respectively.
Acute Toxicity: The oral LD50 of triazolam was found to be greater than 5000mg/kg in the rat and greater than 100mg/kg in mice.
The intraperitoneal LD50 was also greater than 5000mg/kg in the rat and 2426mg/kg in the mouse. Signs of toxicity included ataxia, sedation, depression and sleep.
Subacute and Chronic Toxicity: Triazolam was administered orally or intravenously to rats for periods of 14 days, 3 months and 2 years. In the two 14-day tolerance studies (0, 500 and 1000mg/kg/day p.o.), sedation was observed after dosing. Toward the end of the study, only the 500mg/kg rats appeared to be affected. The higher doses produced increased kidney and adrenal weights in both sexes and increased liver weights in females.
In the two-year study (0, 10, 30 and 100mg/ kg/day p.o.), the pharmacologic effects noted were drowsiness, increased aggressiveness in females and some unsteadiness. Male rats receiving the two higher dose levels had shorter mean survival times than did low dose and control animals. These early deaths were associated with urinary calculi and chronic progressive nephrosis.
The overall incidence of chronic progressive nephrosis was the same for all males, but developed early in rats receiving the higher triazolam doses. Seven treated rats developed large thrombi, mainly in the heart. Similarly, 10 treated animals had microscopic foreign body granulomas in their lungs. Triazolam tended to aggravate the incidence and extent of hepatic necrosis. Serum cholesterol levels increased slightly with increasing doses.
Dogs were administered triazolam for periods of 9 days, 13 days, 3 months and one year. In the 9-day study (0 and 100-300mg/kg/day p.o.), anxiety, ataxia and sedation were seen for the first two days and polydypsia was the only consistent observation throughout the study. In the 13-day study (0. 0.1, 0.5 and 1.0mg/kg/day i.v.), triazolam produced relaxation and ataxia and a dose-related increase in SGOT, cholesterol and BUN. One dog in the mid-dose group had marked elevation of liver enzymes, hepatocellular degeneration with focal necrosis and raised BSP.
In the 3-month study (0, 0.5, 10 and 50mg/kg/ day p.o.), indications of tolerance development were seen and the dose was increased to 0, 10, 30 and 100mg/kg/day. Hyperactivity, hyperexcitability, ataxia, sedation and polydypsia were observed. Despite increased food consumption, treated dogs showed lower weight gain than controls. Dogs treated with the two higher triazolam doses had elevated alkaline phosphatase and slightly increased liver weights. Two out of four dogs at the highest dose had reduced liver glycogen and one had a suggestion of bile duct proliferation.
In the one-year study (0, 3, 10 and 30mg/kg/ day p.o.), triazolam caused ataxia, ptosis, hyperactivity, increased food consumption and loose stools. Dogs in all treated groups had raised alkaline phosphatase levels and decreased prothrombin times. Liver weights were increased in the mid-dose group. At the two higher dose levels, elevation of platelet and leukocyte counts was observed. One high-dose dog was sacrificed at one year after being moribund and convulsing for 24 hours and was found to have acute myocardial degeneration.
Douglas Pharmaceuticals Ltd
PO Box 45-027
AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
20 August 1999