Clorazepate dosing

As with the barbiturates, the most common adverse reaction seen with the use of clonazepam (Klonopin), clorazepate (Tranxene), and diazepam (Valium) is sedation in varying degrees. Additional adverse effects may include anorexia, constipation, or diarrhea. Some adverse reactions are dose dependent, whereas others may diminish in intensity or cause few problems after several weeks of therapy. 

Greenblatt DJ, Shader RI, Harmatz JS, et al Self-rated sedation and plasma concentrations of desmethyldiazepam following single doses of clorazepate. Psychopharmacology (Berl) 66 289-290, 1979... 

Diazepam and clorazepate have high lipophilicity and are rapidly absorbed and distributed into the CNS. They have a shorter duration of effect after a single dose than would be predicted on the basis of half-life, as they are rapidly distributed to the periphery. 

Signs and symptoms of BZ withdrawal are similar to those of alcohol withdrawal, including muscle pain, anxiety, restlessness, confusion, irritability, hallucinations, delirium, seizures, and cardiovascular collapse. Withdrawal from short-acting BZs (e.g., oxazepam, lorazepani, alprazolam) has an onset within 12 to 24 hours of the last dose. Diazepam, chlordiazep-oxide, and clorazepate have elimination half-lives (or active metabolites with elimination half-lives) of 24 to greater than 100 hours. So, withdrawal may be delayed for several days after their discontinuation. 

Most BZs are completely absorbed from the gastrointestinal (GI) tract. The one exception is clorazepate, a pro-drug that undergoes acid hydrolysis in the stomach and is decarboxylated to form N-desmethyl-diazepam, which is then completely absorbed into the bloodstream (Bellantuono et ak, 1980 Hobbs et ak, 1996 Chouinard et ak, 1999). In contrast, most BZs, with the exception of lorazepam and midazolam, are not consistently absorbed from intramuscular injection (Chouinard et ak, 1999). Lorazepam is available as a sublingual form that reaches clinical effect at the same rate as an oral dose. In general, intravenous administration is used only for anesthesia or for the acute management of seizures. When BZs are given via this route, the onset of action is almost immediate (Chouinard et ak, 1999). 

BZDs differ considerably in potency, which refers to the milligram dose needed to produce a given clinical effect. These differences are in part due to differences in receptor site affinity. If given in the appropriate dose, any BZD may exert anxiolytic, hypnotic, or anticonvulsant effects. For example, anxiolytic BZDs, such as clorazepate and diazepam, are often used as hypnotics when anxiety is a prominent symptom associated with insomnia. 

T effects OF amiodarone, astemizole, atorvastadn, barbiturates, bepridil, bupropion, cerivastatin, cisapride, clorazepate, clozapine, clarithromycin, desipramine, diazepam, encainide, ergot alkaloids, estazolam, flecainide, flurazepam, indinavir, ketoconazole, lovastatin, meperidine, midazolam, nelfinavir, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, simvastatin, SSRIs, TCAs, terfenadine, triazolam, troleandomycin, zolpidem X effects W/ barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, St. John s wort, tobacco X effects OF didanosine, hypnotics, methadone, OCPs, sedatives, theophylline, warfarin EMS T Effects of amiodarone, diazepam, midazolam and BBs, may need X- doses concurrent use of Viagra-type drugs can lead to hypotension X- effects of warfarin concurrent EtOH use can T adverse effects T glucose ODs May cause an extension of adverse SEs symptomatic and supportive Rivasrigmine (Exelon) [Cholinesterase Inhibitor/Anri ... 

A 31-year-old man developed priapism after taking zuclopenthixol 30 mg/day for 8 days, the dose having been increased to 75 mg the day before, while he was still taking oral carbamazepine 600 mg/day and clora-zepate dipotassium 30 mg/day. He had a history of perinatal anoxic encephalopathy with severe motor sequelae and dyslalia, alcohol dependence, and a personality disorder. On the day before the priapism occurred, he had been physically restrained and given an extra dose of intramuscular clorazepate dipotassium 50 mg. When priapism occurred, all drugs except clorazepate were withdrawn and about 6 hours later the corpora cavernosa were washed and infused with noradrenaline in glucose (8 doses of 40 pg), after which the priapism resolved. 

Following a single oral dose of 15 mg to 4 subjects, peak blood concentrations of desmethyldiazepam of 0.14 to 0.18 pg/ml (mean 0.16) were attained in 0.5 to 1 hour peak blood-clorazepate concentrations of 0.03 to 0.11 pg/ml (mean 0.06) were reported at about 1 hour (C. W. Abruzzoe al., J. Pharmacokinet. Biopharm., 1977, 5, 377-390). 

Dose. 7.5 to 22.5 mg of clorazepate dipotassium daily up to 60 mg daily has been given. 

The effects of nordazepam and a precursor, potassium clorazepate, on sleep were evaluated in humans (92). A dose of 5 or 10 mg nordazepam or 15 mg of potassium cloraz-... 

Clorazepate in 22.5-mg daily doses administered for 8 days decreased REM sleep, stage 4 sleep, sleep latency, and total waking (94), whereas total sleep time was increased. During recovery, REM sleep, and sleep latency were increased (95). 

Although diazepam is an effective agent for treatment of status epilepticus, its short duration of action is a disadvantage, leading to the more frequent use of lorazepam. Although diazepam is not useful as an oral agent for the treatment of seizure disorders, clorazepate is effective in combination with certain other drugs in the treatment of partial seizures. The maximal initial dose of clorazepate is 22.6 mg per day in three portions for adults and 15 mg per day in two doses in children. Clorazepate is not recommended for children under the age of 9. 

As well as the opioids cocaine and cannabis, polytoxicomane drug abusers also consume bromazepam, diazepam and flunitrazepam in high doses, and fatalities among drug abusers and substitution patients can often be blamed on the consumption of these substances, often in combination with alcohol [48]. Patients who suffer low-dose dependence, in addition to consuming the three above-named substances, also consume therapeutic amounts of dipotassium clorazepate, flurazepam, lorezepam, nitrazepam or oxazepam, sometimes also in combination with amphetamines or antihistamines. 

In a three-period study 10 healthy subjects were given clorazepate 7.5 mg at night, with either water, or with Maalox 30 mL, or with Maalox 30 mL three times daily before meals. The mean steady-state serum levels of the active metabolite of clorazepate, desmethyidiazepam, were not affected by Maalox, although they varied widely between individuals. This is in line with another report, but contrasts with a single-dose study, in which the peak plasma concentration of desmethyidiazepam was delayed and reduced by about one-third by the use of Maalox. The AUC0.48 was reduced by about 10%. ... 

There seems to be only one report (with temazepam) of a olinieally signif-ieant interaction between disiifiram and the benzodiazepines, and this report is unconfirmed, as the patient did not take temazepam alone. The other reports only describe potential interactions that have been identified by single-dose studies. These do not necessarily reliably predict what will happen in practice. However, it seems possible that some patients will experience increased drowsiness, possibly because of this interaction, and because drowsiness is a very common adverse effect of disulfiram. Reduce the dosage of the benzodiazepine if necessary. Benzodiazepines that are metabolised by similar pathways to diazepam and chlordiazepoxide, may possibly interact in the same way (e.g. bromazepam, clonazepam, clorazepate, prazepam, ketazolam, clobazam, flurazepam, nitrazepam, medazepam) but this needs confirmation. Alprazolam, oxazepam and lo-razepam appear to be non-interacting alternatives. 

Two elderly patients, both smokers, taking triazolam with lorazepam or flurazepam, developed gait disturbances when they were given omeprazole 20 mg daily. They rapidly recovered when eitherthe benzodiazepines or the omeprazole were stopped. A brief report deseribes a patient taking omeprazole who became wobbly and sedated by small, unspeeified doses of diazepam, and another report describes a patient who developed toxie levels of nordiazepam and remained unconscious for 13 days after reeeiv-ing a high dose of clorazepate (1500 mg over about 29 hours) and omeprazole 80 mg daily. ... 

Norman TR, Fulton A, Burrows GD, Maguire KP. Pharmacokinetics of N-desmethyldi-azepam after a single oral dose of clorazepate the effect of smoking. EurJ Clin Pharmacol (1981)21,229-33,... 

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