Lorazepam

Lorazepam
Systematic (IUPAC) name
(RS)-9-chloro-6-(2-chlorophenyl)-4-hydroxy-
2,5-diazabicyclo[5.4.0]undeca-
5,8,10,12-tetraen-3-one
Identifiers
CAS number 846-49-1
ATC code N05BA06
PubChem CID 3958
DrugBank APRD00116
ChemSpider 3821
Chemical data
Formula C15H10Cl2N2O2 
Mol. mass 321.2 g/mol
Pharmacokinetic data
Bioavailability 85% of oral dose
Metabolism Hepatic glucuronidation
Half-life 9–16 hours[1][2][3]
Excretion Renal
Therapeutic considerations
Pregnancy cat. D(US)
Legal status Schedule IV (CA) CD (Benz) POM (UK) Schedule IV (US)
Routes Oral, I.M., I.V., sublingual, and transdermal
 YesY(what is this?)  (verify)

Lorazepam (initially marketed under the brand names Ativan and Temesta) is a high potency benzodiazepine drug which has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant and muscle relaxant.[4][5] Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including status epilepticus and sedation of hospitalised patients, as well as sedation of aggressive patients.[5][6][7][8]

Lorazepam is considered to be a short-acting drug which, similar to other benzodiazepines, exerts its therapeutic as well as adverse effects via its interaction at benzodiazepine binding sites, which are located on GABAA receptors in the central nervous system. After its introduction in 1977, lorazepam's principal use was in treating anxiety. Among benzodiazepines, lorazepam has a relatively high addictive potential.[4][9] Lorazepam also has abuse potential; the main types of misuse are for recreational purposes or continued use against medical advice.[10] The sedative-hypnotic and anterograde amnesia properties of lorazepam are sometimes used for criminal purposes.[11][12]

Long-term effects of benzodiazepines include tolerance, dependence, a benzodiazepine withdrawal syndrome and cognitive impairments which may not completely reverse after cessation of treatment; however, for most patients, cognitive impairment is not severe. Withdrawal symptoms can range from anxiety and insomnia to seizures and psychosis. Due to tolerance and dependence, lorazepam is recommended for short-term use, 2–4 weeks only. Adverse effects including anterograde amnesia, depression and paradoxical effects such as excitement or worsening of seizures may occur. Children and the elderly are more sensitive to the adverse effects of benzodiazepines.[4][13][14] Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly.[15]

Contents

Indications

1987 Ativan advertisement. "In a world where certainties are few...no wonder Ativan (lorazepam)(Schedule IV) is prescribed by so many caring clinicians."

Lorazepam has relatively potent anxiolytic effects and its best-known indication is the short-term management of severe anxiety; the FDA advises against use of benzodiazepines such as lorazepam for longer than 2–4 weeks.[14][16] It is fast acting, and useful in treating fast onset panic anxiety.[17]

Lorazepam has strong sedative/hypnotic effects, and the duration of clinical effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, in particular in the presence of severe anxiety. Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after only 7 days' administration of lorazepam.[18]

Lorazepam is sometimes used for individuals receiving mechanical ventilation. However, in critically ill patients, propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam for this indication is discouraged.[6]

Its relatively potent amnesic effect,[5] with its anxiolytic and sedative effects, makes lorazepam useful as premedication. It is given before a general anaesthetic to reduce the amount of anaesthetic agent required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Oral lorazepam is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures.[19][20][21] Lorazepam is sometimes used as an alternative to midazolam in palliative sedation.[22] In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia.[23]

Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus.[7][24] Lorazepam is more effective than diazepam in the treatment of status epilepticus.[25] However, phenobarbitol has a superior success rate compared to lorazepam and other drugs, at least in the elderly.[26][27]

The marked anticonvulsant properties of lorazepam, and its pharmacokinetic profile, make intravenous lorazepam a reliable agent for terminating acute seizures, but it has relatively prolonged sedation after-effects. Oral lorazepam, and other benzodiazepines, have a role in long-term prophylactic treatment of resistant forms of petit mal epilepsy, but not as first-line therapies, mainly because of the development of tolerance to their effects.[28]

Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome. In this setting, it is relevant that impaired liver function is not a hazard with lorazepam since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism.[29][30]

Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals,[8][31] however, haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function.[32] However, adverse effects such as behavioural disinhibition may make benzodiazepines inappropriate for some acutely psychotic patients.[33] Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol.[34] Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.

Catatonia with inability to speak is responsive and sometimes controlled with a single 2 mg oral, or slow intravenous dose of lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or too rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment.[35] As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly.[34][36]

It is sometimes used in chemotherapy as an adjunct to antiemetics for treating anticipatory nausea and vomiting, i.e. nausea and vomiting caused or worsened by psychological sensitisation to the thought of being sick.[37] It is also used as adjunct therapy for cyclic vomiting syndrome.

Formulation and administration

0.5mg tablets of the Ativan brand of lorazepam.

Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, lorazepam is mainly available as tablets and a solution for injection, but, in some locations, it is also available as a skin patch, an oral solution, and a sublingual tablet.

Lorazepam tablets and syrups are administered by mouth only. The tablets contain 0.5 mg, 1 mg, or 2 mg lorazepam, with some differences between countries. Lorazepam tablets of the Ativan brand also contain lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate, and colouring agents (indigo carmine—E132—in blue tablets and tartrazine—E102— in yellow tablets).

Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous injection. The injectable solution comes in 1 mL ampoules containing 2 mg or 4 mg lorazepam. The solvents used are polyethylene glycol 400 and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol.[38] Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion.[39] Intravenous injections should be given slowly and patients closely monitored for side effects, such as respiratory depression, hypotension, or loss of airway control.

Peak effects roughly coincide with peak serum levels,[40] which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration,[40][41] but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for 6 to 12 hours, making it unsuitable for regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly.

Adverse effects

Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic, and anticonvulsant) may be considered as "adverse effects," or "side effects," if unwanted.[5] Adverse effects can include, ataxia, sedation and hypotension; the effects of lorazepam are increased in combination with other CNS depressant drugs.[7][8] Other adverse effects include confusion, ataxia, anterograde amnesia and hangover effects. With long-term use of benzodiazepines it is unclear whether cognitive impairments fully return to normal after cessation of therapy; cognitive deficits persist for at least 6 months post-withdrawal, but it is possible that longer than 6 months is required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; lorazepam impairs both explicit memory and implicit memory. In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger patients. Benzodiazepines can cause or worsen depression. Paradoxical effects can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse and in people with a history of aggression or anger problems.[4] Lorazepam's effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects.

Sedation is the most complained-of side effect. In a group of around 3500 patients treated for anxiety, the most common side effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side effects such as sedation and unsteadiness increased with age.[42] Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur.[23][33]

High dose or prolonged parentally administered lorazepam is sometimes associated with propylene glycol intoxication.[23][52]

Full lists of Lorazepam side effects:

For lists of lorazepam side effects, refer to the manufacturers' data sheets. Please note that some may list side effects for the entire benzodiazepine class, not the specific side effect profile for lorazepam.

Contraindications and special considerations

Contraindications

Lorazepam must be avoided in patients with the following conditions:

Special groups and situations

Tolerance and dependence

Dependence typified by a withdrawal syndrome occurs in approximately one third of individuals who are treated for longer than 4 weeks with a benzodiazepines. The higher doses and the longer periods benzodiazepines are taken have a greater risk of developing a benzodiazepine dependence. Potent benzodiazepines such as lorazepam, alprazolam and triazolam have the highest risk of causing a dependence.[4] Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects, undesirable with anxiolytic, hypnotic, and anticonvulsant effects. Patients at first experience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepine use, there is little evidence of continued efficacy. If regular treatment is continued for longer than this, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be benzodiazepine withdrawal symptoms.[58] Due to the development of tolerance to the anticonvulsant effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, however, tolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism of tolerance to benzodiazepines is complex and involves GABAA receptor downregulation, alterations to subunit configuration of GABAA receptors, uncoupling and internalisation of the benzodiazepine binding site from the GABAA receptor complex as well as changes in gene expression.[4]

The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam's relatively short serum half-life, its confinement mainly to the vascular space, and its inactive metabolite results in interdose withdrawal phenomena and next-dose cravings. This may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose reduction (in the UK, the smallest tablet strength is 1.0 mg, which further accentuates this difficulty). To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, degree of dependence and the individual. Coming off long-term lorazepam may be more realistically achieved by a gradual switch to an equivalent dose of diazepam, a period of stabilization on this and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half lives (20–200 hours) of diazepam and its active metabolites.[59]

Withdrawal

On abrupt, or overly rapid discontinuation of lorazepam, anxiety and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with other benzodiazepine drugs, can cause physical dependence, addiction, and what is known as the benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen.[60] Rebound effects often resemble the condition being treated but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as seizures and psychosis. The risk and severity of withdrawal is increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.[4]

Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. It takes approximately 18–36 hours for the benzodiazepine to remove itself from the body.[61] The ease of addiction to Lorazepam, (the Ativan brand was particularly cited), and its withdrawal were brought to the attention of the British public during the early 1980s in Esther Rantzen's BBC TV series "That's Life!", in a feature on the drug over a number of episodes.

Pharmacology

Lorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant as well as muscle relaxant properties.[62] Lorazepam is high-potency and an intermediate-acting benzodiazepine and its uniqueness,[63][64] advantages and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and non-oxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1 mg is equal in effect to diazepam 10 mg).[65][66] The half life of lorazepam is 10–20 hours.[67]

Pharmacokinetics

Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites.[4] Due to its poor lipid solubility lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. But its poor lipid solubility and high degree of protein binding (85-90%[41]) mean that lorazepam's volume of distribution is mainly the vascular compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble diazepam, which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular body fat. This explains why one lorazepam dose, despite lorazepam's shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose.[68] On regular administration diazepam will however accumulate more, since it has a longer half-life and active metabolites with even longer half-lives.

Clinical example: Diazepam has long been a drug of choice for status epilepticus: Its high lipid solubility means it gets absorbed with equal speed whether given intravenously, orally, or rectally (non-intravenous routes are convenient in non-hospital settings). But diazepam's high lipid solubility also means it does not remain in the vascular space but soon redistributes into other body tissues. So it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation. Lorazepam is a different case: Its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once injected will not get significantly redistributed beyond the vascular space. Therefore, lorazepam's anticonvulsant effects are more durable, thus reducing the need for repeated doses. If a patient is known to usually stop convulsing after only one or two diazepam doses, diazepam may be preferable because sedative after-effects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24 hours).[69] The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the patient needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures,[70] lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus.[71][72]

Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peak total serum lorazepam level of around 20 nanograms/ml around two hours later,[40][41] half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide.[73] A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of unmetabolised (active) lorazepam.[74] On regular administration, maximum lorazepam serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation.[41] On discontinuation, lorazepam serum levels become negligible after 3 days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation and, therefore, is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor and, therefore, gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys[41], and, because of its tissue accumulation, it remains detectable - particularly in the urine - for substantially longer than lorazepam.

Pharmacodynamics

Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors,[75] which may also explain its marked[5] amnesic effects. The main pharmacological effects of lorazepam are the enhancement of the effects of GABA at the GABAA receptor.[4] Benzodiazepines, such as lorazepam enhance the effects of GABA at the GABAA receptor via increasing the frequency of opening of the chloride ion channel on the GABAA receptors; which results in the therapeutic actions of benzodiazepines. Benzodiazepines however, do not on their own enhance the GABAA receptors but require the neurotransmitter GABA to be present. Thus the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA.[4][57]

The magnitude and duration of lorazepam effects are dose-related, meaning that larger doses have stronger and longer-lasting effects. This is because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors.[76]

The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation in mouse spinal cord cell cultures.[77]

Interactions

Lorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose with alcohol. The combination also causes synergistic enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or criminal consequences. Some experts advise that patients should be warned against drinking alcohol while on lorazepam treatment,[5][78] but such clear warnings are not universal.[79] Synergistic adverse effects may also occur when lorazepam is administered with other drugs such as opioids or other hypnotics.[57] Lorazepam may also interact with rifabutin.[80] Valproate, inhibits the metabolism of lorazepam, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin, rifampin increases the rate of metabolism of lorazepam. Some antidepressants, anti-epileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol when taken with lorazepam may result in enhanced sedative effects.[4]

Overdose

In cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain whether other drugs were also ingested.

Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression, and death.

Early management of alert patients includes emetics, gastric lavage, and activated charcoal. Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving intravenous flumazenil.

Patients are ideally nursed in a kind, non-frustrating environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues.[81] Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced anterograde amnesia.

Detection in body fluids

Lorazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma lorazepam concentrations are usually in a range of 10-300 ug/L in persons either receiving the drug therapeutically or in those arrested for impaired driving, and 300-1000 ug/L in victims of acute overdosage.[82]

Abuse and misuse

Lorazepam is a drug with the potential for misuse. Two types of drug misuse can occur. Recreational misuse, wherein the drug is taken to achieve a "high," or when the drug is continued long term against medical advice.[10]

In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: Criminals may take them to deliberately seek disinhibition before committing crimes[11] (which increases their potential for violence). The anterograde amnesia and sedative-hypnotic effects of benzodiazepines such as lorazepam are sometimes used by predators on unwitting victims as date rape drugs, or for the purpose of robbery, however, alcohol is the most common drug involved in such crimes.[12]

In Northern Ireland in cases where drivers had low or no alcohol readings, but were thought to be impaired through drugs, benzodiazepines were found to be present in 87% of cases.[83]

A large-scale, nationwide, U.S. government study of pharmaceutical-related ED visits by SAMHSA found that sedative-hypnotics in the United States are the most frequently abused pharmaceuticals, with 35% of drug-related emergency room visits involving sedative-hypnotics. In this category, benzodiazepines are most commonly abused. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. Lorazepam was the third-most-commonly abused benzodiazepine in these ED visit statistics.[84]

History and legal status

Early lorazepam marketing, a 1977 direct-to-patient advertisement implying its positive effects: "Now it can be yours - The Ativan Experience."

Historically, lorazepam is one of the "classical" benzodiazepines. Other classical benzodiazepines include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate.[85] Lorazepam was first introduced by Wyeth Pharmaceuticals in 1971 under the brand names of Ativan and Temesta.[86] The drug was developed by President of Research, D.J. Richards. Wyeth's original patent on lorazepam is expired in the United States but the drug continues to be commercially viable. As a measure of its ongoing success, it has been marketed under more than seventy generic brands since then:

Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorafen (PL), Lorazon, Lorenin, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L, Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Piralone, Placidia, Placinoral, Punktyl, Quait, Renaquil, Rocosgen, Securit, Sedarkey, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Titus, Tolid, Tranqil, Tranqipam, Trapax, Trapaxm, Trapex, Upan, Wintin, and Wypax.

In 2000, the U.S. drug company Mylan agreed to pay $147 million to settle accusations by the F.T.C. that they had raised the price of generic lorazepam by 2600 percent and generic clorazepate by 3200 percent in 1998 after having obtained exclusive licensing agreements for certain ingredients.[87]

Lorazepam is a Schedule IV drug under the Controlled Substances Act in the U.S. and internationally under the United Nations Convention on Psychotropic Substances.[88] Lorazepam is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, lorazepam is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.[89]

See also

References

  1. ↑ Greenblatt DJ, Shader RI, Franke K, Maclaughlin DS, Harmatz JS, Allen MD, Werner A, Woo E (1991). "Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans". J Pharm Sci 68 (1): 57–63. doi:10.1002/jps.2600680119. PMID 31453. http://www3.interscience.wiley.com/cgi-bin/abstract/113291369/ABSTRACT?CRETRY=1&SRETRY=0. 
  2. ↑ Greenblatt DJ, von Moltke LL, Ehrenberg BL, Harmatz JS, Corbett KE, Wallace DW, Shader RI (2000). "Kinetics and dynamics of lorazepam during and after continuous intravenous infusion". Crit Care Med 28 (8): 2750–2757. doi:10.1097/00003246-200008000-00011. PMID 10966246. http://www.ccmjournal.com/pt/re/ccm/abstract.00003246-200008000-00011.htm;jsessionid=HGxHJZZnNrV1TQp6TnmT8PwGtRJvLwT61g1pvt3TJCTTvWnpB6Sq!-667243907!181195629!8091!-1. 
  3. ↑ Papini O, da Cunha SP, da Silva Mathes Ado C, Bertucci C, Moisés EC, de Barros Duarte L, de Carvalho Cavalli R, Lanchote VL (2006). "Kinetic disposition of lorazepam with a focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples" (PDF). J Pharm Biomed Anal 40 (2): 397–403. doi:10.1016/j.jpba.2005.07.021. PMID 16143486. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TGX-4H21K93-7-C&_cdi=5266&_user=308069&_orig=search&_coverDate=02%2F13%2F2006&_sk=999599997&view=c&wchp=dGLbVzz-zSkWb&md5=fe760a63ce75494ac2ad7528878afbfe&ie=/sdarticle.pdf. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics.". Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Hindmarch, Ian (January 30, 1997). "Benzodiazepines and their effects". benzo.org.uk. http://www.benzo.org.uk/hindmarch.htm. Retrieved 2007-05-13. 
  6. ↑ 6.0 6.1 Cox, CE.; Reed, SD.; Govert, JA.; Rodgers, JE.; Campbell-Bright, S.; Kress, JP.; Carson, SS. (Mar 2008). "Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation." (PDF). Crit Care Med 36 (3): 706–14. doi:10.1097/CCM.0B013E3181544248. PMID 18176312. PMC 2763279. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763279/pdf/nihms112536.pdf. 
  7. ↑ 7.0 7.1 7.2 Walker, M. (Sep 2005). "Status epilepticus: an evidence based guide." (PDF). BMJ 331 (7518): 673–7. doi:10.1136/bmj.331.7518.673. PMID 16179702. PMC 1226249. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1226249/pdf/bmj33100673.pdf. 
  8. ↑ 8.0 8.1 8.2 Battaglia, J. (2005). "Pharmacological management of acute agitation.". Drugs 65 (9): 1207–22. doi:10.2165/00003495-200565090-00003. PMID 15916448. 
  9. ↑ Kemper N; Poser W, Poser S. (December 5, 1980). "[Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed (author's transl)]". Deutsche medizinische Wochenschrift (1980). 105 (49): 1707–12. doi:10.1055/s-2008-1070941. PMID 7439058. 
  10. ↑ 10.0 10.1 Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry 66 Suppl 9: 31–41. PMID 16336040. 
  11. ↑ 11.0 11.1 11.2 Michel L, Lang JP (2003). "[Benzodiazepines and forensic aspects]" (in French). L'Encéphale 29 (6): 479–85. PMID 15029082. 
  12. ↑ 12.0 12.1 Kintz, P. (Aug 2007). "Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes." (PDF). Anal Bioanal Chem 388 (7): 1467–74. doi:10.1007/s00216-007-1209-z. PMID 17340077. http://www.springerlink.com/content/k6w77661421pr404/fulltext.pdf. 
  13. ↑ Stewart, SA. (2005). "The effects of benzodiazepines on cognition.". J Clin Psychiatry 66 Suppl 2: 9–13. PMID 15762814. 
  14. ↑ 14.0 14.1 Food and Drug Administration; Wyeth Pharmaceuticals Inc, Biovail Pharmaceuticals, Inc. (March 2007). "Ativan® (lorazepam) Tablets Rx only" (PDF). USA: Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017794s034s035lbl.pdf. "In general, benzodiazepines should be prescribed for short periods only (e.g. 2- 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended." 
  15. ↑ 15.0 15.1 Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (Feb 2010). "Effect of hypnotic drugs on body balance and standing steadiness.". Sleep Med Rev 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127. 
  16. ↑ RONI CARYN RABIN, "Disparities: Study Finds Risk in Off-Label Prescribing"[1]
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NK2 Antagonists
GR-159,897 • Saredutant
MCH1 antagonists
ATC-0175 • SNAP-94847
mGluR2/3 Agonists
Eglumegad
mGluR5 NAMs
Fenobam
TSPO agonists
DAA-1097 • DAA-1106 • Emapunil • FGIN-127 • FGIN-143
σ1 agonists
Afobazole • Opipramol
Others
Benzoctamine • Carbetocin • Demoxytocin • Mephenoxalone • Mepiprazole • Oxanamide • Oxytocin • Promoxolane • Tofisopam • Trimetozine • WAY-267,464
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

: PSO/PSI

mepr

dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)
Antiemetics (A04)
5-HT3 Antagonists
Alosetron • Azasetron • Bemesetron • Cilansetron • Clozapine • Dazopride • Dolasetron • Granisetron • Lerisetron • Metoclopramide • Mianserin • Mirtazapine • Olanzapine • Ondansetron • Palonosetron • Ramosetron • Ricasetron • Tropisetron • Zatosetron
CB1 Agonists (Cannabinoids)
Dronabinol • Nabilone • Nonabine
D2/D3 Antagonists
Alizapride • Bromopride • Chlorpromazine • Clebopride • Domperidone • Haloperidol • Itopride • Metoclopramide • Metopimazine • Prochlorperazine • Thiethylperazine
H1 Antagonists (Antihistamines)
Cyclizine • Dimenhydrinate • Diphenhydramine • Meclozine • Promethazine
mACh Antagonists (Anticholinergics)
Atropine • Hyoscyamine • Scopolamine
NK1 Antagonists
Aprepitant • Casopitant • Ezlopitant • Fosaprepitant • Maropitant • Vestipitant
Others
Cerium oxalate • Dexamethasone • Lorazepam • Midazolam • Propofol • Trimethobenzamide

: DIG

anat(t, g, p)/phys/devp/cell/

noco/cong/tumr, sysi/

proc, drug(A2A/2B/3/4//6/7/14/16), blte