Lorazepam

(BAN, USAN, rINN)
Lorazepam Chemical formula
Synonyms: Loratsepaami; Lorazépam; Lorazepám; Lorazepamas; Lorazepamum; Wy-4036. 7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-1,4-benzodiazepin-2-one.
Cyrillic synonym: Лоразепам.

💊 Chemical information

Chemical formula: C15H10Cl2N2O2 = 321.2.
CAS — 846-49-1.
ATC — N05BA06.
ATC Vet — QN05BA06.

Pharmacopoeias.

In Eur., Jpn, and US.

Ph. Eur. 6.2

(Lorazepam). A white or almost white, crystalline powder. It exhibits polymorphism. Practically insoluble in water; sparingly soluble in alcohol; sparingly or slightly soluble in dichloromethane. Store in airtight containers. Protect from light.

USP 31

(Lorazepam). A white or practically white, practically odourless powder. Insoluble in water; sparingly soluble in alcohol; slightly soluble in chloroform. Store in airtight containers. Protect from light.

Incompatibility.

Visual incompatibility has been noted with lorazepam and sargramostim 1 or aztreonam. 2 1. Trissel LA, et al. Visual compatibility of sargramostim with selected antineoplastic agents, anti-infectives, or other drugs during simulated Y-site injection. Am J Hosp Pharm 1992; 49: 402–6. 2. Trissel LA, Martinez JF. Compatibility of aztreonam with selected drugs during simulated Y-site administration. Am J HealthSyst Pharm 1995; 52: 1086–90.

Solubility.

The solubility of lorazepam in fluids for intravenous use (water, glucose injection, lactated Ringer’s injection, and sodium chloride injection) was greatest in glucose injection (5%) at 62 micrograms/mL and lowest in sodium chloride injection (0.9%) at 27 micrograms/mL; 1 these differences in solubility appeared to be pH related. Commercial injections are reported to contain polyethylene glycol in propylene glycol to overcome this poor solubility. However, precipitation has been noted 2 in solutions prepared by dilution of lorazepam injection with sodium chloride injection (0.9%) to a concentration of 500 micrograms/mL. One group of workers 3 have reported that they had overcome such problems with precipitation by using glucose injection (5%) as a diluent and by avoiding final concentrations of lorazepam between 0.08 mg/mL and 1 mg/mL. It was suggested that the propylene glycol in the mixture might account for the unusual concentration effect. Such recommendations have been adopted by another group 4 although they observed that precipitation occurred if a formulation of lorazepam containing 4 mg/mL was used to prepare the injection; no precipitation was noted when a formulation containing 2 mg/mL was used. The group also commented that, in the USA, licensed product information for lorazepam injection advises that admixtures should be prepared with the 2 mg/mL formulation only. 1. Newton DW, et al. Lorazepam solubility in and sorption from intravenous admixture solutions. Am J Hosp Pharm 1983; 40: 424–7. 2. Boullata JI, et al. Precipitation of lorazepam infusion. Ann Pharmacother 1996; 30: 1037–8. 3. Volles DF, et al. More on usability of lorazepam admixtures for continuous infusion. Am J Health-Syst Pharm 1996; 53: 2753–4. 4. Levanda M. Noticeable difference in admixtures prepared from lorazepam 2 and 4 mg/ml. Am J Health-Syst Pharm 1998; 55: 2305.

Sorption.

Significant loss of lorazepam has been reported from solutions stored in PVC 1 or polypropylene 2 giving equipment; polyolefin 3-5 or glass 6 equipment appears to be more suitable. 1. Hoey LL, et al. Lorazepam stability in parenteral solutions for continuous intravenous administration. Ann Pharmacother 1996; 30: 343–6. 2. Stiles ML, et al. Stability of deferoxamine mesylate, floxuridine, fluorouracil, hydromorphone hydrochloride, lorazepam, and midazolam hydrochloride in polypropylene infusion-pump syringes. Am J Health-Syst Pharm 1996; 53: 1583–8. 3. Trissel LA, Pearson SD. Storage of lorazepam in three injectable solutions in polyvinyl chloride and polyolefin bags. Am J Hosp Pharm 1994; 51: 368–72. 4. Norenberg JP, et al. Stability of lorazepam in 0.9% sodium chloride stored in polyolefin bags. Am J Health-Syst Pharm 2004; 61: 1039–41. 5. Trissel LA, et al. Drug compatibility with new polyolefin infusion solution containers. Am J Health-Syst Pharm 2006; 63: 2379–82. 6. Martens HJ, et al. Sorption of various drugs in polyvinyl chloride, glass, and polyethylene-lined infusion containers. Am J Hosp Pharm 1990; 47: 369–73.

💊 Dependence and Withdrawal

As for Diazepam.

💊 Adverse Effects, Treatment, and Precautions

As for Diazepam. Pain and a sensation of burning have occurred following injection of lorazepam.

Breast feeding.

The American Academy of Pediatrics1 considers that, although the effect of lorazepam on breast-fed infants is unknown, its use by mothers during breast feeding may be of concern since anxiolytic drugs do appear in breast milk and thus could conceivably alter CNS function in the infant both in the short and long term. Free lorazepam concentrations in the breast milk of 4 mothers ranged from 8 to 9 nanograms/mL four hours after receiving a 3.5-mg oral dose.2 This represented about 15 to 26% of the concentration in plasma, and was probably sufficiently low to cause no adverse effects in breast-fed infants.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 28/04/04
2. Summerfield RJ, Nielsen MS. Excretion of lorazepam into breast milk. Br J Anaesth 1985; 57: 1042–3.

Effects on the blood.

A case of pancytopenia associated with oral lorazepam was reported1 in 1988; only 5 instances of thrombocytopenia and none of leucopenia had been reported to the UK CSM or the UK manufacturers over the previous 13 years.
1. El-Sayed S, Symonds RP. Lorazepam induced pancytopenia. BMJ 1988; 296: 1332.

Effects on fluid and electrolyte homoeostasis.

Inappropriate secretion of antidiuretic hormone related to ingestion of lorazepam was considered to be the cause of hyponatraemia in an 81-year-old woman.1
1. Engel WR, Grau A. Inappropriate secretion of antidiuretic hormone associated with lorazepam. BMJ 1988; 297: 858.

Effects on the nervous system.

For reference to extrapyramidal disorders associated with use of lorazepam, see Diazepam.

The elderly.

For discussion of the need for reduced dosage of benzodiazepines in elderly patients, including mention of lorazepam, see Diazepam.

Formulation.

There have been reports of toxicity, presumed to be due to polyethylene glycol1,2 or propylene glycol,3 after prolonged parenteral use of lorazepam; polyethylene glycol in propylene glycol is included as a solubiliser in lorazepam solutions. Diarrhoea in an infant given large enteral doses of lorazepam or diazepam solutions may have been due to the combined osmotic effect of polyethylene glycol and propylene glycol in these preparations.4
1. Laine GA, et al. Polyethylene glycol nephrotoxicity secondary to prolonged high-dose intravenous lorazepam. Ann Pharmacother 1995; 29: 1110–4
2. Tayar J et al. Severe hyperosmolar metabolic acidosis due to a large dose of intravenous lorazepam. N Engl J Med 2002; 346: 1253–4
3. Seay RE, et al. Possible toxicity from propylene glycol in lorazepam infusion. Ann Pharmacother 1997; 31: 647–8. Woycik CL, Walker PC. Correction and comment: possible toxicity from propylene glycol in injectable drug preparations. ibid.: 1413
4. Marshall JD, et al. Diarrhea associated with enteral benzodiazepine solutions. J Pediatr 1995; 126: 657–9.

Hepatic impairment.

Lorazepam is contra-indicated in severe hepatic impairment; patients with mild to moderate impairment may require reduced doses. Although the elimination halflife of lorazepam was increased in 13 patients with alcoholic cirrhosis compared with 11 control subjects, this was not associated with an impairment in systemic plasma clearance.1 With the exception of a modest decrease in the extent of plasma protein binding, acute viral hepatitis had no effect on the disposition kinetics of lorazepam.
1. Kraus JW, et al. Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther 1978; 24: 411–19.

Local reactions.

Of 40 patients given a single intravenous dose of lorazepam 4 mg three had local thrombosis 2 to 3 days later and 6 had local thrombosis 7 to 10 days later.1 The incidence was lower than in those given diazepam [in solution].
1. Hegarty JE, Dundee JW. Sequelae after the intravenous injection of three benzodiazepines—diazepam, lorazepam, and flunitrazepam. BMJ 1977; 2: 1384–5.

💊 Interactions

As for Diazepam.

💊 Pharmacokinetics

Lorazepam is readily absorbed from the gastrointestinal tract after oral doses, with a bioavailability of about 90%; peak plasma concentrations are reported to occur about 2 hours after an oral dose. The absorption profile after intramuscular injection is similar to that after oral dosage. Lorazepam is about 85% bound to plasma proteins. It crosses the blood-brain barrier and the placenta; it is also distributed into breast milk. Lorazepam is metabolised in the liver to the inactive glucuronide, and excreted in urine. The elimination half-life has been reported to range from about 10 to 20 hours.
1. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 1981; 6: 89–105
2. Swart EL, et al. Comparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients. Br J Clin Pharmacol 2004; 57: 135–45.

Children.

References to the pharmacokinetics of lorazepam in children.
1. Relling MV, et al. Lorazepam pharmacodynamics and pharmacokinetics in children. J Pediatr 1989; 114: 641–6.
NEONATES. References to slow elimination of lorazepam by neonates.
1. Cummings AJ, Whitelaw AGL. A study of conjugation and drug elimination in the human neonate. Br J Clin Pharmacol 1981; 12: 511–15
2. McDermott CA, et al. Pharmacokinetics of lorazepam in critically ill neonates with seizures. J Pediatr 1992; 120: 479–83
3. Reiter PD, Stiles AD. Lorazepam toxicity in a premature infant. Ann Pharmacother 1993; 27: 727–9.

Distribution.

Evidence that lorazepam undergoes enterohepatic recirculation with possible first-pass metabolism.1
1. Herman RJ, et al. Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect. Clin Pharmacol Ther 1989; 46: 18–25.
CNS. In a study involving 6 healthy subjects, peak plasma-lorazepam concentrations were reached 5 minutes after the end of a one-minute intravenous injection.1 CNS effects, as measured by EEG activity, were not maximal until 30 minutes after injection; they declined to baseline values slowly over 5 to 8 hours in a similar manner to plasma concentrations. In contrast, CNS effects of diazepam were maximal immediately after the injection. They also declined more rapidly than lorazepam, but again in a similar way to plasma concentrations. Studies in mice suggested that the slow onset of action of lorazepam that has been reported by some is at least partly explained by a delay in passage from systemic blood into brain tissue.
1. Greenblatt DJ, et al. Kinetic and dynamic study of intravenous lorazepam; comparison with intravenous diazepam. J Pharmacol Exp Ther 1989; 250: 134–40.

💊 Uses and Administration

Lorazepam is a short-acting benzodiazepine with general properties similar to those of diazepam. It is used in the short-term treatment of anxiety disorders, as a hypnotic in the short-term management of insomnia, and as an anticonvulsant in the management of status epilepticus. When used in the treatment of status epilepticus lorazepam has a prolonged antiepileptic action and may be the preferred initial treatment if intravenous access is available. It is also used for its sedative and amnestic properties in premedication and as an adjunct in regimens for the control of nausea and vomiting associated with cancer chemotherapy. Lorazepam is usually given orally or by injection as the base although the pivalate is available for oral use in some countries. Sublingual tablets are used in some countries in doses similar to those for standard tablets. The intramuscular route is usually only used when oral or intravenous dosage is not possible. Injections should usually be diluted before use; intravenous injections should be given at a rate of not more than 2 mg/minute into a large vein. Lorazepam should be given in reduced dosage to elderly or debilitated patients; half the usual adult dose, or less, may be sufficient. The usual oral dose of lorazepam for the treatment of anxiety disorders is 1 to 6 mg daily in 2 or 3 divided doses with the largest dose taken at night; up to 10 mg daily has been given. A dose of 25 to 30 micrograms/kg may be given by injection every 6 hours for acute anxiety. Lorazepam has also been used for panic attacks. A suggested dose in the BNF is 3 to 5 mg daily. A single oral dose of 1 to 4 mg at bedtime may be given for insomnia associated with anxiety. However, the MHRA in the UK advises against the use of oral daily doses of lorazepam above 4 mg for anxiety and phobia, and 2 mg for insomnia. For premedication an oral dose of 2 to 3 mg may be given the night before the operation; the BNF suggests that this may be followed if necessary the next morning by a smaller dose. Alternatively, 2 to 4 mg may be given 1 to 2 hours before an operation. In the UK, although lorazepam tablets are not licensed for premedication of children under 5 years of age, the BNFC suggests that 50 to 100 micrograms/kg (maximum of 4 mg) may be given orally at least 1 hour before an operation to those aged 1 month to 12 years; the same dose may also be given the night before, in addition to, or to replace the dose before, the operation. Lorazepam may also be given parenterally for premedication; a dose of 50 micrograms/kg may be given 30 to 45 minutes before the operation if given intravenously or 1 to 1 1 ⁄ 2 hours before if given intramuscularly. Again, although unlicensed in the UK for premedication of children under 12 years of age, the BNFC suggests that 50 to 100 micrograms/kg (maximum of 4 mg) may be given by slow intravenous injection to those aged 1 month to 18 years. In the management of status epilepticus 4 mg may be given as a single intravenous dose; the BNF suggests that this may be repeated once after 10 minutes if seizures recur. A dose of 2 mg has been suggested for children by one manufacturer (Wy eth). Alternatively, the BNFC suggests that neonates and children up to 12 years of age may be given 100 micrograms/kg (maximum of 4 mg) as a single dose sublingually, rectally, or by slow intravenous injection; this may be repeated once after 10 minutes if necessary. In patients receiving modestly emetogenic chemotherapy, lorazepam 1 to 2 mg orally may be added to antiemetic therapy with domperidone or metoclopramide, for the prophylaxis of nausea and vomiting. The addition of lorazepam may be helpful in the prevention of anticipatory symptoms because of its sedative and amnestic effects.

Disturbed behaviour.

For a discussion of the management of behaviour disturbances associated with various psychotic disorders and the value of benzodiazepines.
1. Bieniek SA, et al. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy 1998; 18: 57–62.

Nausea and vomiting.

References.
1. Malik IA, et al. Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin: a prospective randomized trial. Am J Clin Oncol 1995; 18: 170–5.

Premedication and sedation.

Lorazepam is used as a premedicant and as a sedative for therapeutic and investigative procedures such as dental treatment and endoscopy, and also in intensive care.
1. Maltais F, et al. A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy. Chest 1996; 109: 1195–8.

Substance dependence.

Lorazepam has been used in the management of symptoms of alcohol withdrawal.
1. D’Onofrio G, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 1999; 340: 915–9.

💊 Preparations

BP 2008: Lorazepam Injection; Lorazepam Tablets; USP 31: Lorazepam Injection; Lorazepam Oral Concentrate; Lorazepam Ta b l e t s .

Proprietary Preparations

Arg.: Aplacasse; Calmatron; Emotival; Kalmalin; Lorezan; Microzepam; Nervistop; Sedatival†; Sidenar; Trapax; Tratenamin†; Austral.: Ativan; Austria: Merlit; Temesta; Belg.: Docloraze; Lauracalm; Lorazemed; Lorazetop; Loridem; Optisedine; Serenase; Temesta; Vigiten†; Braz.: Calmogenol†; Lorapan; Lorax; Lorazefast; Lorazepan†; Max-Pax; Mesmerin; Canad.: Ativan; Novo-Lorazem; Nu-Loraz; Chile: Abinol; Amparax; Cz.: Loram†; Ta v or † ; Denm.: Lorabenz; Temesta; Fin.: Te m e s t a ; Fr.: Equitam†; Temesta; Ger.: duralozam†; Laubeel; Somagerol; Tavor; Tolid; Gr.: Aripax; Ativan; Cicletan†; Dorm; Modium; Nifalin; Novhepar; Proneurit†; Tavor; Titus; Trankilium; Hong Kong: Ativan†; LAtiwen; Lorans; Lorivan; Silence; India: Ativan; Calmese; Larpose; Indon.: Ativan; Merlopam; Renaquil; Irl.: Ativan; Israel: Lorivan; Ital.: Control; Loralin; Lorans; Tavor; Zeloram; Malaysia: Ativan; Lorans; Mex.: Ativan; Sinestron†; Neth.: Te m e s t a ; NZ: Ativan; Lorapam†; Pol.: Lorafen; Port.: Ansilor; Lorenin; Lorsedal; Rialam; Rus.: Lorafen (Лорафен); S.Afr.: Ativan; Tranqipam; Singapore: Ativan; Lorans; Spain: Donix; Idalprem; Orfidal; Placinoral; Sedicepan; Swed.: Te me st a; Switz.: Lorasifar; Sedazin; Temesta; Thai.: Anta; Anxira; Ativan†; Lonza; Lora; Loramed; Lorapam; Lorazene†; Lorazep; Ora; Razepam†; Tranavan†; Turk.: Ativan; UK: Ativan; USA: Ativan; Venez.: Ativan. Multi-ingredient: Austria: Somnium†; Switz.: Somnium.
Published January 15, 2019.