What Is Lorazepam (Ativan)? FDA Approval, Authorization and Reimbursement Status in Turkey

• FDA Approval: Yes (Initial approval: September 30, 1977, by Wyeth Pharmaceuticals)
• Brand Name: Ativan (the best-known brand); also sold generically.
• Active Ingredient: Lorazepam
• Route of Administration: Oral tablet, oral solution, injection (intramuscular or intravenous)
• Class: Benzodiazepine derivative; anxiolytic, sedative, anticonvulsant
• Category: Drug used to treat psychiatric and neurological disorders. Also used as antiemetic support to prevent chemotherapy-induced nausea and vomiting
• Manufacturer: Wyeth. Currently also numerous generic manufacturers, including Pfizer, Teva and Sandoz
• Distribution in Turkey: Authorized in Turkey and available from pharmacies with a prescription.
• Cancers for Which It Is Approved: Anxiety disorders, preoperative sedation, status epilepticus (emergency treatment of epileptic seizures), chemotherapy-induced nausea and vomiting

What Is Lorazepam (Ativan)? How Does It Work?

Lorazepam is a benzodiazepine that depresses the central nervous system. Clinically, it is most often used for anxiety disorders, short-term sedation, seizure control and supportive treatment of chemotherapy-induced nausea and vomiting. It is effective in acute and short-term use. Available by prescription, it requires caution because of its potential for dependence.

How Does It Work?

Lorazepam enhances the effect of GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter. By binding to GABA-A receptors in the brain, it increases their sensitivity to GABA. This increases chloride ion entry into cells and reduces neuronal excitability, producing general nervous system depression. This mechanism gives lorazepam sedative, anxiolytic, anticonvulsant and muscle-relaxant effects.

The drug has an intermediate duration of action, with a plasma half-life generally ranging from 10–20 hours. It is metabolized in the liver but, unlike some other benzodiazepines, produces no active metabolites. This provides a more predictable pharmacokinetic profile, particularly in older adults and patients with impaired liver function.

FDA (US Food and Drug Administration) Approval History

• September 30, 1977: The oral tablet was approved for short-term treatment of anxiety disorders.
• July 25, 1980: The injectable formulation was approved for status epilepticus and preoperative sedation.
• August 27, 2021: Loreev XR, an extended-release lorazepam capsule, was approved for anxiety disorders in adults.

Authorization in Turkey

Lorazepam is authorized by the Turkish Medicines and Medical Devices Agency (TİTCK) of the Ministry of Health. In particular, Ativan Expidet 2.5 mg tablets are marketed under Pfizer's authorization.

Therapeutic Indications

Lorazepam's approved therapeutic indications in Turkey are:

• Anxiety Disorders: Used for short-term treatment of anxiety symptoms.
• Anxiety Associated With Depression: Effective for short-term treatment of anxiety accompanying depressive symptoms.
• Surgical Premedication: Used for preoperative sedation.
• Chemotherapy-Induced Nausea and Vomiting: Used with standard antiemetics for prophylactic and symptomatic treatment of nausea and vomiting caused by cancer chemotherapy.

Reimbursement Status

Lorazepam is reimbursed by the Social Security Institution (SGK) for certain indications, provided that it is prescribed on a green prescription and used for the relevant indications.

Price: Ativan 1 mg tablets: 159.49 TL; Ativan 2.5 mg tablets: 284.26 TL.

Resistance Mechanisms

• GABA-A Receptor Regulation: Lorazepam binds to the benzodiazepine-binding site of the GABA-A receptor complex and enhances GABA activity. With prolonged use, however, GABA-A receptor downregulation (fewer receptors) or reduced receptor sensitivity (desensitization) may develop. More drug binding is then required for the same effect, presenting clinically as reduced effectiveness, or tolerance.
• Neuronal Adaptation and Compensation: The central nervous system responds homeostatically to continuously increased GABA activity. Responses include increased activity of excitatory systems, such as glutamate, and adaptations aimed at restoring neuronal balance. These adaptive mechanisms weaken lorazepam's effects over time.
• Pharmacokinetic Changes: Lorazepam is metabolized in the liver but produces no active metabolites, so pharmacokinetic tolerance is less common. Nevertheless, adaptation of liver enzymes or individual differences may have a small effect during chronic use.
• Psychological Dependence and Perceived Resistance: Some patients, particularly those with anxiety disorders, may become psychologically dependent on the drug. Believing its effect has diminished, they may request higher doses, creating a subjective sense of resistance.

Absorption

• Rapidly and well absorbed after oral administration.
• Bioavailability is approximately above 90%.
• Maximum plasma concentration is generally reached within 1–2 hours.
• Food does not significantly affect absorption.

Distribution

• Plasma protein binding is 85–90%, particularly to albumin.
• Volume of distribution (Vd): approximately 1.3 L/kg
• Rapidly crosses the blood-brain barrier, so central effects such as anxiolysis and sedation begin quickly.
• Also crosses the placenta and enters breast milk, requiring caution during pregnancy and breastfeeding.

Metabolism

• Metabolized in the liver.
• Unlike many other benzodiazepines, lorazepam does not undergo phase I (oxidative) metabolism.
• Instead, phase II glucuronidation converts it to lorazepam glucuronide, a pharmacologically inactive metabolite.
• This provides a more predictable and safer pharmacokinetic profile, particularly in older adults and patients with impaired liver function.

Elimination

• Lorazepam and its metabolite are eliminated mainly in urine (approximately 88% within 96 hours).
• A small proportion may be eliminated in feces.
• Plasma elimination half-life: generally 10–20 hours.
• This may be prolonged in older adults and patients with renal or hepatic impairment.

Dose Range

• Anxiety disorder: 1–3 mg/day (in divided doses); 10 mg/day
• Preoperative sedation: 2–4 mg (oral or i.m.)
• Status epilepticus (emergency): 4 mg i.v. (at 2 mg/min), repeated every 10–15 minutes if needed; total 8 mg (usually)
• To prevent anticipatory nausea and vomiting before chemotherapy, the recommended starting lorazepam (Ativan®) dose is a 0.5 to 1 mg oral tablet taken the night before chemotherapy or approximately one to two hours beforehand.
• For nausea and vomiting after chemotherapy, the recommended starting lorazepam (Ativan®) dose is a 0.5 to 1 mg oral tablet every 8 hours as needed.
• Because lorazepam carries a risk of dependence and tolerance, prolonged or high-dose use requires careful monitoring.
• It must not be stopped abruptly; taper the dose gradually, particularly after use for more than 2 weeks.
• It requires a green prescription and is supplied only on a physician's prescription.

Drug Interactions

• Interactions With Central Nervous System Depressants: Increased risk of sedation, respiratory depression, impaired consciousness and coma. Examples include opioids such as morphine, fentanyl and oxycodone, other benzodiazepines, such as diazepam and alprazolam, alcohol, antipsychotics, such as haloperidol and risperidone, hypnotics, such as zolpidem, barbiturates, such as phenobarbital, and anesthetic agents. These combinations may cause excessive sedation leading to respiratory depression and death. Concomitant use should be reserved for essential situations and use low doses.
• Interactions With Anticonvulsants: Drugs such as phenytoin and carbamazepine may increase lorazepam's central effects or alter drug levels. Valproic acid may inhibit lorazepam glucuronidation and raise plasma levels, increasing neurological side effects and sedation.
• Interaction With CYP450 Enzymes (Indirect): Lorazepam is metabolized mainly through phase II glucuronidation and therefore does not interact directly with CYP450 enzymes. However, drugs inhibiting glucuronidation, such as valproate, may raise lorazepam levels.
• Interactions With Antidepressants: SSRIs/SNRIs, such as fluoxetine, sertraline and venlafaxine, may increase sedation. Tricyclic antidepressants, such as amitriptyline, increase anticholinergic burden and the risk of central nervous system depression.
• Other Interactions: Alcohol dramatically increases sedation and respiratory depression. Muscle relaxants further reduce muscle tone and increase fall risk. Oral contraceptives may slightly increase lorazepam levels. Antihistamines may increase sedation.

Situations Requiring Attention

• Risk of Dependence and Tolerance: Lorazepam may cause psychological and physical dependence. Tolerance may develop, particularly with prolonged (>2–4 weeks) or high-dose use. Abrupt discontinuation may cause withdrawal symptoms, including anxiety, insomnia, restlessness and seizures. Use should be short-term and at low doses, with gradual tapering if necessary.
• Use in Older Adults: Older adults are more sensitive to the drug and have higher risks of falls, confusion, delirium and respiratory depression. The starting dose should generally be halved, for example to 0.5–1 mg/day.
• Respiratory Failure / Sleep Apnea: Lorazepam may worsen respiratory depression. Caution is required in COPD, obstructive sleep apnea or hypoventilation syndrome.
• Psychiatric Disorders: When depression is present, lorazepam may increase suicide risk. It is ineffective in psychosis and is not appropriate as monotherapy. Paradoxical effects, such as agitation, anger and restlessness, may occur rarely.
• Hepatic and Renal Impairment: Lorazepam produces no active metabolites, undergoes only glucuronidation and is generally safer in hepatic impairment. However, severe renal dysfunction may slow elimination and require dose adjustment.
• Use With Alcohol and Other Sedatives: Effects are synergistic and may cause profound sedation, respiratory depression and coma. Alcohol consumption is strongly discouraged.
• Pregnancy and Breastfeeding: Pregnancy category D. Use late in pregnancy may cause neonatal respiratory depression, hypotonia and withdrawal. It passes into breast milk and is not recommended during breastfeeding.
• Driving and Workplace Safety: It may impair attention, coordination and reaction time. It is unsafe for tasks requiring alertness, such as driving or operating machinery.
• Green Prescription Requirement: In Turkey, it requires a green prescription and should be supplied only under physician supervision.

Side Effects

The most frequently reported adverse effects in lorazepam (Ativan) prescribing information are:

• Fatigue
• Dizziness
• Weakness
• Drowsiness (Sleepiness)
• Confusion
• Depression
• Memory Loss or Impairment
• Difficulty Maintaining Balance

Note: Lorazepam may impair balance and increase fall risk.

Note: Exact percentages of patients experiencing lorazepam side effects are unknown because the drug has been used in diverse patient groups and clinical studies.