Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Ativan Injection is not recommended for out-patient use unless the patient is accompanied.
Prior to use, Ativan Injection may be diluted for IM administration and should always be diluted for IV administration with equal amounts of compatible diluent (see section 4.2). Intravenous injection should be administered slowly except in the control of status epilepticus where rapid injection is required.
The possibility that respiratory arrest may occur or that the patient may have partial airway obstruction should be considered. Therefore, equipment necessary to maintain a patent airway and to support respiration/ventilation should be available and used where necessary.
The use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence.
Severe anaphylactic/anaphylactoid reactions have been reported with the use of benzodiazepines. Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of benzodiazepines. Some patients taking benzodiazepines have had additional symptoms such as dyspnoea, throat closing, or nausea and vomiting. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with a benzodiazepine should not be rechallenged with the drug.
It is recommended that patients receiving Ativan Injection should remain under observation for at least eight hours and preferably overnight. When Ativan Injection is used for short procedures on an outpatient basis, the patient should be accompanied when discharged.
Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished in the presence of Ativan Injection. Alcoholic beverages should not be consumed for at least 24 to 48 hours after receiving Ativan Injection.
Use of benzodiazepines, including lorazepam, may lead to potentially fatal respiratory depression. Extreme care must be taken in administering Ativan Injection to elderly or very ill patients and to those with limited pulmonary reserve or compromised respiratory function (e.g. chronic obstructive pulmonary disease [COPD]), because of the possibility that apnoea and/or cardiac arrest may occur. Care should also be exercised when administering Ativan Injection to a patient with status epilepticus, especially when the patient has received other central nervous system depressants.
Concomitant use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death.
Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as Ativan with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Ativan concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).
There is no evidence to support the use of Ativan Injection in coma or shock.
Ativan is not intended for the primary treatment of psychotic illness or depressive disorders, and should not be used alone to treat depressed patients. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients.
Pre-existing depression may emerge during benzodiazepine use.
There are no clinical data available for Ativan Injection with regard to abuse or dependence. However, based upon experience with oral benzodiazepines, doctors should be aware that repeated doses of Ativan Injection over a prolonged period of time may lead to physical and psychological dependence. The risk of dependence on Ativan is low when used at the recommended dose and duration, but increases with higher doses and longer term use. The risk of dependence is further increased in patients with a history of alcoholism or drug abuse, or in patients with significant personality disorders. Therefore, use in individuals with a history of alcoholism or drug abuse should be avoided.
Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. Therefore, the drug should always be discontinued gradually - using the oral preparation if necessary.
Symptoms reported following discontinuation of oral benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of “rebound” phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.
In severe cases the following symptoms may occur: derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; vomiting; hallucinations; convulsions. Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold, such as antidepressants.
It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of “rebound” phenomena to minimise anxiety should they occur.
Withdrawal symptoms (e.g. rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy.
There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
When benzodiazepines with a long duration of action are being used, it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Abuse of benzodiazepines has been reported.
Anxiety or insomnia may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is more specific treatment.
Caution should be used in the treatment of patients with acute narrow-angle glaucoma.
As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy.
Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.
As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.
Some patients taking benzodiazepines have developed a blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematologic and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary.
Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This effect may be advantageous when Ativan is used as a premedicant.
Paradoxical reactions have been occasionally reported during benzodiazepine use (see section 4.8). Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.
Although hypotension has occurred only rarely, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.
Ativan Injection contains the excipients polyethylene glycol and propylene glycol. There have been reports of propylene glycol toxicity (e.g. lactic acidosis, hyperosmolality, hypotension) and polyethylene glycol toxicity (e.g. acute tubular necrosis) during administration of Ativan Injection, including at higher than recommended doses. Central nervous system toxicity, including seizures, as well as unresponsiveness, tachypnoea, tachycardia and diaphoresis have also been associated with propylene glycol toxicity. Those prone to propylene glycol accumulation and its potential adverse effects include patients with impaired alcohol and aldehyde dehydrogenase enzyme systems, those with renal or hepatic disease; and paediatric patients.
Intravenous administration of the preservative benzyl alcohol has been associated with serious adverse event, and death in paediatric patients including neonates characterized by central nervous system depression, metabolic acidosis, gasping respirations, cardio-vascular failure and haematological anomalies (“gasping syndrome”). Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Use only if it is necessary and if there are no alternatives possible. If given in high volumes, should be used with caution and preferably for short term treatment in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis)
Premature and low-birth weight infants may be more likely to develop toxicity.
Benzyl Alcohol containing products should not be used in pre-term or full-term neonates unless strictly necessary.
Lorazepam should be used with caution in elderly due to the risk of sedation and/or musculoskeletal weakness that can increase the risk of falls, with serious consequences in this population. Elderly patients should be given a reduced dose (see section 4.2 Posology).
The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.
The benzodiazepines, including Ativan Injection, produce additive CNS depressant effects including respiratory depression, when co-administered with other medications which themselves produce CNS depression, e.g. opioids, barbiturates, antipsychotics, sedatives/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants and anaesthetics (see section 4.4).
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Ativan with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
Concurrent administration of lorazepam with sodium valproate may result in reduced clearance (20 to 40%) and increased concentrations of lorazepam. Therefore clinical monitoring is advised and lorazepam dosage should be reduced when appropriate.
Concurrent administration of lorazepam with probenecid may result in reduced clearance, increased elimination half-life and increased concentrations of lorazepam. Therefore clinical monitoring is advised and lorazepam dosage should be reduced when appropriate.
An enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychic dependence.
Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines which are metabolised only by conjugation.
The addition of scopolamine to Ativan Injection is not recommended, since their combination has been observed to cause an increased incidence of sedation, hallucination and irrational behaviour.
Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, and ataxia.
Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.
There have been reports of apnoea, coma, bradycardia, heart arrest and death with the concomitant use of lorazepam injection solution and haloperidol.
Ativan Injection should not be used during pregnancy, especially during the first and last trimesters, unless in the judgement of the physician such administration is clinically justifiable. Benzodiazepines may cause foetal damage when administered to pregnant women.
If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the drug if she intends to become, or suspects that she is, pregnant.
Use of Ativan Injection during the late phase of pregnancy may require ventilation of the infant at birth.
If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.
Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period.
Symptoms such as hypotonia, hypothermia, respiratory depression, apnoea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.
There are insufficient data regarding obstetrical safety of parenteral Ativan, including use in caesarean section. Such use, therefore, is not recommended.
Benzyl alcohol can cross the placenta, see section 4.4..
Since benzodiazepines are found in breast milk, Ativan Injection should not be given to breast- feeding mothers unless the expected benefit to the woman outweighs the potential risk to the infant.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or use machines. Therefore, patients should not drive or operate machinery within 24-48 hours of administration of Ativan Injection and should be advised not to take alcohol (see section 4.5).
Frequency not known: Thrombocytopenia, agranulocytosis, pancytopenia
Frequency not known: Hypersensitivity reactions, anaphylactic/oid reactions
Frequency not known: SIADH
Frequency not known: Hyponatremia
Common: Confusion depression, unmasking of depression
Uncommon: Change in libido, decreased orgasm
Frequency not known: Disinhibition, euphoria, suicidal ideation/attempt, paradoxical reactions, including anxiety, agitation, excitation, hostility, aggression, rage, sleep disturbances/insomnia, sexual arousal, hallucinations
Very Common: Sedation, drowsiness
Common: Ataxia, dizziness
Frequency not known: Extrapyramidal symptoms, tremor, dysarthria/slurred speech, headache, convulsions/seizures, amnesia, coma, impaired attention/concentration, balance disorder
Frequency not known: Visual disturbances (including diplopia and blurred vision)
Frequency not known: Vertigo
Frequency not known: Hypotension, lowering in blood pressure
Frequency not known: Respiratory depressionβ, apnea, worsening of sleep apnea, worsening of obstructive pulmonary disease
Uncommon: Nausea
Frequency not known: Constipation
Frequency not known: Jaundice
Frequency not known: Angioedema, allergic skin reactions, alopecia
Common: Muscle weakness
Uncommon: Impotence
Very Common: Fatigue
Common: Asthenia
Frequency not known: Hypothermia
Frequency not known: Increase in bilirubin, increase in liver transaminases, increase in alkaline phosphatase
± Benzodiazepine effects on the CNS are dose-dependent, with more severe CNS depression occurring with high doses.
β The extent of respiratory depression with benzodiazepines is dose-dependent, with more severe depression occurring with high doses.
Tolerance at the injection site is generally good although, rarely, pain and redness have been reported after Ativan Injection.
Transient anterograde amnesia or memory impairment may occur using therapeutic doses, the risk increasing at higher doses (see section 4.4).
Paradoxical reactions may be more likely to occur in children and the elderly (see section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
