Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX
Concomitant Use with Opioids: Concomitant use of benzodiazepines, including ATIVAN, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are not possible (see SERIOUS WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant Use with Opioids; DRUG INTERACTIONS, Serious Drug Interactions).
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with benzodiazepines.
If a decision is made to prescribe ATIVAN concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of ATIVAN than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking ATIVAN, prescribe a lower initial dose of the opioid analgesic and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see OVERDOSAGE).
Advise both patients and caregivers about the risks of respiratory depression and sedation when ATIVAN is used with opioids.
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined.
Use of benzodiazepines such as ATIVAN can lead to abuse, misuse, addiction, physical dependence (including tolerance) and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol or illicit drugs. Benzodiazepines may be subject to diversion.
The risk of dependence increases with higher doses and longer term use but can occur with short-term use at recommended therapeutic doses. The risk of dependence is greater in patients with a history of psychiatric disorders and/or substance (including alcohol) use disorder. Interdose daytime anxiety and rebound anxiety may increase the risk of dependency in ATIVAN treated patients.
- Discuss the risks of treatment with ATIVAN with the patient, considering alternative (including non-drug) treatment options.
- Carefully evaluate each patient’s risk of abuse, misuse and addiction, considering their medical condition and concomitant drug use, prior to prescribing ATIVAN. In individuals prone to substance use disorder, ATIVAN should only be administered if deemed medically necessary, employing extreme caution and close supervision.
- ATIVAN should always be prescribed at the lowest effective dose for the shortest duration possible.
- All patients receiving benzodiazepines should be monitored for signs of misuse and abuse. If a substance use disorder is suspected, evaluate the patient and refer them for substance abuse treatment, as appropriate.
Withdrawal: Benzodiazepines, such as ATIVAN, can produce withdrawal signs and symptoms, ranging from mild to severe and even life threatening, following abrupt discontinuation or rapid dose reduction. Other factors that may precipitate withdrawal are switching from a long-acting to a short-acting benzodiazepine, decreasing blood levels of the drug or administration of an antagonist. The risk of withdrawal is higher with higher dosages and/or prolonged use, but can occur with short-term use (days to weeks) at recommended therapeutic doses.
The onset of withdrawal signs and symptoms can range from hours to weeks following drug cessation and occur even with tapered dosage. Some symptoms can persist for months. Since symptoms are often similar to those for which the patient is being treated, it may difficult to distinguish from a relapse of the patient’s condition.
Severe or life-threatening signs and symptoms of withdrawal include catatonia delirium tremens, depression, dissociative effects (e.g. hallucinations), mania, psychosis, seizures (including status epilepticus) and suicidal ideation and behavior have been observed.
Other withdrawal signs and symptoms include abdominal and muscle cramps, cognitive impairment, diarrhea, dysphoria, extreme anxiety or panic attacks, headache, hypersensitivity to light, noise and physical contact, insomnia, irritability, muscle pain or stiffness, paresthesia, restlessness, sweating, tension, tremors and vomiting. There is also a possibility of rebound anxiety or rebound insomnia.
- Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring.
- Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
- If a patient experiences withdrawal signs and symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
- Inform patients of risk of discontinuing abruptly, reducing dosage rapidly or switching medications.
- Stress the importance of consulting with their health care professional in order to discontinue safely.
- Patients experiencing withdrawal signs and symptoms should seek immediate medical attention.
(see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse, Withdrawal; 4 DOSAGE AND ADMINISTRATION, 4.1 Dosing Considerations)
Driving and Operating Machinery
Excessive sedation has been observed with lorazepam at standard therapeutic doses. Therefore, patients on ATIVAN should be warned against engaging in hazardous activities requiring mental alertness and motor coordination, such as operating dangerous machinery or driving motor vehicles.
As is true of other similar CNS-acting drugs, patients receiving lorazepam should not operate machinery or engage in hazardous occupations or drive a motor vehicle for a period of 24 to 48 hours. Impairment of performance may persist for greater intervals because of extremes of age, concomitant use of other drugs, stress of surgery or the general condition of the patient.
Falls and Fractures
There have been reports of falls and fractures among benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), geriatric or debilitated patients.
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 dyspnea, 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.
Since ATIVAN has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs.
ATIVAN is not recommended for use in depressive neurosis or in psychotic reactions.
Use in Mental and Emotional Disorders: ATIVAN is not recommended for the treatment of psychotic or depressed patients. Since excitement and other paradoxical reactions can result from the use of these drugs in psychotic patients, they should not be used in ambulatory patients suspected of having psychotic tendencies.
As with other anxiolytic-sedative drugs, lorazepam should not be used in patients with non-pathological anxiety. These drugs are also not effective in patients with characterological and personality disorders or those with obsessive-compulsive neurosis.
When using ATIVAN, it should be recognized that suicidal tendencies may be present and that protective measures may be required.
Pre-existing depression may emerge or worsen during use of benzodiazepines including lorazepam. The use of benzodiazepines may unmask suicidal tendencies in depressed patients and should not be used without adequate antidepressant therapy.
Use in Patients with Impaired Renal or Hepatic Function: Since the liver is the most likely site of conjugation of lorazepam and since excretion of conjugated lorazepam (glucuronide) is a renal function, the usual precaution of carefully titrating the dose should be taken, should ATIVAN be used in patients with mild to moderate hepatic or renal disease. In patients for whom prolonged therapy with ATIVAN is indicated, periodic blood counts and liver function tests should be carried out.
When lorazepam is used in patients with mild to moderate hepatic or renal disease, the lowest effective dose should be considered since drug effect may be prolonged.
Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response. Lower doses may be sufficient in such patients.
As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy.
Reproductive Health: Female and Male Potential
- Teratogenic Risk
Use in Pregnancy: ATIVAN should not be used during pregnancy. Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepines during pregnancy (see 16 NON-CLINICAL TOXICOLOGY).
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 hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, 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.
Since lorazepam is also a benzodiazepine derivative, its administration is rarely justified in women of child-bearing potential. If the drug is prescribed to a woman of child-bearing potential, she should be warned to contact her physician regarding discontinuation of the drug if she intends to become or suspects that she is pregnant.
In women, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. ATIVAN Injection should not be used during pregnancy. There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in caesarean section. Such use, therefore, is not recommended.
ATIVAN should be used with caution in patients with compromised respiratory function (e.g., COPD, sleep apnea syndrome).
7.1 Special Populations
7.1.1 Pregnant Women
ATIVAN should not be used during pregnancy.
Use in Nursing Mothers: Lorazepam has been detected in human breast milk; therefore it should not be administered to breastfeeding women, unless the expected benefit to the mother outweighs the potential risk to the infant.
Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability).
Use in Children: ATIVAN is not intended for use in children under 18 years of age. The safety and effectiveness of ATIVAN in children less than 18 years of age has not been established (see 16 NONCLINICAL TOXICOLOGY). Because of the lack of sufficient clinical experience, ATIVAN is not recommended for use in patients less than 18 years of age (see 7 WARNINGS AND PRECAUTIONS).
Paradoxical reactions have been occasionally reported during benzodiazepine use (See 8 ADVERSE REACTIONS). Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.
Geriatric patients and debilitated patients, or those with organic brain syndrome, have been found to be prone to CNS depression after even low doses of benzodiazepines. Therefore, medication should be initiated with very low initial doses in these patients, depending on the response of the patient, in order to avoid over sedation or neurological impairment.
As with any premedicant, extreme care must be used in administering ATIVAN to geriatric patients or very ill patients and to those with limited pulmonary reserve, because of the possibility that apnea and/or cardiac arrest may occur.
Clinical trials have shown that patients over the age of 50 years may have a more profound and prolonged sedation with intravenous lorazepam.
For geriatric patients and debilitated patients reduce the initial dose by approximately 50% and adjust the dosage as needed and tolerated.
Long-term use of ATIVAN should be avoided in geriatric patients or debilitated patients who may be more sensitive to benzodiazepines. There is an increased risk of cognitive impairment, delirium, falls, fractures, hospitalizations and motor vehicle accidents in these users. Enhanced monitoring is recommended in this population.