Lorazepam Intensol

Lorazepam is used to relieve anxiety. Lorazepam is in a class of medications called benzodiazepines. It works by slowing activity in the brain to allow for relaxation.

In the U.S.

• Ativan
• Lorazepam Intensol

Available Dosage Forms:

• Tablet
• Solution

Therapeutic Class: Antianxiety

Pharmacologic Class: Benzodiazepine, Short or Intermediate Acting

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of lorazepam in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lorazepam in the elderly. However, elderly patients are more likely to have unwanted effects (eg, severe drowsiness or unsteadiness) and age-related kidney or liver problems, which may require caution and an adjustment in the dose.

Pregnancy

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Amobarbital
• Bromazepam
• Bromopride
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Carbinoxamine
• Carisoprodol
• Chloral Hydrate
• Chlorzoxazone
• Codeine
• Dantrolene
• Dezocine
• Diacetylmorphine
• Difenoxin
• Dihydrocodeine
• Diphenoxylate
• Doxylamine
• Ethchlorvynol
• Ethylmorphine
• Fentanyl
• Flibanserin
• Fospropofol
• Hydrocodone
• Hydromorphone
• Ketobemidone
• Levorphanol
• Meclizine
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Meptazinol
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nicomorphine
• Opium
• Opium Alkaloids
• Orlistat
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Piritramide
• Primidone
• Propofol
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Thiopental
• Tilidine
• Tramadol
• Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Posaconazole
• Probenecid
• Pyrimethamine
• St John's Wort
• Theophylline
• Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse or
• Drug abuse or dependence or
• Lung or breathing problems (eg, COPD, sleep apnea) or
• Seizures, or history of—Use with caution. May make these conditions worse.

• Depression or
• Psychosis—Use is not recommended in patients with these conditions.

• Glaucoma, acute narrow-angle—Should not be used in patients with this condition.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Drowsiness
• relaxed and calm
• sleepiness

• Abdominal or stomach pain
• aggressive, angry
• agitation
• attack, assault, or force
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• bluish lips or skin
• blurred vision
• change in consciousness
• chills
• coma
• confusion
• confusion about identity, place, and time
• convulsions
• cough or hoarseness
• dark urine
• decreased urine output
• difficulty with breathing or swallowing
• difficulty with speaking
• discouragement
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drooling
• dry mouth
• excitation
• false or unusual sense of well-being
• fast or irregular heartbeat
• feeling sad or empty
• fever with or without chills
• general feeling of tiredness or weakness
• headache
• hives, itching, or rash
• hyperventilation
• increased thirst
• irregular, fast or slow, or shallow breathing
• irritability
• loss of appetite
• loss of balance control
• loss of consciousness
• loss of interest or pleasure
• loss of memory
• lower back or side pain
• muscle pain or cramps
• muscle trembling, jerking, or stiffness
• nausea or vomiting
• not breathing
• painful or difficult urination
• pale or blue lips, fingernails, or skin
• pinpoint red spots on the skin
• problems with memory
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• reddening of the skin, especially around ears
• restlessness
• seeing, hearing, or feeling things that are not there
• seizures
• shaking
• shuffling walk
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stiffness of the limbs
• sweating
• swelling of the eyes or inside of the nose
• swelling of the face, ankles, or hands
• swollen glands
• thoughts or attempts at killing oneself
• tightness in the chest
• trouble concentrating
• trouble sleeping
• twisting movements of body
• uncontrolled movements, especially of the face, neck, and back
• unexplained bleeding or bruising
• unpleasant breath odor
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

• Changes in patterns and rhythms of speech
• increased sweating
• loss of strength or energy
• nightmares
• shakiness and unsteady walk
• slurred speech
• trouble speaking
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusual excitement, nervousness, restlessness, or irritability
• unusual paleness
• unusual weak feeling

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Being forgetful
• clumsiness
• constipation
• decreased interest in sexual intercourse
• disturbed color perception
• dizziness or lightheadedness
• double vision
• drowsiness
• feeling of constant movement of self or surroundings
• hair loss or thinning of the hair
• halos around lights
• inability to have or keep an erection
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• lack or loss of self-control
• lethargy
• loss in sexual ability, desire, drive, or performance
• muscle aches, twitching, or weakness
• night blindness
• overbright appearance of lights
• rapid weight gain
• sensation of spinning
• shakiness in the legs, arms, hands, or feet
• shivering
• stupor
• trembling or shaking of the hands or feet
• tunnel vision
• weak or feeble pulse

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Studies in healthy volunteers show that in single high doses lorazepam has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems.

Lorazepam is readily absorbed with an absolute bioavailability of 90 percent. Peak concentrations in plasma occur approximately two hours following administration. The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL.

The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins. Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable CNS activity in animals.

The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months.

Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam. However, in one study involving single intravenous doses of 1.5 mg to 3 mg of lorazepam injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age.

In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate antidepressant therapy.

Lorazepam should be used with caution in patients with compromised respiratory function (e.g. COPD, sleep apnea syndrome).

Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg.

Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.

The usual precautions for treating patients with impaired renal and hepatic function should be observed. 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. Dosage for patients with severe hepatic insufficiency should be adjusted carefully according to patient response; lower doses may be sufficient in such patients.

In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component.

Esophageal dilation occurred in rats treated with lorazepam for more than one year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day (approximately 6 times the maximum human therapeutic dose of 10 mg per day). The effect was reversible only when the treatment was withdrawn within two months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper G.I. disease.

Safety and effectiveness of lorazepam in children of less than 12 years have not been established.

Information for Patients

To assure the safe and effective use of lorazepam, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.

Essential Laboratory Tests

Some patients on lorazepam have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver-function tests are recommended for patients on long-term therapy.

Clinically Significant Drug Interactions

The benzodiazepines, including lorazepam, produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics.

Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest.

Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when co-administered with valproate.

Concurrent administration of lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when co-administered with probenecid.

The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation.

Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

Carcinogenesis and Mutagenesis

No evidence of carcinogenic potential emerged in rats during an 18-month study with lorazepam. No studies regarding mutagenesis have been performed.

Pregnancy

Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses.

The clinical significance of the above findings is not known. However, an increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because the use of these drugs is rarely a matter of urgency, the use of lorazepam during this period should be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.

In humans, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. 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.

Nursing Mothers

Lorazepam has been detected in human breast milk; therefore, it should not be administered to breast-feeding women, unless the expected benefit to the woman 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).

Geriatric Use

Clinical studies of lorazepam generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age (see ADVERSE REACTIONS).

Age does not appear to have a significant effect on lorazepam kinetics (see CLINICAL PHARMACOLOGY).

Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity (e.g., sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, and lower doses may be sufficient in these patients (see DOSAGE AND ADMINISTRATION).

Lorazepam Intensol™ Oral Concentrate USP

The 2 mg per mL oral concentrate is supplied as a clear colorless solution.

NDC 0054-3532-44: Bottle of 30 mL with calibrated dropper (graduations of 0.25 mL [0.5 mg], 0.5 mL [1 mg], 0.75 mL 1.5 [mg] and 1 mL [2 mg] on the dropper).