Lorafen (Tablets) Instructions for Use

Marketing Authorization Holder

Tarchomin Pharmaceutical Works Polfa, S.A. (Poland)

ATC Code

N05BA06 (Lorazepam)

Active Substance

Lorazepam (Rec.INN registered by WHO)

Dosage Forms

	Lorafen	Film-coated tablets, 1 mg: 25 pcs.
		Film-coated tablets, 2.5 mg: 25 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex.

Excipients: potato starch – 6 mg, sodium carboxymethyl starch – 0.1 mg, gelatin – 1.5 mg, talc – 1.8 mg, magnesium stearate – 1.2 mg, lactose monohydrate – 68.4 mg.

Coating composition: polyvinyl alcohol – 0.125 mg, talc – 7 mg, maltodextrin – 0.23 mg, sucrose – 22.5 mg, titanium dioxide – 0.18 mg, opaglos 6000 – q.s.

25 pcs. – blisters (1) – carton packs.

Film-coated tablets pink, round, biconvex.

Excipients: potato starch – 6 mg, sodium carboxymethyl starch – 0.5 mg, gelatin – 1.5 mg, talc – 1.8 mg, ponceau 4R dye – 0.00286 mg, magnesium stearate – 1.2 mg, lactose monohydrate – up to 80 mg.

Coating composition: polyvinyl alcohol – 0.125 mg, talc – 7 mg, maltodextrin – 0.23 mg, sucrose – 22.5 mg, ponceau 4R aluminum lake dye – 0.1 mg, titanium dioxide – 0.17 mg, opaglos 6000 – q.s.

25 pcs. – blisters (1) – carton packs.

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Anxiolytic agent

Pharmacological Action

Anxiolytic agent (tranquilizer), a benzodiazepine derivative. It has anxiolytic, sedative, hypnotic, anticonvulsant, central muscle relaxant, and antiemetic effects. The mechanism of anxiolytic, sedative, and hypnotic action is associated with the enhancement of GABA’s inhibitory influence in the CNS.

The anticonvulsant effect is apparently partly due to the enhancement of presynaptic inhibition; it suppresses the spread of epileptogenic activity arising in epileptogenic foci in the cortex, thalamus, and limbic structures, but does not relieve the excited state of the focus.

The muscle relaxant effect is primarily associated with the suppression of spinal polysynaptic afferent pathways and, apparently, the inhibition of monosynaptic afferent pathways; a direct inhibitory effect on motor nerves and muscle function is also possible.

Pharmacokinetics

When taken orally, Lorazepam is well absorbed from the gastrointestinal tract, bioavailability is about 90%. Plasma protein binding is about 85%. C_max is reached in approximately 2 hours. V_d is 1.3 L/kg.

Lorazepam is metabolized in the liver by conjugation to form inactive metabolites. It penetrates the blood-brain barrier and the placental barrier. It is excreted in breast milk. T_1/2 is about 12 hours. It is excreted mainly by the kidneys.

Indications

Neurotic and neurosis-like conditions occurring with anxiety, irritability, increased fatigue, sleep disorders, autonomic disorders; alcohol withdrawal syndrome (as part of complex therapy); hypertonicity of skeletal muscles of various origins; premedication (preparation for long-term diagnostic procedures and surgeries).

ICD codes

Dosage Regimen

Administer orally. The dosage regimen is individualized based on indication, clinical response, and patient age.

For anxiety disorders in adults, initiate with a total daily dose of 1 mg to 3 mg, administered in two or three divided doses.

For insomnia associated with anxiety, administer a single dose of 1 mg to 2 mg at bedtime.

For premedication, administer a single dose of 2 mg to 4 mg the evening before surgery and a single dose of 2 mg to 4 mg one to two hours prior to the procedure.

For alcohol withdrawal, initiate with a total daily dose of 2 mg to 6 mg in divided doses.

For elderly or debilitated patients, initiate therapy at a lower dose of 0.5 mg to 1 mg daily in divided doses. Adjust the dose cautiously based on response and tolerance.

The maximum recommended daily dose is 10 mg.

Adjust the dose gradually in small increments. Titrate to the lowest effective dose for the shortest necessary duration.

Do not abruptly discontinue therapy after prolonged use. Taper the dose gradually to minimize the risk of withdrawal symptoms.

Monitor patients for signs of tolerance or dependence, particularly those with a history of substance abuse.

Adverse Reactions

From the nervous system (especially in elderly patients) frequent – drowsiness, increased fatigue, dizziness, decreased ability to concentrate, ataxia (unsteady gait and poor coordination of movements leading to loss of balance), disorientation, lethargy, muscle atony, emotional blunting, slowing of mental and motor reactions; infrequent – headache, euphoria, depression, tremor, depressed mood, catalepsy, amnesia, confusion, dystonic extrapyramidal reactions (uncontrolled body movements, including eyes), myasthenia during the day, dysarthria; very rare – paradoxical reactions (aggressive outbursts, fear, suicidal tendency, muscle spasm, confusion, hallucinations, acute agitation, irritability, anxiety, insomnia).

From the organ of vision infrequent – visual impairment (diplopia).

From the hematopoietic system infrequent – leukopenia, neutropenia, agranulocytosis (chills, hyperthermia, sore throat, excessive fatigue, or weakness), anemia, thrombocytopenia.

From the digestive system frequent – dryness of the oral mucosa or salivation; infrequent – heartburn, nausea and/or vomiting, decreased appetite, constipation or diarrhea; impaired liver function, increased activity of hepatic transaminases, LDH and ALP, jaundice.

From the urinary system rare – urinary incontinence, urinary retention, impaired renal function.

From the reproductive system rare – impaired or decreased libido, dysmenorrhea.

Allergic reactions skin rash (including erythema, urticaria), itching; very rare – anaphylactic reactions.

Effect on the fetus teratogenicity, respiratory depression and suppression of the sucking reflex in newborns whose mothers used Lorazepam.

Other habituation, drug dependence, decreased BP; rare – respiratory center depression, bulimia, weight loss, tachycardia; very rare – angioedema, inappropriate secretion of antidiuretic hormone.

With a sharp dose reduction or discontinuation of use, a withdrawal syndrome may develop (irritability, headache, anxiety, agitation, excitement, feeling of fear, nervousness, sleep disorders, dysphoria, spasm of smooth muscles of internal organs and skeletal muscles, myalgia, depersonalization, perspiration, increased sweating, depression, nausea, vomiting, tremor, perception disorders, including hyperacusis, paresthesia, photophobia, tachycardia, convulsions, hallucinations, rarely – acute psychosis).

Contraindications

Hypersensitivity to lorazepam and other 1,4-benzodiazepine derivatives; severe respiratory failure, regardless of cause; severe hepatic and/or renal failure; myasthenia gravis; glaucoma; acute porphyria; alcohol poisoning; sleep apnea syndrome; children under 12 years of age (safety and efficacy not established).

With caution mild to moderate hepatic and/or renal failure, chronic respiratory failure, porphyria, depression, history of suicidal thoughts and attempts, history of drug, narcotic or alcohol dependence, cerebral and spinal ataxia, hyperkinesis, organic brain diseases, hypoproteinemia, elderly age.

Use in Pregnancy and Lactation

The use of lorazepam in pregnant women is allowed only if its use in the mother has absolute indications, and the use of a safer, alternative agent is impossible.

Lorazepam is excreted in breast milk. During treatment, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment. Use with caution in mild to moderate hepatic impairment. The dose is selected individually, depending on the degree of hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal impairment. Use with caution in mild to moderate renal impairment. The dose is selected individually, depending on the degree of renal impairment.

Pediatric Use

Contraindicated for use in children under 12 years of age (safety and efficacy not established);

Geriatric Use

Should be used with caution in elderly patients, due to the increased incidence of adverse events in this age group, mainly impaired orientation and coordination of movements, which can lead to loss of balance. When using lorazepam in elderly patients, it is recommended to prescribe the lowest effective dose possible.

Special Precautions

Lorazepam should be used strictly as prescribed by a doctor to avoid complications. States of mental tension and anxiety associated with everyday problems are not an indication for the use of lorazepam.

Lorazepam must be used under strict medical supervision.

It is not recommended to use Lorazepam in patients with psychoses. Use with particular caution in suspected angle-closure glaucoma, severe chronic obstructive pulmonary diseases, in comatose state, shock, epilepsy, impaired renal function, hyperkinesis, hypoproteinemia, severe depression, organic brain diseases, porphyria, psychoses, suspected sleep apnea. In case of impaired liver function, a minimal increase in the T_1/2 of lorazepam is observed.

If after 7-14 days of using lorazepam there is no relief of disease symptoms or a relapse occurs, the patient should consult a doctor.

The development of adverse reactions is more likely at the beginning of treatment and in cases of exceeding recommended doses.

With long-term use of lorazepam, the development of habituation and drug dependence is possible. In case of drug dependence development, abrupt discontinuation of lorazepam use can lead to the appearance of withdrawal syndrome.

Characteristic manifestations of withdrawal syndrome are: headache, increased irritability, muscle pain, psychomotor agitation and emotional tension, motor restlessness, confusion and disorientation, sleep disturbance. In severe cases, the following may appear: loss of the sense of reality of the surroundings (derealization), personality disorders (depersonalization), increased sensitivity to touch (tactile hyperesthesia), increased sensitivity to auditory and visual stimuli (acoustic and light hyperesthesia), sensation of “crawling” and numbness of the extremities, hallucinations or seizures. Abrupt discontinuation of long-term treatment during which Lorazepam was used in doses exceeding average ones can be especially dangerous. In this case, the manifestations of withdrawal syndrome are more pronounced.

There is evidence that with the use of short-acting benzodiazepines and benzodiazepine-like drugs, manifestations of withdrawal syndrome can be observed even in the intervals between individual doses, especially if the drug is used in large doses.

After the end of treatment, a temporary relapse of symptoms may occur to a more pronounced degree than those that were the reason for the initial treatment (so-called “rebound” insomnia). These symptoms are often accompanied by mood changes, fear, anxiety, increased motor activity. The likelihood of developing withdrawal syndrome or the appearance of “rebound” insomnia increases with abrupt discontinuation of lorazepam.

Lorazepam, like benzodiazepines and similar-acting drugs, can cause paradoxical reactions, such as psychomotor agitation, increased irritability, aggressiveness, nightmares, hallucinations, psychoses, somnambulism, depersonalization disorders, pronounced sleep disturbance and other behavioral side effects. These reactions are observed significantly more often in elderly patients.

If such symptoms appear, it is necessary to immediately discontinue treatment with lorazepam.

Lorazepam should be used with great caution in elderly patients (over 65 years of age), due to the increased incidence of adverse events in this age group, mainly impaired orientation and coordination of movements, which can lead to loss of balance.

Gradual reduction of the lorazepam dose is recommended in order to minimize the risk of such symptoms.

Lorazepam should be used with caution in patients with chronic respiratory failure, as it has been established that benzodiazepines have a depressant effect on the respiratory center.

Lorazepam should be used with caution in patients with symptoms of depression. These patients may develop suicidal thoughts. Due to the possibility of intentional overdose, these patients should be prescribed Lorazepam in the smallest possible doses. Also, benzodiazepines and similar-acting drugs should not be used as the sole drug for the treatment of depression or anxiety associated with depression. Monotherapy with these drugs may enhance suicidal tendencies. Benzodiazepines and similar-acting drugs must be used with great caution in patients with a history of alcohol, narcotic or drug dependence. These patients, while taking lorazepam, should be under strict medical supervision, as they are at risk of developing habituation, mental and physical dependence.

Lorazepam should be used with caution in patients with a non-acute form of porphyria. The use of lorazepam may lead to an exacerbation of the symptoms of this disease.

During prolonged therapy with lorazepam, periodic blood tests (morphological analysis with smear) and urine analysis are indicated.

During treatment with lorazepam and for 3 days after its completion, no alcoholic beverages should be consumed.

In case of using lorazepam for premedication, it may be necessary to reduce the dose of fentanyl derivatives used for induction anesthesia, and it is possible to reduce the time to loss of consciousness with induction doses.

Effect on the ability to drive vehicles and machinery

Patients taking Lorazepam should refrain from engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Drug Interactions

The depressant effect of lorazepam on the CNS is enhanced by opioid analgesics, general anesthetics, psychotropic drugs, antidepressants, antihistamines, centrally acting antihypertensive drugs.

Consumption of alcohol during treatment with lorazepam enhances the depressant effect on the CNS and can lead to the development of paradoxical reactions, such as psychomotor agitation, aggressive behavior. In addition, alcohol can enhance the sedative effect of lorazepam, up to coma.

Lorazepam, when used concomitantly with other agents having a muscle relaxant effect, prolongs and enhances the effect of the latter. Disulfiram, cimetidine, erythromycin, ketoconazole, being inhibitors of cytochrome P450 isoenzymes, inhibit the biotransformation processes of 1,4-benzodiazepine derivatives and enhance their depressant effect on the CNS. Drugs that induce the activity of cytochrome P450 (e.g., rifampicin, phenobarbital, phenytoin, carbamazepine) affect the biotransformation processes of 1,4-benzodiazepine derivatives and lead to a weakening of their pharmacological action.

Theophylline and caffeine can weaken the hypnotic effect of benzodiazepines, including lorazepam, because they have a stimulating effect on the CNS and are able to induce liver enzymes responsible for drug metabolism. This effect caused by theophylline and caffeine may be absent in smokers.

Oral contraceptive agents used simultaneously with lorazepam may enhance its metabolism, the T_1/2 of lorazepam may decrease.

Concomitant use of lorazepam with valproic acid derivatives leads to an increase in plasma concentration and a decrease in the clearance of lorazepam. The effect of valproate on Lorazepam may be caused by inhibition of lorazepam glucuronidation.

MAO inhibitors inhibit the metabolism of lorazepam with an increase in its action and the development of severe side effects.

St. John’s wort reduces the pharmacological activity of lorazepam.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.