استطباب: Anticonvulsant, Anti-anxiety with sedating effect .

COMPOSITION :

Each tablet contains:

• Active Ingredient: Diazepam 2 mg, 5 mg or 10 mg.
• Inactive Ingredient: Calcium stearate, Anhydrous Lactose, pregelatinized Starch, Corn Starch.

Excipients:

CLINICAL PHARMACOLOGY:Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of – these effects are thought to result from a facilitation of the …Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the …

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system.

Pharmacokinetics:

Absorption

After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting.

Distribution

Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). Diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours.

Metabolism

Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation.

Elimination

Half-life up to 48 hours: The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life is slightly prolonged.

Pharmacokinetics in Special Populations

Children

In children 3 – 8 years old the mean half-life of diazepam has been reported to be 18 hours.

Newborns

In full term infants, elimination half-lives around 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 – 34 weeks gestational age and 8 – 81 days post-partum. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways.

Geriatric

Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance.

Hepatic Insufficiency

In mild and moderate cirrhosis, average half-life is increased. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also prolonged with hepatic fibrosis to 90 hours, with chronic active hepatitis to 60 hours, and with acute viral hepatitis to 74 hours. In chronic active hepatitis, clearance is decreased by almost half.

INDICATIONS

-Valium is indicated for the management of anxiety – disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually …

Valium is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually …

DiaManagement of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

-In acute alcohol withdrawal,  Diazepam  may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.

-Diazepam  is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome.

Oral  Diazepam  may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.

The effectiveness of  Diazepam  in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Valium is contraindicated in patients with a known – hypersensitivity to diazepam and, because of lack of sufficient clinical – experience, in pediatric patients under 6 months of age. Valium …

Valium is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Valium is …

Diazepam  is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age.  Diazepam  is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma.

WARNINGS

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect …

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect …

Diazepam  is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.

Since  Diazepam  has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during  Diazepam  therapy.

As with other agents that have anticonvulsant activity, when  Diazepam  is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of  Diazepam  in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.

Pregnancy: Category D

In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.

Labor and Delivery

Special care must be taken when  Diazepam  is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates.

Nursing Mothers

Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving  Diazepam .

PRECAUTIONS

General If Valium is to be combined with other psychotropic – agents or anticonvulsant drugs, careful consideration should be given to – the pharmacology of the agents to …

General If Valium is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be …

If  Diazepam  is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed – particularly with known compounds that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary.

Psychiatric and paradoxical reactions are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly.

A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated).

Some loss of response to the effects of benzodiazepines may develop after repeated use of  Diazepam  for a prolonged time.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 months have not been established.

Geriatric Use

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated).

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Insufficiency

Decreases in clearance and protein binding, and increases in volume of distribution and half-life have been reported in patients with cirrhosis. In such patients, a 2- to 5- fold increase in mean half-life has been reported. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis.

Benzodiazepines are commonly implicated in hepatic encephalopathy.

Information for Patients

To assure the safe and effective use of benzodiazepines, 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. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during  Diazepam  therapy. As is true of most CNS-acting drugs, patients receiving  Diazepam  should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Drug Interactions

Centrally Acting Agents

If  Diazepam  is to be combined with other centrally acting agents careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of  Diazepam , such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

Alcohol

Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.

Antacids

Diazepam peak concentrations are 30% lower when antacids are administered concurrently.

Compounds Which Inhibit Certain Hepatic Enzymes

There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole.

Phenytoin

There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.

ADVERSE REACTIONS:

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been – reported: Central Nervous System: confusion …

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported: Central Nervous System: confusion …

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported:

Central Nervous System:

Confusion, depression, headache, slurred speech, tremor, vertigo, dysarthria.

Gastrointestinal System:

Constipation, nausea, gastrointestinal disturbances

Special Senses:

Blurred vision, diplopia, dizziness

Cardiovascular System:

Hypotension

Psychiatric and Paradoxical Reactions:

Stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.

Urogenital System:

incontinence, changes in libido, urinary retention:

Skin:

Skin reactions

Laboratories:

elevated transaminases and alkaline phosphatase.

Other: changes in salivation, including dry mouth, hypersalivation.

DRUG ABUSE AND DEPENDENCE:

Diazepam is subject to Schedule IV control under the – Controlled Substances Act of 1970. Abuse and dependence of – benzodiazepines have been reported. Addiction-prone individuals (such as …

Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. Addiction-prone individuals (such as …

Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.

OVERDOSAGE:

Overdose of benzodiazepines is usually manifested by – central nervous system depression ranging from drowsiness to coma. In – mild cases, symptoms include drowsiness, confusion, and lethargy …

Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy …

Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy. In more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely). Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored.

Management of over dosage

Following overdose with oral benzodiazepines, general – supportive measures should be employed including the monitoring of – respiration, pulse, and blood pressure. Vomiting should be induced …

Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced …

Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced (within 1 hour) if the patient is conscious. Gastric lavage should be undertaken with the airway protected if the patient is unconscious. Intravenous fluids should be administered. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiac function in intensive care. General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected.

DOSAGE AND ADMINISTRATION:

Dosage should be individualized for maximum – beneficial effect. While the usual daily dosages given below will meet – the needs of most patients, there will be some who may require higher …

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher …

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects:

 

ADULTS:	USUAL DAILY DOSE:
Management of Anxiety Disorders and Relief of Symptoms of Anxiety.	Depending upon severity of symptoms—2 mg to 10 mg, 2 to 4 times daily
Symptomatic Relief in Acute Alcohol Withdrawal.	10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed
Adjunctively for Relief of Skeletal Muscle Spasm.	2 mg to 10 mg, 3 or 4 times daily
Adjunctively in Convulsive Disorders.	2 mg to 10 mg, 2 to 4 times daily
Geriatric Patients,or in the presence of debilitating disease.	2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated
PEDIATRIC PATIENTS:
Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in pediatric patients under 6 months.	1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated

PACKAGE: Each box of  Dialin 2, 5, 10 mg contains 20 tablets (2 blisters ,each blister  has 10 tablets ).

STORAGE: Store at room temperature ( 15-30)° C. Protect from light.

COMPOSITION :

Each tablet contains:

• Active Ingredient: Diazepam 2 mg, 5 mg or 10 mg.
• Inactive Ingredient: Calcium stearate, Anhydrous Lactose, pregelatinized Starch, Corn Starch.

Excipients:

CLINICAL PHARMACOLOGY:Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of – these effects are thought to result from a facilitation of the …Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the …

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system.

Pharmacokinetics:

Absorption

After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting.

Distribution

Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). Diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours.

Metabolism

Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation.

Elimination

Half-life up to 48 hours: The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life is slightly prolonged.

Pharmacokinetics in Special Populations

Children

In children 3 – 8 years old the mean half-life of diazepam has been reported to be 18 hours.

Newborns

In full term infants, elimination half-lives around 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 – 34 weeks gestational age and 8 – 81 days post-partum. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways.

Geriatric

Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance.

Hepatic Insufficiency

In mild and moderate cirrhosis, average half-life is increased. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also prolonged with hepatic fibrosis to 90 hours, with chronic active hepatitis to 60 hours, and with acute viral hepatitis to 74 hours. In chronic active hepatitis, clearance is decreased by almost half.

INDICATIONS

-Valium is indicated for the management of anxiety – disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually …

Valium is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually …

DiaManagement of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

-In acute alcohol withdrawal,  Diazepam  may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.

-Diazepam  is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome.

Oral  Diazepam  may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.

The effectiveness of  Diazepam  in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Valium is contraindicated in patients with a known – hypersensitivity to diazepam and, because of lack of sufficient clinical – experience, in pediatric patients under 6 months of age. Valium …

Valium is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Valium is …

Diazepam  is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age.  Diazepam  is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma.

WARNINGS

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect …

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect …

Diazepam  is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.

Since  Diazepam  has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during  Diazepam  therapy.

As with other agents that have anticonvulsant activity, when  Diazepam  is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of  Diazepam  in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.

Pregnancy: Category D

In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.

Labor and Delivery

Special care must be taken when  Diazepam  is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates.

Nursing Mothers

Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving  Diazepam .

PRECAUTIONS

General If Valium is to be combined with other psychotropic – agents or anticonvulsant drugs, careful consideration should be given to – the pharmacology of the agents to …

General If Valium is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be …

If  Diazepam  is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed – particularly with known compounds that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary.

Psychiatric and paradoxical reactions are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly.

A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated).

Some loss of response to the effects of benzodiazepines may develop after repeated use of  Diazepam  for a prolonged time.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 months have not been established.

Geriatric Use

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated).

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Insufficiency

Decreases in clearance and protein binding, and increases in volume of distribution and half-life have been reported in patients with cirrhosis. In such patients, a 2- to 5- fold increase in mean half-life has been reported. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis.

Benzodiazepines are commonly implicated in hepatic encephalopathy.

Information for Patients

To assure the safe and effective use of benzodiazepines, 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. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during  Diazepam  therapy. As is true of most CNS-acting drugs, patients receiving  Diazepam  should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Drug Interactions

Centrally Acting Agents

If  Diazepam  is to be combined with other centrally acting agents careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of  Diazepam , such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

Alcohol

Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.

Antacids

Diazepam peak concentrations are 30% lower when antacids are administered concurrently.

Compounds Which Inhibit Certain Hepatic Enzymes

There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole.

Phenytoin

There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.

ADVERSE REACTIONS:

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been – reported: Central Nervous System: confusion …

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported: Central Nervous System: confusion …

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported:

Central Nervous System:

Confusion, depression, headache, slurred speech, tremor, vertigo, dysarthria.

Gastrointestinal System:

Constipation, nausea, gastrointestinal disturbances

Special Senses:

Blurred vision, diplopia, dizziness

Cardiovascular System:

Hypotension

Psychiatric and Paradoxical Reactions:

Stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.

Urogenital System:

incontinence, changes in libido, urinary retention:

Skin:

Skin reactions

Laboratories:

elevated transaminases and alkaline phosphatase.

Other: changes in salivation, including dry mouth, hypersalivation.

DRUG ABUSE AND DEPENDENCE:

Diazepam is subject to Schedule IV control under the – Controlled Substances Act of 1970. Abuse and dependence of – benzodiazepines have been reported. Addiction-prone individuals (such as …

Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. Addiction-prone individuals (such as …

Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.

OVERDOSAGE:

Overdose of benzodiazepines is usually manifested by – central nervous system depression ranging from drowsiness to coma. In – mild cases, symptoms include drowsiness, confusion, and lethargy …

Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy …

Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy. In more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely). Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored.

Management of over dosage

Following overdose with oral benzodiazepines, general – supportive measures should be employed including the monitoring of – respiration, pulse, and blood pressure. Vomiting should be induced …

Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced …

Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced (within 1 hour) if the patient is conscious. Gastric lavage should be undertaken with the airway protected if the patient is unconscious. Intravenous fluids should be administered. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiac function in intensive care. General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected.

DOSAGE AND ADMINISTRATION:

Dosage should be individualized for maximum – beneficial effect. While the usual daily dosages given below will meet – the needs of most patients, there will be some who may require higher …

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher …

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects:

 

ADULTS:	USUAL DAILY DOSE:
Management of Anxiety Disorders and Relief of Symptoms of Anxiety.	Depending upon severity of symptoms—2 mg to 10 mg, 2 to 4 times daily
Symptomatic Relief in Acute Alcohol Withdrawal.	10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed
Adjunctively for Relief of Skeletal Muscle Spasm.	2 mg to 10 mg, 3 or 4 times daily
Adjunctively in Convulsive Disorders.	2 mg to 10 mg, 2 to 4 times daily
Geriatric Patients,or in the presence of debilitating disease.	2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated
PEDIATRIC PATIENTS:
Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in pediatric patients under 6 months.	1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated

PACKAGE: Each box of  Dialin 2, 5, 10 mg contains 20 tablets (2 blisters ,each blister  has 10 tablets ).

STORAGE: Store at room temperature ( 15-30)° C. Protect from light.

COMPOSITION :

Each tablet contains:

• Active Ingredient: Diazepam 2 mg, 5 mg or 10 mg.
• Inactive Ingredient: Calcium stearate, Anhydrous Lactose, pregelatinized Starch, Corn Starch.

Excipients:

CLINICAL PHARMACOLOGY:Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of – these effects are thought to result from a facilitation of the …Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the …

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system.

Pharmacokinetics:

Absorption

After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting.

Distribution

Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). Diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours.

Metabolism

Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation.

Elimination

Half-life up to 48 hours: The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life is slightly prolonged.

Pharmacokinetics in Special Populations

Children

In children 3 – 8 years old the mean half-life of diazepam has been reported to be 18 hours.

Newborns

In full term infants, elimination half-lives around 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 – 34 weeks gestational age and 8 – 81 days post-partum. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways.

Geriatric

Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance.

Hepatic Insufficiency

In mild and moderate cirrhosis, average half-life is increased. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also prolonged with hepatic fibrosis to 90 hours, with chronic active hepatitis to 60 hours, and with acute viral hepatitis to 74 hours. In chronic active hepatitis, clearance is decreased by almost half.

INDICATIONS

-Valium is indicated for the management of anxiety – disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually …

Valium is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually …

DiaManagement of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

-In acute alcohol withdrawal,  Diazepam  may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.

-Diazepam  is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome.

Oral  Diazepam  may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.

The effectiveness of  Diazepam  in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Valium is contraindicated in patients with a known – hypersensitivity to diazepam and, because of lack of sufficient clinical – experience, in pediatric patients under 6 months of age. Valium …

Valium is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Valium is …

Diazepam  is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age.  Diazepam  is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma.

WARNINGS

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect …

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect …

Diazepam  is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.

Since  Diazepam  has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during  Diazepam  therapy.

As with other agents that have anticonvulsant activity, when  Diazepam  is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of  Diazepam  in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.

Pregnancy: Category D

In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.

Labor and Delivery

Special care must be taken when  Diazepam  is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates.

Nursing Mothers

Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving  Diazepam .

PRECAUTIONS

General If Valium is to be combined with other psychotropic – agents or anticonvulsant drugs, careful consideration should be given to – the pharmacology of the agents to …

General If Valium is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be …

If  Diazepam  is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed – particularly with known compounds that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary.

Psychiatric and paradoxical reactions are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly.

A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated).

Some loss of response to the effects of benzodiazepines may develop after repeated use of  Diazepam  for a prolonged time.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 months have not been established.

Geriatric Use

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated).

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Insufficiency

Decreases in clearance and protein binding, and increases in volume of distribution and half-life have been reported in patients with cirrhosis. In such patients, a 2- to 5- fold increase in mean half-life has been reported. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis.

Benzodiazepines are commonly implicated in hepatic encephalopathy.

Information for Patients

To assure the safe and effective use of benzodiazepines, 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. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during  Diazepam  therapy. As is true of most CNS-acting drugs, patients receiving  Diazepam  should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Drug Interactions

Centrally Acting Agents

If  Diazepam  is to be combined with other centrally acting agents careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of  Diazepam , such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

Alcohol

Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.

Antacids

Diazepam peak concentrations are 30% lower when antacids are administered concurrently.

Compounds Which Inhibit Certain Hepatic Enzymes

There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole.

Phenytoin

There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.

ADVERSE REACTIONS:

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been – reported: Central Nervous System: confusion …

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported: Central Nervous System: confusion …

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported:

Central Nervous System:

Confusion, depression, headache, slurred speech, tremor, vertigo, dysarthria.

Gastrointestinal System:

Constipation, nausea, gastrointestinal disturbances

Special Senses:

Blurred vision, diplopia, dizziness

Cardiovascular System:

Hypotension

Psychiatric and Paradoxical Reactions:

Stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.

Urogenital System:

incontinence, changes in libido, urinary retention:

Skin:

Skin reactions

Laboratories:

elevated transaminases and alkaline phosphatase.

Other: changes in salivation, including dry mouth, hypersalivation.

DRUG ABUSE AND DEPENDENCE:

Diazepam is subject to Schedule IV control under the – Controlled Substances Act of 1970. Abuse and dependence of – benzodiazepines have been reported. Addiction-prone individuals (such as …

Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. Addiction-prone individuals (such as …

Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.

OVERDOSAGE:

Overdose of benzodiazepines is usually manifested by – central nervous system depression ranging from drowsiness to coma. In – mild cases, symptoms include drowsiness, confusion, and lethargy …

Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy …

Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy. In more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely). Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored.

Management of over dosage

Following overdose with oral benzodiazepines, general – supportive measures should be employed including the monitoring of – respiration, pulse, and blood pressure. Vomiting should be induced …

Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced …

Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced (within 1 hour) if the patient is conscious. Gastric lavage should be undertaken with the airway protected if the patient is unconscious. Intravenous fluids should be administered. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiac function in intensive care. General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected.

DOSAGE AND ADMINISTRATION:

Dosage should be individualized for maximum – beneficial effect. While the usual daily dosages given below will meet – the needs of most patients, there will be some who may require higher …

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher …

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects:

 

ADULTS:	USUAL DAILY DOSE:
Management of Anxiety Disorders and Relief of Symptoms of Anxiety.	Depending upon severity of symptoms—2 mg to 10 mg, 2 to 4 times daily
Symptomatic Relief in Acute Alcohol Withdrawal.	10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed
Adjunctively for Relief of Skeletal Muscle Spasm.	2 mg to 10 mg, 3 or 4 times daily
Adjunctively in Convulsive Disorders.	2 mg to 10 mg, 2 to 4 times daily
Geriatric Patients,or in the presence of debilitating disease.	2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated
PEDIATRIC PATIENTS:
Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in pediatric patients under 6 months.	1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated

PACKAGE: Each box of  Dialin 2, 5, 10 mg contains 20 tablets (2 blisters ,each blister  has 10 tablets ).

STORAGE: Store at room temperature ( 15-30)° C. Protect from light.