Tuesday, 1 December 2015

Generic Diazepam 5mg

Product Description
Diazepam (daɪˈæzɨpæm/), first marketed as Valium (ˈvæliəm/) by Hoffmann-La Roche, is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex.



It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms (such as in cases of tetanus), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal and Ménière's disease. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties.The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the GABAA receptor (via the constituent chlorine atom) leading to central nervous system depression  Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation as well as paradoxical effects such as excitement, rage or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen depression.

Long-term effects of benzodiazepines such as diazepam include tolerance, benzodiazepine dependence as well as a benzodiazepine withdrawal syndrome upon dose reduction; additionally after cessation of benzodiazepines cognitive deficits may persist for at least 6 months and may not fully return to normal, however it was suggested that longer than 6 months may be needed for recovery from some deficits.Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long term use. However, compared to other benzodiazepines, physical withdrawal from diazepam following long term use is usually far more mild due to its long elimination half life. Nevertheless, urgent action by National Governments to improve prescribing practices has been recommended.  Advantages of diazepam are a rapid onset of action and high efficacy rates which is important for managing acute seizures, anxiety attacks and panic attacks; benzodiazepines also have a relatively low toxicity in overdose.Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system. Diazepam was first synthesized by Leo Sternbach, is used to treat a wide range of conditions, and has been one of the most frequently prescribed medications in the world since its launch in 1963.

Medical uses:

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g., endoscopy).  Intravenous diazepam or lorazepam are first line treatments for status epilepticus; However, lorazepam has advantages over diazepam including a higher rate of terminating seizures and a more prolonged anticonvulsant effect.Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for that purpose. Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood pressure control measures have failed. Benzodiazepines do not have any pain relieving properties of themselves and are generally recommended to be avoided in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle relaxant properties to alleviate pain which is caused by muscle spasms, caused by various dystonias, including blepharospasmTolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofenor tizanidine is sometimes used as an alternative to diazepam. Tizanidine has been found to be equally effective as other antispasmodic drugs and have superior tolerability than baclofen and diazepam.  The anticonvulsant effects of diazepam, can help in the treatment of seizures, due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, soman (or other organophosphate poisons; See #CANA), lindane, chloroquine, physostigmine, or pyrethroids Diazepam is sometimes used intermittently for the prophylaxis of febrile seizures which occur as a result of a high fever in children and neonates under 5 years of age.Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup individuals with treatment resistant epilepsy benefit from long-term benzodiazepines and for such individuals clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects.

 Diazepam has a broad spectrum of indications (most of which are off-label), including:

Treatment of anxiety, panic attacks, and states of agitation     Treatment of neurovegetative symptoms associated with vertigo     Treatment of the symptoms of alcohol, opiate and benzodiazepine withdrawal     Short-term treatment of insomnia     Treatment of tetanus, together with other measures of intensive-treatment     Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)     Palliative treatment of stiff person syndrome     Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g., before endoscopic or surgical procedures)     Treatment of complications with a hallucinogen crisis and stimulant overdoses and psychosis, such as LSD, cocaine, or methamphetamine.     Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy  Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have. Availability  Diazepam is marketed in over 500 brands throughout the world.It is supplied in oral, injectable, inhalation and rectal forms.  The United States military employs a specialized diazepam preparation known as CANA (Convulsive Antidote, Nerve Agent), which contains a mixture of diazepam, atropine and pralidoxime (2-PAM). One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using auto-injectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care.

Contraindications  Use of diazepam should be avoided, when possible, in individuals with the following conditions:      Ataxia.     Severe hypoventilation.     Acute narrow-angle glaucoma.     Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2).     Severe renal deficiencies (for example, patients on dialysis).     Liver disorders.     Severe respiratory disorders.     Severe sleep apnea.     Severe depression, particularly when accompanied by suicidal tendencies.     Psychosis.     Pregnancy or breast feeding.     Caution required in elderly or debilitated patients.     Coma or shock.     Abrupt discontinuation of therapy.     Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens and/or stimulants, where it is occasionally used as a treatment for overdose).     History of alcohol or drug dependence.     Myasthenia gravis, or MG, an autoimmune disorder causing marked fatiguability.     Hypersensitivity or allergy to any drug in the benzodiazepine class.  Special caution needed      Benzodiazepines require special precaution if used in the alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.      Pediatric patients         Less than 18 years of age – Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.         Under 6 months of age – Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.      Elderly and very ill patients – Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients. The elderly metabolise benzodiazepines much more slowly than younger adults and are also more sensitive to the effects of benzodiazepines even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger individuals and treatment limited to a maximum of 2 weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly.Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.      I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.

Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.  Pregnancy  Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Adverse effects  Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam such as confusion, amnesia, ataxia and hangover effects as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance, benzodiazepine dependence as well as a benzodiazepine withdrawal syndrome.Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before benzodiazepines is not impaired. Tolerance to the cognitive impairing effects of benzodiazepines does not tend to develop with long-term use. The elderly are more sensitive to the cognitive impairing effects of benzodiazepines.Additionally after cessation of benzodiazepines cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression.Infusions or repeated intravenous injections of diazepam when managing seizures for example may lead to drug toxicity including respiratory depression, sedation as well as hypotension. Tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours.Adverse effects such as sedation, benzodiazepine dependence and abuse potential limit the use of benzodiazepines.  Diazepam has a range of side-effects that are common to most benzodiazepines.

Most common side-effects include:

Suppression of REM sleep     Impaired motor function         Impaired coordination         Impaired balance         Dizziness and nausea     Depression     Reflex tachycardia  Less commonly paradoxical side-effects can occur and include nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido (increased or decreased libido) and in some cases, rage, and violence. These adverse reactions are more likely to occur in children, the elderly, individuals with a history of drug or alcohol abuse and people with a history of aggression.Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.Very rarely dystonia can occur.  Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.  During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.  Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.  Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness. Tolerance and dependence  Diazepam as with other benzodiazepine drugs can cause tolerance, physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms that are similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short-term use and can range from insomnia and anxiety to more serious symptoms including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, however, tolerance may then develop to the higher dose and adverse effects may increase.

The mechanism of tolerance to benzodiazepines includes: uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. Approximately one third of individuals who take benzodiazepines for longer than 4 weeks become dependent and experience a withdrawal syndrome upon cessation.The difference in rates of withdrawal (50–100%) varies depending on the patient sample being investigated. For example, a random sample of long-term benzodiazepine users typically finds that around 50% will experience little or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups will show a higher rate of notable withdrawal symptoms, up to 100%.Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction.There is a significant risk of pharmacological dependence on diazepam and patients experiencing symptoms of benzodiazepine withdrawal syndrome if it is taken for 6 weeks or longer.In humans tolerance to the anticonvulsant effects of diazepam occurs frequently. Dependence  Improper or excessive use of Diazepam can lead to psychological dependence/drug addiction.At a particularly high risk for diazepam misuse, abuse or psychological dependence are:      People with a history of alcohol or drug abuse or dependenceDiazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.     People with severe personality disorders, such as Borderline Personality Disorder  Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if physical dependence has developed therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these people is not recommended.  People suspected of being physiologically dependent on benzodiazepine drugs should be very gradually tapered off the drug. Although rare, withdrawals can be life-threatening particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.  Diazepam in and of itself is not a recreational drug, but may be used to either enhance or "come down" from the effects of other recreational drugs. For example, diazepam increases the euphoriant effects of heroin (and other recreational opiates), yet decreases the undesirable side-effects of cocaine and/or methamphetamine come-down.

Overdose Main article:

Benzodiazepine overdose  An individual that has consumed too much diazepam will typically display one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose:      Drowsiness     Mental confusion     Hypotension     Impaired motor functions         Impaired reflexes         Impaired coordination         Impaired balance         Dizziness     Coma  Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.  The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites, esmethyldiazepam, oxazepam, and temazepam; according to samples taken in the hospital and as follow-up.  Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.  An Australian study has found people who take sleeping pills or anti-anxiety medications are more dangerous on the roads than drunk drivers. Interactions  If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.  Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.  Agents that have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.

Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), narcotics, other muscle relaxants, certain antidepressants, sedative antihistamines, opiates, and antipsychotics as well as anticonvulsants such as phenobarbital, phenytoin and carbamazepine. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.     Cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine and valproic acid prolong the action of diazepam by inhibiting its elimination.     Alcohol (ethanol) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.     Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.     Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects. Dexamethasone and St John's wort also increase the metabolism of diazepam.     Diazepam increases the serum levels of phenobarbital.     Nefazodone can cause increased blood levels of benzodiazepines.     Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.     Small doses of theophylline may inhibit the action of diazepam.     Diazepam may block the action of levodopa (used in the treatment of Parkinson's Disease).     Diazepam may alter digoxin serum concentrations.     Other drugs that may have interactions with diazepam include: Antipsychotics (e.g. chlorpromazine), MAO inhibitors, ranitidine.     Caffeine may antagonise the effects of diazepam and vice versa.     Smoking tobacco can enhance the elimination of diazepam and decrease its action.     Because it acts on the GABA receptor the herb Valerian may produce an adverse effect.     Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.     Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.     There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.

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