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dormicum Ampoules roche 10amps Midazolam From Wikipedia, the free encyclopedia (Redirected from Dormicum) Jump to: navigation, search Midazolam Systematic (IUPAC) name 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine Identifiers CAS number 59467-70-8 ATC code N05CD08 PubChem 4192 DrugBank APRD00680 Chemical data Formula C18H13ClFN3 Mol. mass ? Pharmacokinetic data Bioavailability Oral ~36% I.M. 90%+ Metabolism Hepatic Half life 1.8-6.4 hours Excretion Renal Therapeutic considerations Pregnancy cat. D (USA) C (Aus) Legal status Schedule IV(US) Routes Oral, I.M., I.V., parenteral Midazolam (marketed under brand names Dormicum, Flormidal, Versed, Hypnovel and Dormonid, pronounced mɪˈdæzəlæm) is a drug which is a benzodiazepine derivative. It has powerful anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties. It is considered a short-acting benzodiazepine, with a short elimination half-life. It is therefore a very useful drug to use for short minor procedures such as dental extraction. Midazolam was first synthesized in 1976 by Fryer and Walser. Contents [hide] 1 Mechanism of action 2 Indications 3 Interactions 4 Contraindications 5 Side Effects 6 Pregnancy 7 Overdose 8 Availability 9 Legal status 10 Law enforcement and criminal justice 11 Popular Culture 12 See also 13 External links 14 Notes 15 References [edit] Mechanism of action Like other benzodiazepines, midazolam acts on the benzodiazepine binding site of GABAA receptors. When bound it enhances the binding of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system.[1] [edit] Indications Midazolam is indicated for the short term treatment of insomnia in patients who did not adequately react to other (benzodiazepines) hypnotics, and who have persistent trouble in falling asleep. Because of midazolam's extremely short duration, midazolam is not used for patients who have trouble staying asleep through the night; moderate to long acting benzodiazepines like temazepam, nitrazepam, flunitrazepam and lormetazepam are used for those purposes. Like other benzodiazepines, midazolam produces a decrease in delta activity, though the effect of benzodiazepines on delta may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep; it is thought to reflect sleep quality, with lower levels of delta sleep reflecting poorer sleep. Thus midazolam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to nitrazepam in the treatment of insomnia as it enhances sleep quality based on EEG studies.[2] Midazolam is also indicated for the acute management of aggressive or delirious patients and also is sometimes used for the acute management of seizures such as status epilepticus. Long term use for the management of epilepsy is not recommended however, due to the significant risk of tolerance which renders midazolam and other benzodiazepines ineffective and as well the significant side effect of sedation.[3] In mice given chronic midazolam a slowly evolving tolerance developed to the anticonvulsant properties of midazolam over 15 days, although some anticonvulsant effects were still apparent after 15 days of continued administration.[4] [edit] Interactions Midazolam is metabolized almost completely by cytochrome P450-3A4. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations, which could result in overdose. [edit] Contraindications Hypersensitivity, acute narrow angle glaucoma, shock, hypotension, head injury, and drug or alcohol use. Most are relative contraindications. [edit] Side Effects Residual 'hangover' effects after nighttime administration of midazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.[5] [edit] Pregnancy Midazolam when taken during the third trimester of pregnancy may cause severe risk to the neonate, including benzodiazepine withdrawal syndrome with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[6] [edit] Overdose Symptoms of midazolam overdose include: Somnolence (difficulty staying awake) Mental confusion Hypotension Impaired motor functions Impaired reflexes Impaired coordination Impaired balance Dizziness Coma Death In animal models, the oral LD50 of midazolam is 825 mg/kg. Midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil (Anexate). The risk of midazolam overdose is increased significantly if midazolam is abused in conjunction with opiates as was highlighted in a review of deaths of users of the opiate buprenorphine in Singapore.[7] [edit] Availability Dormicum brand midazolam is marketed by Roche as white, oval 7.5mg tablets in boxes of 2 or 3 blisterstrips of 10 tablets, and as blue, oval 15mg tablets in boxes of 2 blisterstrips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1ml, 3ml and 10ml ampoules at a concentration of 5mg/ml. [edit] Legal status In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.[8] [edit] Law enforcement and criminal justice Midazolam is offered to death row inmates before execution in the United States, according to the 1992 film The Execution Protocol. A Missouri prison doctor interviewed in the film said virtually no prisoners turned down the drug when it was offered a few hours prior to execution. The drug is also used by trained Paramedics to assist in controlling psychotic or mentally disturbed patients

restoril caps (tamazepam) 30mg 10s novartis. restoril caps (tamazepam) 30mg 10s novartis The Drugs Section is undoubtedly one of the busiest sections in the Forensic Support Department. Cases vary enormously in size and complexity - from alcohol in blood or urine samples from suspected drink-drivers to multi-million pound drug seizures. A number of examinations are carried out in the section, including: identification of controlled drugs, such as cannabis, cannabis resin, amphetamine, cocaine, diamorphine and ecstasy, principally using GC-MS determining the purity of controlled drugs, principally using GC-FID or HPLC physical examination of packaging materials development of new techniques. A normal day could entail setting up sophisticated analytical instrumentation, which runs automatically almost 24 hours per day, and examining and analysing a huge seizure of controlled drugs. Scientific reports, detailing the section’s findings, also have to be prepared for court. Forensic scientists from this section also attend court as expert witnesses and participate in continual professional development schemes. Routinely, the work of the Drugs Section is laboratory-based, but occasionally forensic scientists attend crime scenes to assist police officers or scene examiners in recovering relevant evidence. As well as being fluent in many aspects of analytical chemistry, forensic scientists must have a working knowledge of relevant pieces of legislation, such as the Misuse of Drugs Act 1971 and the Misuse of Drugs Regulations 2001. Great care must be taken when working to avoid cross-contamination, which is why a strong emphasis is placed on the lab’s Quality System. The Quality System puts in place many checks in order to ensure that the final reported result is correct. Another skill of the forensic scientist is to communicate complicated scientific principles to lay people in a clear, concise and unambiguous manner, both verbally and in writing

VALIUM TABS (DIAZEPAM) 10MG ROCHE 30S Diazepam From Wikipedia, the free encyclopedia Jump to: navigation, search Diazepam Systematic (IUPAC) name 7-chloro-1-methyl- 5-phenyl-1,3-dihydro-2H- 1,4-benzodiazepin-2-one Identifiers CAS number 439-14-5 ATC code N05BA01 N05BA17 PubChem 3016 DrugBank APRD00642 Chemical data Formula C16H13ClN2O Mol. mass 284.7 g/mol Pharmacokinetic data Bioavailability 93% Metabolism Hepatic Half life 20–100 hours Excretion Renal Therapeutic considerations Pregnancy cat. C(AU) D(US) Legal status Prescription Only (S4)(AU) Schedule IV(CA) Schedule IV(US) Schedule IV (International) Routes Oral, IM, IV, suppository Diazepam (IPA: /daɪˈæzɨpæm/), first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine derivative drug. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms. 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.[1][2] 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.[3] Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years. It was first synthesized by Dr. Leo Sternbach. Contents [hide] 1 History 2 Physical properties 3 Pharmacology 4 Mechanism of action 5 Pharmacokinetics 6 Indications 6.1 Veterinary uses 6.2 Judicial executions 7 Dosage 8 Trade names 8.1 Availability 9 Side effects 10 Interactions 11 Contraindications 11.1 Special caution needed 12 Dependence 12.1 Patients at a high risk for abuse, dependence, tolerance, or addiction 13 Pregnancy 14 Overdose 15 Recreational and illicit use 16 Legal status 17 Toxicity 18 Further reading 19 References 20 External links [edit] History Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is two and a half times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.[4] The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).[5] Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.[4] Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia.[6] While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.[7] [edit] Physical properties Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.[8] Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.[9] Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.[9] [edit] Pharmacology Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include clonazepam, lorazepam, oxazepam, alprazolam, nitrazepam, flurazepam, bromazepam and clorazepate.[10] Diazepam has anticonvulsant properties.[11] Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs insofar from some other anticonvulsive drugs, it was compared to.[12] Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.[13] Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.[14] Diazepam binds with high affinity to glial cells in animal cell cultures.[15] Diazepam binds to peripheral benzodiazepine receptors and inhibits the proliferation of rat thymoma cell cultures, mouse Swiss 3T3 cells cultures, B103 and B104 rat neuroblastoma cell cultures, and Friend mouse erythroleukemia cell cultures and inhibits the uptake of radiolabeled thymidine into rat thymoma cell cultures.[16] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.[17] Diazepam also decreases prolactin release in rats.[18] [edit] Mechanism of action See also: Benzodiazepine Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the binding site of the endogenous GABA molecule.[19][20] The GABAA receptor is an inhibitory channel which, when activated, decreases neuronal activity. Because of the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the post-synaptic membrane owing to the control exerted over negative chloride ions by GABAA receptors.[19][21] Benzodiazepines including diazepam however, do not have any effect on the levels of GABA in the brain.[22] Diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity.[1][19] Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.[23] The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.[24] The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[25] [edit] Pharmacokinetics Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.[8] When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1–5 minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration.[26] Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.[27][9] Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.[8][9] There is preferential storage of diazepam in some organs including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.[28] Diazepam is metabolised via oxidative pathways in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1–2 and 2–5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.[27][9][29] Diazepam is also metabolised to a benzophenone compound.[30] Diazepam has a half-life (t1/2α) of 20–50 hours, and desmethyldiazepam has a half-life of 30–200 hours and is considered to be a long acting benzodiazepine.[9] Most of the drug is metabolised; very little diazepam is excreted unchanged.[8] In humans, the protein binding of diazepam is around 98.5%.[27] The elimination half life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly which may result in prolonged action as well as accumulation of the drug during repeated administration.[31] [edit] Indications Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g. endoscopy).[27] 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 this purpose and also because of side-effects - in particular sedation.[8][32] Diazepam has a broad spectrum of indications (most of which are off-label), including: Treatment of anxiety, panic attacks, and states of agitation.[27] Treatment of status epilepticus, adjunctive treatment of other forms of epilepsy[27] Treatment of vertigo associated with Meniere's Disease. Treatment of the symptoms of alcohol and opiate withdrawal[27] Short-term treatment of insomnia.[27] Treatment of tetanus, together with other measures of intensive-treatment[33] Initial management of mania, together with firstline drugs like lithium, valproate, lamotrigine or other antipsychotics[citation needed] Adjunctive treatment of painful muscle conditions[7] 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)[7] Palliative treatment of stiff person syndrome.[21] Used to alleviate the symptoms of Lesch-Nyhan Syndrome Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures)[7] Treatment of overdosage with hallucinogens or CNS stimulants.[8] Adjunctive treatment of drug-induced seizures, resulting from exposure to sarin, VX, soman (or other organophosphate poisons; See CANA), lindane, chloroquine, physostigmine, or pyrethroids[8] Emergency treatment of eclampsia, along with IV magnesium sulfate Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy.[34] Used in the treatment for irritable bowel syndrome.[35] Used to treat pain resulting from muscle spasms caused by various spastic dystonias, including blepharospasm, spasmodic dysphonia and Meige's Syndrome. [edit] Veterinary uses Diazepam is used as a short term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously or 1–2 mg/kg per rectum of the injectable solution.[36] Diazepam is also used as a muscle relaxant for horses, to be given intravenously, the usual dose is 0.02 - 0.1 mg/kg in conjunction with or just after induction of general anesthesia. [edit] Judicial executions The State of California offers diazepam to condemned inmates as a pre-execution sedative.[37] [edit] Dosage 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.[8] Typical dosages for healthy adults range from 2 mg per dose to 10 mg per dose taken 2 to 4 times per day, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.[21] [edit] Trade names Valium tablets in USA and many other countries; Valium capsules in Italy, Spain; Novodipam in Canada; Relanium in Poland; Seduxen in Hungary, Russia; Diazepam-Desitin rectal solution in Hungary, and other European countries; Diazepam-Intensol; Valrelease Diapam in Finland Stesolid Sweden, Iceland, Norway Anxicalm Ireland Valpam, Antenex in Australia Vival tablets in Norway Normabel tablets in Croatia Bensedin in Serbia Stedon tablets in Greece Plidex tablets in Uruguay, Argentina, Chile Betapam in South Africa Dipaz in Ecuador [edit] Availability Diazepam is supplied in the following forms: For oral administration: Tablets - 2 mg, 5 mg, 10 mg.[21] Generic versions available. Capsules, time-release - 15mg (marketed by Roche as Valrelease)[9] Liquid solution - 1 mg/ml in 500 ml containers and unit-dose (5 mg & 10 mg); 5 mg/ml in 30 ml dropper bottle (marketed by Roxane as Diazepam Intensol)[9] For parenteral administration: Solution for IV/IM injection - 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.[38][9] Notice: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly. Seduxen (Diazepam, in Hungary, Russia, Poland, and other Eastern-European countries) is supplied in the following forms: For oral administration: Tablets 5mg Injection 5 mg/ml for intravenous, intramuscular or subcutaneous usage For parenteral administration: Solution for IV/IM injection - 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.[38][9] Notice: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly. For rectal administration: Solution[8] Suppositories - 5mg and 10mg[39][8] Rectal tubes For inhalation administration: This method uses heating diazepam to form a vapor later producing an aerosol. This allows the drug to be passed through an inhalation route during an inhalation therapy. Provided in doses 2mg-20mg either in a single inhalation or multiple small inhalations[40] Diazepam, is available in the United States military as CANA (Convulsive Antidote, Nerve Agent). 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.)[41] [edit] Side effects Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include: Somnolence Suppression of REM sleep Addiction Impaired motor function Impaired coordination Impaired balance Dizziness and nausea Depression Impaired learning Anterograde amnesia (especially pronounced in higher doses) Cognitive deficits[42] Reflex tachycardia[26] Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence.[43][44][45] If these side effects are present, diazepam treatment should be immediately terminated. Benzodiazepines such as diazepam impair learning and memory via their action on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system.[46] 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.[21] During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[47] Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death. Organic changes such as leukopenia[48] and liver-damage of the cholostatic type with or without jaundice (icterus) have been observed in a few cases.[citation needed] Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.[49] [edit] 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.[21] 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.[8] Agents which 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.[8] Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g. barbiturates), narcotics, and other muscle relaxants. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.[50][51] Cimetidine, omeprazole, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine and valproic acid prolong the action of diazepam by inhibiting its elimination.[8][9] Alcohol (ethanol) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.[52] Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.[51][53] Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.[8] Diazepam increases the serum levels of phenobarbital.[54] Nefazodone can cause increased blood levels of benzodiazepines.[51] Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.[55] Small doses of theophylline may inhibit the action of diazepam.[56] Diazepam may block the action of levodopa (used in the treatment of Parkinson's Disease).[50] Diazepam may alter digoxin serum concentrations.[8] Other drugs that may have interactions with diazepam include: Antipsychotics (e.g. chlorpromazine), MAO inhibitors, ranitidine.[51] Smoking tobacco can enhance the elimination of diazepam and decrease its action.[50] Because it acts on the GABA receptor the herb Valerian may produce an adverse effect.[57] Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.[50] Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.[8] There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.[50] [edit] 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 (e.g. patients on dialysis) Severe sleep apnea Severe depression, particularly when accompanied by suicidal tendencies Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens, where it is occasionally used as a treatment for overdose) Myasthenia gravis, or MG, an autoimmune disorder causing marked fatiguability. Hypersensitivity or allergy to any drug in the benzodiazepine class [edit] Special caution needed 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.[51] Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.[21][51] 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.[21][51][58] Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.[59] I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.[58] Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes and therefore rapidly crosses 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.[60] [edit] Dependence Diazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.[61] It has been shown in a clinical study that 100% of patients on low dose diazepam therapy long term are physically dependent on their medication.[62] Increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch and panic attacks may be experienced as withdrawal symptoms in low therapeutic dose long term users of diazepam when discontinuing their diazepam medication.[63] Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[64] 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.[65] There is a significant risk of pharmacological dependence on diazepam and patients experiencing the benzodiazepine withdrawal syndrome if it is taken for 6 weeks or longer.[66] In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.[67] [edit] Patients at a high risk for abuse, dependence, tolerance, or addiction Diazepam can lead to physiological tolerance, and psychological and/or physical dependence.[68] At a particularly high risk for diazepam misuse, abuse, or dependence are: Patients with a history of alcohol or drug abuse or dependence[21][69] Patients with severe personality disorders, such as Borderline Personality Disorder[70] Patients with an anxiety disorder[68] Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.[21][69] The American Society of Addiction Medicine has policy indicating that patients with addictive disease should not be prescribed benzodiazepines such as diazepam.[citation needed] Patients suspected of being physiologically addicted to 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 addiction has occurred in therapeutic or recreational contexts. A large scale nation wide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is however, alprazolam. Clonazepam is the 2nd most abused benzodiazepine. Lorazepam is the third most commonly abused benzodiazepine and diazepam the 4th most commonly abused benzodiazepine in the USA. Alprazolam is also commonly abused in combination with alcohol.[71] [edit] Pregnancy There is inconclusive evidence that diazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some newborns, however the data is inconclusive. Diazepam when taken during late in pregnancy, 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.[72] [edit] Overdose An individual who has consumed too much diazepam will display one or more of the following symptoms:[21][73] 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.[8][5][21][73] The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[21] 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 important complications in spite of having high concentrations of diazepam and its metabolites—desmethyldiazepam, oxazepam, and temazepam—according to samples taken in the hospital and as follow-up.[74] Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.[5][75] [edit] Recreational and illicit use Diazepam is a drug of potential dependence and addiction. Between 50 and 64% of rats will self administer diazepam.[76] Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines.[77] Diazepam has been found as an adulterant in heroin.[78] This may be because diazepam greatly amplifies the effects of opioids. Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.[79] Benzodiazepines, including diazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.[80] Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.[81] In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.[82] [edit] Legal status Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[83] In the UK, it is classified as a Class C drug. [edit] Toxicity Laboratory tests assessing the toxicity of diazepam, nitrazepam and chlordiazepoxide on mice spermatozoa found that diazepam produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam however caused more profound abnormalities than diazepam.[84]

ZOLPIDEM tabs 10mg 20s generic Zolpidem From Wikipedia, the free encyclopedia Jump to: navigation, search Zolpidem Systematic (IUPAC) name N,N,6-trimethyl-2-(4-methylphenyl)- imidazo(1,2-a)pyridine-3-acetamide Identifiers CAS number 82626-48-0 ATC code N05CF02 PubChem 5732 DrugBank APRD00095 Chemical data Formula C19H21N3O Mol. mass 307.395 g/mol SMILES eMolecules & PubChem Pharmacokinetic data Bioavailability 70% (oral) 92% bound in plasma Metabolism Hepatic CYP34A Half life 2 to 2.6 hours Excretion 56% renal 34% fecal Therapeutic considerations Pregnancy cat. B3(AU) B(US) Legal status Schedule IV(US) Class C / POM (UK) Routes Oral Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to benzodiazepine receptors which are located on the gamma-aminobutyric acid receptors.[1] It works quickly (usually within 15 minutes) and has a short half-life (2–3 hours). Some trade names of zolpidem are Ambien,[2] Hypnogen, Myslee.[3] Nimadorm, Nitrest, Sanval, Stilnoct, Stilnox,[4] Zoldem(HEXAL AG), Zolfresh, and Zolt. Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is actually classified as an imidazopyridine. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic effects. As an anticonvulsant and muscle relaxant, the beneficial effects start to emerge at 10 and 20 times the dose required for sedation, respectively.[5] For that reason, it has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are more inclined to induce one or more negative side effects, including hallucinations and/or amnesia. (See below.) The patent 4382938 in the United States on zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. On April 23, 2007 the U.S. FDA approved 13 generic versions of zolpidem tartrate. Zolpidem is available from several generic manufacturers in the UK, as generic from Sandoz in South Africa, as well as from other manufacturers such as ratiopharm. Recently, zolpidem has been cited in various medical reports mainly in the United Kingdom as waking persistent vegetative state (PVS) patients, and dramatically improving the conditions of people with brain injuries.[6][7][8][9][10] Contents [hide] 1 Uses 2 Mechanism of action 3 New research 4 Recreational use and abuse 5 Dependence and withdrawal 6 Overdose 7 Elderly 8 Side-effects 9 In the news and other media 10 See also 11 References 12 Notes 13 External links [edit] Uses Zolpidem is approved for the short-term (usually two to six weeks) treatment of insomnia, and it has been studied for nightly use up to six months in a single-blind trial published in 1991,[11] an open-label study lasting 180 days published in 1992 (with continued efficacy in patients who had kept taking it as of 180 days after the end of the trial), [12] and in an open-label trial lasting 179 days published in 1993.[13] The United States Air Force uses zolpidem as a substitute for temazepam, under trade name Ambien, as "no-go pills" to help pilots sleep after a mission; the main drug used for the purpose is temazepam (Normison/Restoril). (Cf. the "go-pills" dextroamphetamine, served under the name Dexedrine, or its recent modafinil (Provigil) replacement, act as a stimulant for the same pilots, the effects of which are reversed by the aforementioned "no-go pills")[14] Zolpidem is also used off-label to treat restless leg syndrome and, as is the case with many prescription sedative/hypnotic drugs, it is sometimes used by stimulant users to "come down" after the use of stimulants such as amphetamines (including methamphetamine), cocaine, or MDMA (ecstasy).[15] Recently, the drug has been reported anecdotally to have positive effects for patients in persistent vegetative state.[6] Results from phase IIa trials are expected in June 2007. The trials are being conducted by Regen Therapeutics of the UK, who have a patent pending on this new use for Zolpidem.[16][17] A clinical trial on a single patient performed at the Toulouse University Hospital using PET shows that zolpidem repeatably improves brain function and mobility of a patient immobilized by akinetic mutism caused by hypoxia.[18] [edit] Mechanism of action Zolpidem binds with high affinity to the α1 containing GABAA receptors, about 10-fold lower affinity for those containing the α2, α3-GABAA receptor subunits, and with no appreciable affinity for α5 subunit containing receptors.[19] Like the vast majority of benzodiazepine like molecules, zolpidem has no affinity for α4 and α6 subunit containing receptors.[20] Zolpidem positively modulates GABAA receptors, probably by increasing the GABAa receptor complexes apparent affinity for GABA, without affecting desensitization or peak current.[21] Zolpidem increases slow wave sleep and caused no effect on stage 2 sleep in laboratory tests.[22] A meta-analysis of the randomised controlled clinical trials which compared benzodiazepines against Z drugs has shown that there are few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness.[23] [edit] New research Zolpidem has recently been very strongly related to certain instances of patients in a minimally conscious coma state being brought to a fully conscious state. While it was initially given to these supposed permanent coma patients to put them to sleep, it actually brought them to a fully conscious state in which they were capable of communicating and interacting for the first time in years. CAT scans have shown that the use of the drug actually does dramatically increase the activity in the frontal lobe of the brain in some patients in a minimally conscious state. Large scale studies are currently being done to see if it has the same universal effect on all or most patients in a minimally conscious state.[24] It may be that zolpidem's ability to stimulate the brain, particularly in the semi-comatose, may be related to one of its side effects, which sometimes causes sleepwalking and other activity while asleep, that appears to observers to be fully conscious activity. [edit] Recreational use and abuse The neutrality of this section is disputed. Please see the discussion on the talk page. (December 2007) Please do not remove this message until the dispute is resolved. The transition from medicinal use to recreational use of Zolpidem can occur when the drug is used without the doctor's recommendation to continue using it, in high doses (more than the usual 5mg or 10 mg), when consumed other than orally (snorting or injecting), or when taken for purposes other than as a sleep aid. Abuse is more prevalent in those who have been dependent on other drugs, tobacco, or alcohol in the past. Zolpidem effects can increase and intensify if mixed with other substances like alcohol and cannabis. In the U.S., recreational use of this drug is becoming more common in young people.[25] Recreational users claim that "fighting" the effects of the drug by forcing themselves to stay awake will sometimes cause vivid visuals and a body high (see side-effects below). However, others who are already in an anxious state, claim it is not hard to fight the main effect of sedation, experiencing the side-effect of euphoria more than the sedation itself.[citation needed] Thus some users report decreased anxiety, and even mild euphoria, as well as perceptual changes, visual distortions, and light-based hallucinations. It is also not uncommon for one who has developed a tolerance to the drug to eventually feel such a decrease in the sedation effect that only the euphoric, perceptual, and anxiety decreasing side effects remain. With regular use at high dosage, there can be a risk of a severe physical dependence on zolpidem with cases being reported in the medical literature of epileptic seizures forming part of the withdrawal syndrome. One case involved a woman detoxing off a high dose of zolpidem experiencing a generalized seizure. The clinical withdrawal and dependence effects were reported to be similar to those of benzodiazepines in this case report.[26] Zolpidem and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs including the benzodiazepines and zopiclone are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone.[27] As Ambien's patent expired April 21, 2007, new generic versions were approved, which do not have the "protective cover" present on the Sanofi name-brand Ambien they once previously had to prevent users from crushing, snorting, or injecting the drugs. [edit] Dependence and withdrawal Alcohol has cross tolerance with GABAa receptor positive modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason alcoholics or recovering alcoholics may be at increased risk of physical dependency on zolpidem. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zolpidem. Zolpidem should be avoided in those with a history of Alcoholism, drug misuse, or in those with history of physical dependency or psychological dependency on sedative-hypnotic drugs. [edit] Overdose Overdose of zolpidem may present with excessive sedation, pin-point pupils, depressed respiratory function, which may progress to coma and possibly death. Zolpidem combined with alcohol, opiates or other CNS depressants may be even more likely to lead to fatal overdoses. Zolpidem overdosage can be treated with the benzodiazepine receptor antagonist flumazenil which displaces zolpidem from its binding site the benzodiazepine receptor and therefore rapidly reverses the effects of zolpidem.[28] [edit] Elderly An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine (including zolpidem) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[29] [edit] Side-effects Side effects at any dose may include: Anterograde amnesia Hallucinations, through all physical senses, of varying intensity Delusions Altered thought patterns Ataxia or poor motor coordination, difficulty maintaining balance[30] Euphoria and/or dysphoria Increased appetite Decreased libido Amnesia Impaired judgment and reasoning Uninhibited extroversion in social or interpersonal settings Increased impulsivity When stopped rebound insomnia may occur Some users take zolpidem recreationally for these side effects. However, it may be less common than benzodiazepine abuse. In the United States, recreational use may be less common than in countries where the drug is available as a less expensive generic (or in countries, such as the UK, where prescriptions are free or heavily subsidised). It is not yet known whether there is a link between the cost and availability of zolpidem and the level at which it is abused. Zolpidem can become addictive if taken for extended periods of time, due to dependence on its ability to put one to sleep or to the euphoria it can sometimes produce. Like most addictive drugs, a tolerance in the zolpidem user develops and increases all the more quickly the longer the user has been regularly taking it. Under the influence of the drug it is common to take more zolpidem than is necessary due to either forgetting that one has already taken a pill (elderly users are particularly at risk here), or knowingly taking more than the prescribed dosage. Users with a predilection for abuse are advised to keep additional zolpidem in a safe place that is unlikely to be remembered or accessed while intoxicated to avoid this risk. A trustworthy friend or relative is the best defense if such people are available; otherwise, a box or cupboard locked with a combination padlock is a good defense against this tendency, as the above-mentioned side-effects can easily prevent a user from operating such a lock while under the drug's influence. The recent release of Ambien CR (zolpidem tartrate extended release) in the United States renewed interest in the drug among recreational drug users. Before a user becomes fully acclimated to these effects (or if the user does not become acclimated), these symptoms can be severe enough to be deemed as drug-induced psychosis. Incidentally, antipsychotics like ziprasidone (Geodon) or quetiapine (Seroquel) may be prescribed alongside zolpidem to both combat these side effects and to aid in sleep-induction, as both of them contain mild hypnotic properties. However, because some antidepressants are known for being mildly sedating (i.e., paroxetine), it may be inadvisable to use zolpidem and an antidepressant simultaneously. Some zolpidem users (especially those suffering from chronic insomnia), however, commonly use these drug combination due to the relative ease with which the user gains no benefit from one or the others of these drugs, while both together can assist sufferers of insomnia in getting to sleep. Some users have reported unexplained sleepwalking while using zolpidem, and a few have reported driving, binge eating, sleep talking, and performing other daily tasks while sleeping. The sleepwalker can sometimes perform these tasks as normally as they might if they were awake. They can sometimes carry on complex conversations and respond appropriately to questions or statements so much so that the observer may believe the sleepwalker to be awake. This is similar to, but unlike typical sleep talking, which can usually be identified easily and is characterised by incoherent speech that often has no relevance to the situation or that is so disorganised as to be completely unintelligible. These statements bear a strong resemblance to that of schizophasia, one of many symptoms commonly seen in individuals suffering from schizophrenia. A person under the influence of this medication may seem fully aware of their environment even though they are still asleep. This can bring about concerns for the safety of the sleepwalker and others. These side effects may be related to the mechanism that also causes zolpidem to bring some semi-comatose people back to consciousness. Driving while under the drug's influence is generally considered several orders of magnitude more dangerous than the average drunk driver, due to the diminished motor controls and delusions that may affect the user. It is unclear if the drug is responsible for the behavior, but a class-action lawsuit was filed against Sanofi-Aventis in March 2006 on behalf of those who reported symptoms.[31] Residual 'hangover' effects such as sleepiness, impaired psychomotor and cognitive after nighttime administration may persist into the next day which may impair the ability of users to drive safely, increase risks of falls and hip fractures.[32] More recently, the Sydney Morning Herald in Australia reported on 4 March 2007 that a man who fell 30 metres to his death from a high-rise unit balcony may have been sleepwalking under the influence of Stilnox. The coverage prompted over 40 readers to contact the newspaper with their own accounts of Stilnox related automatism and the drug is now under review by the Adverse Drug Reactions Advisory Committee.[33] [edit] In the news and other media On 6 April 2007 Australia's Therapeutic Goods Administration ordered the manufacturer to upgrade its warning about mixing the pills with alcohol.[34] There are also plans to move the drug to a tougher class of medicines (Schedule 8 status) in Australia because of its susceptibility to abuse and addiction. This would place the drug in the same class as opioids (eg. morphine), psychostimulants (eg. methylphenidate, dexamphetamine), and flunitrazepam (Rohypnol, Hypnodorm).[35] There are many unsubstantiated reports on the internet of people who have had issues with this medication.[36] On March 14, 2007, the US Food and Drug Administration ordered stronger warnings on 13 prescription sleep-hypnotic drugs including zolpidem and eszopiclone. The dangers of allergic reactions and driving while intoxicated, while serious, are not thought to be sufficient to withdraw the drugs from the market.[37] In April 2007, Slovenian serial killer Silvo Plut committed suicide by consuming a large quantity of Zolpidem, sold under the brandname Sanval.[citation needed] The media reports of side effects of Zolpidem have caused them to become referred to in popular culture. In the Simpsons episode Crook and Ladder, Homer Simpson becomes addicted to an insomnia pill known as Nappien and starts experiencing strange side effects. To this, Lisa Simpson says "I've read that people do strange things in their sleep when they've taken Ambien... I mean Nappien." Actor Heath Ledger was taking Ambien in the weeks prior to his death on 22 January 2008. In addition, early reports state that a bottle of Ambien was found near his body.[1] The drug has been the subject of much controversy in his native Australia, where it is available as Stilnox brand.[2] Actor Jack Nicholson told reporters in London that he almost drove off a cliff once while under the influence of Ambien.[38] Janene Johns, a mother with no previous criminal record, was sentenced to six years in the California State Prison system for causing a fatal accident while under the influence of prescribed Ambien in 2006