Clonazepam

2.41

log Kow = 2.41

2.7

White crystals from ethanol-methylene chloride

Off-white to light yellow crystalline powder

100

In water, <100 mg/L at 25 °C

Insoluble in benzene; slightly soluble in acetone, methanol, chloroform

Solubility in mg/mL at 25 °C: acetone 31; chloroform 15; methanol 8.6; ether 0.7; benzene 0.5

1.06e-02 g/L

238-240

237.5 °C

236.5 - 238.5 °C

The commercially available conventional tablets have an expiration date of 5 years following the date of manufacture.

Stable under recommended storage conditions.

2803；2860；2806；2833；2832；2856；2878；2813；2885；2857.1；2843.3；2827；2860；2885；2814；2885

2934.6；2853；2835.2；2863；2833；2848.4；2879

168.2 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

171 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

This chemical does not meet GHS hazard criteria for 12.5% (1 of 8) of reports.

Danger

H336 (50%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]；H360 (12.5%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H361 (50%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]；H362 (25%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]；H412 (50%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]；H413 (12.5%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

P203, P260, P261, P263, P264, P270, P271, P273, P280, P304+P340, P318, P319, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 8 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 1 of 8 reports by companies.；There are 7 notifications provided by 7 of 8 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

DEA schedule IV controlled substance

Clonazepam: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Clonazepam (DEA Code Number: 2737) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonazepam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Teboul E, Chouinard G; A Guide to Benzodiazepine Selection. Part II: Clinical Aspects. Can J Psychiatry 36 (1): 62-73 (1991). To suit the specific needs of various clinical situations, selection of an appropriate benzodiazepine derivative should be based on consideration of their different pharmacokinetic and pharmacodynamic properties. Benzodiazepine derivatives that are rapidly eliminated produce the most pronounced rebound and withdrawal syndromes. Benzodiazepines that are slowly absorbed and slowly eliminated are most appropriate for the anxious patient, since these derivatives produce a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually more appropriate for patients with sleep disturbances, since the rapid absorption induces sleep and the slower elimination rate may induce less tolerance to the sedative effect. Rational selection of a benzodiazepine for the elderly and for the suspected drug abuser is more problematic. The relevant pharmacokinetic and clinical considerations for these users are discussed. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine class; empirical studies have suggested the existence of anti-panic properties for alprazolam and clonazepam, antidepressant properties for alprazolam, and anti-manic properties for clonazepam and possibly lorazepam.

Trimble MR, Cull C; Children of School age: The Influence of Antiepileptic Drugs on Behavior and Intellect. Epilepsia 29 (Suppl 3): S15-9 (1988). The role of antiepileptic drugs in behavior and cognitive function in children is well documented the literature. In general, behavioral problems occur most frequently with phenobarbital and clonazepam, and appear least often with valproate and carbamazepine. Cognitive impairments occur with phenytoin, are less evident with valproate, and minimal with carbamazepine. Monotherapy, as with adults, leads to improvements in both cognitive abilities and behavior.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Keep container tightly closed in a dry and well-ventilated place.

Clonazepam tablets and orally disintegrating tablets should be stored in air-tight, light-resistant containers at 25 °C, but may be exposed to temperatures ranging from 15-30 °C. The commercially available conventional tablets have an expiration date of 5 years following the date of manufacture.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

Appropriate engineering controls: General industrial hygiene practice.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place.

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. 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. (L1712)

Increased salivation, hypersecretion in upper respiratory passages, chest congestion, rhinorrhea, and shortness of breath may occur in patients receiving clonazepam. In one study, increased salivation, mucous obstruction of the nasopharynx and bronchi, and difficulty in swallowing occurred in infants receiving the drug. The investigator reported that these effects occurred most frequently when clonazepam was used in conjunction with phenobarbital.

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Additive CNS depression may occur when clonazepam is administered concomitantly with other CNS depressants, including alcohol, opiate agonists, barbiturates, anxiolytics, sedatives and hypnotics, some antipsychotic agents, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, and other anticonvulsants. If clonazepam is used concomitantly with other CNS depressants, caution should be used to avoid excessive CNS depression. Patients also should be advised to avoid alcohol while receiving clonazepam therapy.

In one study, increased serum phenytoin concentrations were reported to occur when clonazepam and phenytoin were administered concomitantly. In another study, plasma clonazepam concentrations decreased when the two drugs were administered. Although the clinical importance of these reports has not been established, it may be desirable to monitor serum concentrations of both drugs during initial concomitant therapy, making dosage adjustments as necessary.

For more Interactions (Complete) data for Clonazepam (8 total), please visit the HSDB record page.

Clonazepam, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from clonazepam is extremely rare. However, at least one convincing case report of acute liver injury from clonazepam with recurrence on reexposure has been reported. Rare instances of drug induced liver injury has been reported with other benzodiazepines, such as chlordiazepoxide, diazepam, flurazepam, triazolam, clorazepate and alprazolam. In benzodiazepine related cases of acute liver injury, the latency has ranged from a few weeks to 6 months; the typical pattern of liver enzyme elevations has been cholestatic or mixed, but hepatocellular patterns have also been reported. The injury is usually mild to moderate in severity and self-limited. Fever and rash have not been described nor has autoantibody formation.；Likelihood score: D (possible but rare cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 12,000(SRC), determined from a structure estimation method(2), indicates that clonazepam is expected to be immobile in soil(SRC). Volatilization of clonazepam from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.0X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Clonazepam is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2017).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 12,000(SRC), determined from a structure estimation method(2), indicates that clonazepam is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.0X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Clonazepam is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). According to a classification scheme(4), an estimated BCF of 18(SRC), from its log Kow of 2.41(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2017).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), clonazepam, which has an estimated vapor pressure of 7.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase clonazepam may be removed from the air by wet or dry deposition(SRC). Clonazepam contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The adverse effects of clonazepam derive from its property to act as a central nervous system depressant like all the other BZD drugs.；Common Side Effects；The use of clonazepam is most commonly associated with lethargy, fatigue, sedation, drowsiness, and motor impairment (impaired coordination, impaired balance, dizziness).；Less Common Side Effects；Clonazepam can cause blurred vision, confusion, irritability, loss of libido, lack of motivation, psychomotor agitation, hallucination, worsening of depression, short-term memory loss, and anterograde amnesia, especially with high doses.；Occasional Side Effects；Occasional adverse effects of clonazepam include personality changes, behavioral disturbance, ataxia, increased frequency of seizures, thrombocytopenia, and dysphoria.；Rare Side Effects；Rare but important side effects of clonazepam include paradoxical disinhibition, i.e., excitement, rage, and impulsive behavior. Older patients are especially prone to this side effect. Other side effects are suicide, psychosis, and incontinence. Long-term use of benzodiazepine can lead to depression and sexual dysfunction. There have been reports of Lichenoid drug eruption with the use of clonazepam. Paradoxical sleep-related eating disorder (SRED) has been described, although clonazepam is used to treat SRED.；Drug-Drug Interactions；* Concurrent use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death. Avoid combination.；* The use of clonazepam along with kratom may lead to increased CNS depression and death. Avoid combination.；* Concurrent use of clonazepam with antidepressants, antipsychotics, hypnotics, antiepileptic drugs, and antihistamines leads to increased sedation due to pharmacodynamic synergism. Monitor the therapy.；* Concurrent administration of clonazepam with CYP3A4 inducers like carbamazepine, phenobarbital, phenytoin, and primidone can reduce the concentration of clonazepam.；* Concurrent administration of clonazepam with CYP3A4 inhibitors like clarithromycin, itraconazole, ketoconazole, nirmatrelvir/ritonavir, telithromycin, and voriconazole can increase the serum concentration of clonazepam.

IDENTIFICATION AND USE: Clonazepam is off-white to light yellow crystalline powder with a faint odor. It is a Schedule IV Controlled Substance. It is anticonvulsant and gamma-aminobutyric acid (GABA) modulator. A significant increase in the illegal use of clonazepam has been seen. HUMAN STUDIES: Overdosage of clonazepam may produce somnolence, confusion, ataxia, diminished reflexes, or coma. The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors. Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. In a study of 118 liveborn infants, there were 6 (5.1%) with major malformations, 4 of whom were prenatally exposed to clonazepam monotherapy and all of whom were full term infants. These included two with bilateral inguinal hernias requiring surgery, one with bilateral communicating hydroceles requiring surgery, one with midline pit over the nasal bridge, one with a uretero-pelvic junction obstruction requiring surgery and one with a PDA and ASD diagnosed at one day of age for which no follow-up is available. Sixty five (55.1%) of liveborn infants received a dysmorphological exam performed by an examiner who was blinded to the prenatal exposure. Although 16 (13.6%) children had 3 or more minor malformations, only one of the 16 was exposed to monotherapy. It is notable that 3 fullterm infants, all of whom were prenatally exposed to clonazepam monotherapy, had either inguinal hernias or communicating hydroceles requiring surgery. ANIMAL STUDIES: No adverse maternal or embryo-fetal effects were observed

The therapeutic range of clonazepam is from 0.02 to 0.08 mcg/mL. Any level over 0.08 mcg/mL is considered toxic. The symptoms of overdose develop rapidly.；Initial Presentation；The initial symptoms appear within a few hours with symptoms of CNS depression such as:；* Somnolence；* Diplopia；* Slurred speech；* Motor impairment；Severe Presentation；If the overdose is severe, then it may result in severe symptoms such as:；* Respiratory depression；* Hypoxemia；* Apnea；* Hypotension；* Bradycardia；* Cardiac arrest；* Pulmonary aspiration；* Coma；Severe consequences of clonazepam use alone are rare, but the toxicity increases significantly if other CNS depressants, such as opioids, ethanol, barbiturates, etc., are coadministered.；Treatment of Toxicity；Supportive care and medical observation are the mainstays of the treatment. The supportive care includes monitoring vitals, IV fluids for hypotension, atropine for bradycardia, and maintaining the patency of the airway by intubation or artificial respiration if respiratory depression develops.

Allosteric interactions between central benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptors potentiate the effects of GABA. As GABA is an inhibitory neurotransmitter, this results in increased inhibition of the ascending reticular activating system. Benzodiazepines, in this way, block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.

DEA schedule IV controlled substance

Clonazepam: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Clonazepam (DEA Code Number: 2737) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonazepam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N03AE01

N - Nervous system；N03 - Antiepileptics；N03A - Antiepileptics；N03AE - Benzodiazepine derivatives；N03AE01 - Clonazepam

QN - Nervous system；QN03 - Antiepileptics；QN03A - Antiepileptics；QN03AE - Benzodiazepine derivatives；QN03AE01 - Clonazepam

The pharmacodynamic properties of clonazepam are common among benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations, as well as irregular spikes and waves. Moreover, the agent can also decrease the frequency, amplitude, duration, and spread of discharge in minor motor seizures. Generalized EEG abnormalities are more readily suppressed by clonazepam than are focal EEG abnormalities such as focal spikes. Clonazepam has beneficial effects in generalized and focal epilepsies.

Gamma-Aminobutyric acid (GABA) is considered the principal inhibitory neurotransmitter in the human body. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons. Subsequently, benzodiazepines like clonazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors. This binding acts to enhance the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors. This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the aforementioned chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells. Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist both peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action. In particular, when out of the ordinary rapid and repetitive electrical signals are released in the CNS, it is proposed that the brain can become over-stimulated and ordinary functions are disrupted - resulting in seizure activity. By enhancing the neuro-inhibitory activity of GABA, it is believed that clonazepam can facilitate in decreasing any excessive electrical nerve activity in the CNS that might be contributing to seizures. Concurrently, it is also believed that clonazepam's actions in enhancing GABA effects may inhibit neuronal activity proposed to occur

The mean elimination half-life determined for clonazepam is independent of the dose given and has been documented as being about 30-40 hours.

Elimination half-life ... 18.7 to 39 hr.

Clonazepam is metabolized principally in the liver. The metabolic pathways include hydroxylation, reduction of the nitro groups to amine groups, and the addition of acetate to the amino grouping. In particular, clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamido-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites.

The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors. Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders. The patients' CYP3A4 expression was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263.5 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, P<0.0001). Consequently, the dose requirement for the therapeutic concentration of clonazepam was substantially lower in low-CYP3A4 expresser patients than in normal expressers (0.029 +/- 0.011 vs 0.058 +/- 0.024 mg/kg bodyweight, P<0.0001). Furthermore, significantly higher (about 2-fold) plasma concentration ratio of 7-amino-clonazepam and clonazepam was observed in the patients displaying normal CYP3A4 expression and slower N-acetylation than all the others. Prospective assaying of CYP3A4 expression and N-acetyl transferase 2 acetylator phenotype can better identify the patients with higher risk of adverse reactions and can facilitate the improvement of personalized clonazepam therapy and withdrawal regimen.

Clonazepam is extensively metabolized in the liver to several metabolites including 7-aminoclonazepam, 7-acetaminoclonazepam, and 3-hydroxy derivatives of these metabolites and clonazepam. Clonazepam metabolites are excreted in urine by first-order kinetics, principally as their glucuronide and/or sulfate conjugates.

Hepatic (cytochrome P450, including CYP3A). Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated, and glucuronidated. Route of Elimination: Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Metabolites of Klonopin are excreted by the kidneys. Clonazepam also undergoes acetylation via NAT2. Half Life: 30-40 hours

5PE9FDE8GB

CLONAZEPAM

Established Pharmacologic Class [EPC] - Benzodiazepine

Chemical Structure [CS] - Benzodiazepines

Clonazepam is a Benzodiazepine.

CLONAZEPAM

Drugs used to prevent SEIZURES or reduce their severity.

Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.

Clonazepam is rapidly and almost entirely absorbed after oral administration as tablets. Peak plasma concentrations of clonazepam administered by the oral route are reached within 1-4 hours and the associated absorption half-life is about 25 minutes. The absolute bioavailability is approximately 90% - but with substantially large differences between individuals.

Approximately 50-70% of a clonazepam dose is excreted in the urine and 10-30% is excreted in the feces as metabolites. The excretion of unchanged clonazepam in the urine is typically less than 2% of the administered dose. Metabolites of clonazepam are present in urine as both free and conjugated (glucuronide and sulfate) compounds.

Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures. The apparent volume of distribution has been documented as approximately 3 L/kg.

The documented clearance for clonazepam is approximately 55 ml/min regardless of gender. Nevertheless, clearance values normalized by weight decline with increasing body weight.

/MILK/ A 2750-g female infant was born at 36 weeks' gestation to a 40-year-old woman treated with clonazepam throughout her pregnancy. The infant developed apnea, cyanosis, and hypotonia within a few hours of birth. The mother's serum clonazepam level at delivery was 32 ng/mL; the cord blood level was 19 ng/mL. The infant had no congenital malformations, evidence of infection, or seizures. Clinical episodes ceased by ten days of age. The woman elected to breastfeed; breast milk clonazepam levels were between 11 and 13 ng/mL. She was discharged with a cardiorespiratory monitor. The authors suggest that infants of mothers receiving this agent during pregnancy or while nursing have serum levels measured. Additionally, these infants should be monitored for central nervous system depression or apnea.

Clonazepam is rapidly and well absorbed from the GI tract. The absolute bioavailability is approximately 90%. In one study, peak blood concentrations of 6.5-13.5 ng/mL were usually reached within 1-2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4-8 hours. Although the plasma concentration of clonazepam required for anticonvulsant effects has not been definitely established, some studies indicate it may be 20-80 ng/mL. Plasma concentrations in this range have been reported to be maintained in adults receiving 6 mg of clonazepam daily in 3 divided doses and in children 6-13 years of age receiving 1.5-4 mg of the drug daily in 3 divided doses. The onset of anticonvulsant action usually occurs within 20-60 minutes, and the duration of action usually is 6-8 hours in infants and young children and up to 12 hours in adults.

Clonazepam (DEA Code Number: 2737) is a Schedule IV controlled substance.

Schedule IV Controlled Substance: (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III. (B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III.

MEDICATION

MEDICATION (VET)

Anticonvulsants; GABA Modulators

Use (kg; approx.) in Germany (2009): >25；Use (kg) in USA (2002): 409；Use (kg) in France (2004): 21；Consumption (g per capita; approx.) in Germany (2009): 0.000305；Consumption (g per capita) in the USA (2002): 0.00145；Consumption (g per capita) in France (2004): 0.000348；Calculated removal (%): 10.3

ortho-Chlorobenzoyl chloride is reacted with para-nitroaniline to form 2-amino-5-nitro-2'-chlorozophenone, and this is condensed with bromacetyl to form 2-bromoacetamido-5-nitro-2'-chlorobenzophenone, then with ammonia to form the corresponding acetamido compound. The acetamido compound is converted to its hydrochloride with anhydrous HCl in methanol, dissolved in boiling methanol, and cyclized to clonazepam with pyridine as the catalyst.