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  #1  
Old 08-08-2010, 15:04
Wanderer Wanderer is offline
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Clonazepam Wiki Discussion

>>
Note: This is a discussion thread for the Clonazepam (no location ATM) wiki. Please post completed chapters with a bold title in this thread, or mention if you have added them to the wiki. Please make sure you add citations as well.
>>

Well, here it is, I'm going to put the stake in the ground and start as per Alfa's suggestion and begin the Wiki entry for the Benzodiazapine Clonazepam.

It's under construction, and the next post I make will probably be the basic Wiki page structure for Cloneazepam.

Please have some patience because it will probably take me a day or two to get the initial rough of the entry done. This is also one of the "big" benzos and will probably be a very large entry.

Go easy, this is my first attempt at one of these

EDIT 1.1: Just added the "Official" Roche Package Insert for Klonopin PDF as an attachment here. Figure that's a good place to source information from. Will relocate this file to some other place when I figure out where it should go.

EDIT 1.2: Created skeleton wiki entry.

EDIT 1.3: Added Intruduction, Using and Uses information. The uses is copies pretty much word for word from the package insert monograph. I've re-worded and added information in the others beyond the basic package monograph information.

EDIT 1.4: Information on combinations and ROA's.

EDIT 1.5: Added link to picture.

EDIT 1.6: More information on interactions and effects

EDIT 1.7: More information on warnings, pharmacology - metabolic, and changed brand name refs.

EDIT 2.0: Converted most of the BBCode tags to the new tags. The tag [showthreads] doesn't seem to be working correctly. Also, need to create a TOC.

EDIT 2.1: Changed heading tags to conform to new Wiki. Added locations which need further reference and changed some of the wording as per suggestions from NeuroChi and Jatelka. Added information regarding IV delivery and the Rivotril information from eMC. Documents need to be moved to the document repository and made into links, but that will be another revision.

Post Quality Evaluations:
A great start, thanks for the time and effort put into this
Attached Files
File Type: pdf Clonazepam-package-insert.pdf (286.0 KB, 30 views)
File Type: pdf Rivotril Ampoules - electronic Medicines Compendium (eMC).pdf (145.3 KB, 17 views)

Last edited by Wanderer; 18-12-2010 at 02:37. Reason: Version 2.0 with updated BBCode for headings.
  #2  
Old 09-08-2010, 09:03
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Re: Clonazepam Wiki Discussion

[top]Introduction to Clonazepam


Clonazepam (from Roche as: Antelepsin, Antilepsin, Cloazepam, Clonopin, Iktorivil, Klonopin, Klonopin Rapidly Disintegrating, Landsen, Rivotril) is a long acting benzodiazapine with a half-life of 30-40 hours. Clonazepam is a CNS depressant with anxiolytic, anticonvulsant, and hypnotic effects.

Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72 and the following structural formula C15H10ClN3O3:

In addition to it's official labelled uses, it has other off-label and is sometime used recreationally as well. It is also used to counteract the effects of overdose symptoms for many licit and illicit drugs.

[top]Using Clonazepam


Branded clonazepam (Klonopin) is supplied as tablets with a K-shaped perforation containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation containing 1 mg or 2 mg of clonazepam. These tablets also contain the following inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5 mgFD&C Yellow No. 6 Lake; 1 mgFD&C Blue No. 1 Lake and FD&C Blue No. 2 Lake.

Clonazepam is also supplied as scored orally disintegrating tablets containing 0.125 mg, 0.25 mg, 0.5 mg, 1 mg or 2 mg clonazepam. These tablets are usually dissolved sub-lingually. These contain the following inactive ingredients: gelatin, mannitol, methylparaben sodium, propylparaben sodium and xanthan gum.

Generic clonazepam are supplied in the form of 0.5 mg, 1 mg or 2 mg scored orally disintegrating tablets.

Clonazepam is also supplied as Rivotril in 1mg/ml sterile solution as listed in the attached information from electronic Medicines Compendium.

[top]Routes Of Administration

[top]Orally

Tablets taken orally are swallowed according to the desired dosage. Scored tablets may be broken to adjust dosage.

[top]Sub-lingual


The orally disintegrating tablets are administered sublingually where some of the dose is absorbed through the mucous membrane, but more so the tablet is dissolved in saliva so it can be administered either with or without water.

[top]Insufflation


Tablets may be ground into a powder and insufflated, but this is not really more effective than sublingual absorption. Additionally, unless it is extracted the binders and fillers will be insufflated as well.

[top]IV

Rivotril sterile concentrate is for intravenous administration. For the treatment of status epilepticus, the dose and rate of administration are governed by the response of the patient.

Adults
1mg (one ampoule of active substance mixed with one ampoule of solvent for parenteral use) by slow intravenous injection.

Elderly
Care should be taken with the elderly.

Children
0.5mg (equivalent to half an ampoule of active substance mixed with half an ampoule of solvent for parenteral use) by slow intravenous injection.

Special dosage instructions
Rivotril can be administered with one or several other antiepileptic agents, in which case the dosage of each drug must be adjusted to achieve optimum effect.


As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but must be reduced in a stepwise fashion (see section 4.8 Undesirable effects).


Mode of administration
Rivotril must be diluted prior to administration in order to avoid irritation of the veins, see section 6.6 Instructions for use/handling.


Intravenous injection of Rivotril should be into a large vein of the antecubital fossa. The injection should be given slowly - in adults, the rate of injection must not exceed 0.25mg 0.5mg (0.5 1.0ml of the prepared solution) per minute and should be administered with continuous monitoring of EEG, respiration and blood pressure. This will greatly diminish the rare possibility of hypotension or apnoea occurring. Nevertheless, facilities for resuscitation should always be available. A total dose of 20mg should not be exceeded.

Rivotril sterile concentrate may be diluted when given in intravenous infusions of saline or glucose, such as are customary in the treatment of status epilepticus.

[top]Rectally

[top]Effects of Clonazepam


The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.

Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.

[top]Combinations with Clonazepam

[top]Alcohol


Alcohol use with clonazepam is not recommended because the two have a tendency to potentiate CNS depressant effects which can include somnolence, confusion, coma and diminished reflexes and even death.

[top]Antidepressants


With some antidepressants clonazepam is indicated to reduce the potential risk of seizure.

[top]Cocaine


Clonazepam has been known to moderate the anxiety associated with cocaine use.

Benzodiazapines such as clonazepam are indicated for acute cocaine ingestion in order to moderate the effects, though sometimes additional treatments such as nitroglycerine therapy are require in extreme cases.(need reference)

[top]LSD


Some users have reported that regular daily use of clonazepam can significantly reduce the effects of LSD.

Anecdotally, clonazepam is indicated for acute LSD ingestion in order to moderate the effects.(need reference)

[top]Other Drugs


Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.

[top]Different Uses for Clonazepam

[top]Seizure Disorders

Clonazepam is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam may be useful.

In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.

[top]Panic Disorder

Clonazepam is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of clonazepam was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder.

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The effectiveness of clonazepam in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use clonazepam for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

[top]Pharmacology of Clonazepam

[top]Pharmacodynamics

The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.

[top]Pharmacokinetics

Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.

[top]Pharmacokinetics in Demographic Subpopulations and in Disease States

At the time the attached referenced monograph was written it states that, controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients.

There is new updated information from patient studies done to recommend that monitoring liver function be done during extended clonazepam therapy. (need reference)

[top]The dangers of Clonazepam

[top]Pharmacodynamic Interactions


The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

[top]Warnings


Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.

[top]Overdosage

Human Experience: Symptoms of clonazepam overdosage, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished reflexes and possibly death.

Overdose Management: 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. Dialysis is of no known value.

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. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.

Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.

Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.

[top]Producing Clonazepam

[top]Forms of Clonazepam

[top]Legal status of Clonazepam

[top]United Nations

[top]USA

[top]EU

[top]Other Countries

[top]History of Clonazepam

[top]More Clonazepam Sections

[top]The latest Clonazepam threads

[showthreads]50[/showthreads]

Category: Benzodiazapine

[top]References


Roche Klonopin Tablet Package Insert Monograph

Drugbank Entry for Clonazepam

DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan;36(Database issue): D901-6. 
PMID: 18048412
DrugBank: a comprehensive resource for in silico drug discovery and exploration. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. Nucleic Acids Res. 2006 Jan 1;34(Database issue): D668-72. 
PMID: 16381955


Post Quality Evaluations:
excellent contribution, and good use of discussion thread correctly updating progress
Attached Files
File Type: pdf Clonazepam-package-insert.pdf (286.0 KB, 62 views)
File Type: pdf Rivotril Ampoules - electronic Medicines Compendium (eMC).pdf (145.3 KB, 10 views)

Last edited by Wanderer; 18-12-2010 at 02:32. Reason: Added overdose information
  #3  
Old 09-08-2010, 17:03
Alfa Alfa is offline
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Re: Clonazepam Wiki Discussion

Quote:
Originally Posted by wanderer View Post
[h4]Alcohol[/h4]
Alcohol use with clonazepam is not recommended because the two have a tendency to potentiate each CNS depressant effects.
Its very important not to understate dangers, when writing wiki articles. Risks need to be communicated very clearly. The above statement is correct, but does not sufficiently warn the reader. I suggest to make the statement a little bit stronger and to add an explanation why these drugs potentate each other(both act on GABA) and what it means when a CNS depressant effect is too strong(loss of functions, coma, death).
  #4  
Old 09-08-2010, 17:24
Wanderer Wanderer is offline
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Re: Clonazepam Wiki Discussion

I agree with you completely, and was just putting some text in as a placeholder, but you are correct that the combination there between alcohol and benzos is very serious.

Thanks again for pointing that out, and perhaps warnings and contra-indications should be in bold or another typeface to call attention to them?

Be well...
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Old 10-08-2010, 05:16
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Re: Clonazepam Wiki Discussion

Have stated what the potential increased CNS depressant effects are in the alcohol combination. This will likely not be the last location it appears.
  #6  
Old 10-08-2010, 15:09
Wanderer Wanderer is offline
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Re: Clonazepam Wiki Discussion

Have added additional information WRT warnings, pharmacology/metabolism and a few other edits.

I'm trying to find information on history, think i have a few located, but if anyone has any pointers it would be helpful.

Also, I'm pretty sure it can be administered IV, but cannot find any references to clonazepam being supplied for IV, if anyone has pointers to that, it would be helpful.

Thanks!
  #7  
Old 10-08-2010, 15:19
Wanderer Wanderer is offline
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Re: Clonazepam Wiki Discussion

Added more information pertaining to pharmacology.
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Old 10-08-2010, 15:40
Wanderer Wanderer is offline
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Re: Clonazepam Wiki Discussion

Added overdose information.
  #9  
Old 14-12-2010, 21:58
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Re: Clonazepam Wiki Discussion

Updated with new BBCode tags. [showthreads] does not seem to be working correctly. Or at least I can't figure it out and the documentation on that tag seems a bit lacking in what features and options are available in the local documentation.

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Great Work on this one !
  #10  
Old 16-12-2010, 21:18
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Re: Clonazepam Wiki Discussion

Nice work all the way through wanderer. Some notes:

top level headers should be h=1, and chapters should be h=2. currently yours start at h=2 and wont display properly if moved to the wiki.

'growing' can be removed from 'producing clonazepam'. Actually, I think the whole producing/growing section can be removed unless the synth is readily available.

Quote:
"Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied."
> Are you 100% sure this is the case? Bold statements should be avoided unless you can identify the reason you know that no studies of this nature have been done.

The same goes for the indication of Clonazepam for LSD ingestion. I suppose and medium acting benzo might be indicated, or clonazepam specifically? I've heard lorazepam being given to individuals in this case as well.
  #11  
Old 17-12-2010, 01:11
Wanderer Wanderer is offline
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Re: Clonazepam Wiki Discussion

Thanks for the review, when the hamster gets off the wheel, he'll follow-up on this.

Be well...
  #12  
Old 17-12-2010, 08:01
Jatelka Jatelka is offline
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Re: Clonazepam Wiki Discussion

Looking lovely wanderer.

Just a little nit-pick (sorry): When you say "Clonazepam is indicated for acute LSD ingestion in order to moderate the effects" (or the same for Cocaine), this implies a recognised medical indication. If this is the case, then a reference should be supplied. If a reference can't be given, then the language needs to be moderated...

"Anecdotally, some people use LSD to combat unwanted adverse effects from X, Y or Z"

(or something similar)

EDIT: Re IV Clonazepam, I can see multiple references to it being available (in Europe, at least) as Ampoules containing 1mg/ml, but I can't work out which company supplies it!
(Textbook of therapeutics: drug and disease management Richard A. Helms, David J. Quan 2006, ISBN: 0781757347)

There are also references to it being used IV in neonates, and a couple of it being used SC in Palliative Care

Last edited by Jatelka; 17-12-2010 at 08:17.
  #13  
Old 17-12-2010, 08:09
Wanderer Wanderer is offline
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Re: Clonazepam Wiki Discussion

Thanks for the input. Now with the upgrade, I'll try to make the changes and move the thing into the real wiki as well.

I'd also like to get information on IV administration if anyone knows about that. Can't seem to find anything about it.

Thanks again for the comments.


Be well...
  #14  
Old 17-12-2010, 08:17
Jatelka Jatelka is offline
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Re: Clonazepam Wiki Discussion

^^^ LOL, see my edit!

I've pmed a link to the emc re Roche's Clonazepam Ampoules

Re Rectal: "Clonazepam is well absorbed after rectal administration with peak blood levels occurring in 10 to 30 minutes (Jensen, P.K., Abild, K et al. Serum concentrations of clonazepam after rectal administration. Acta Neurologica Scardinavica 1983; 68, 417-20)

Last edited by Jatelka; 17-12-2010 at 08:27.
  #15  
Old 18-12-2010, 02:40
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Re: Clonazepam Wiki Discussion

Updated the Wiki entry here as follows:

  • Changed heading tags to conform to new Wiki.
  • Added locations which need further reference and changed some of the wording as per suggestions from NeuroChi and Jatelka.
  • Added information regarding IV delivery and the Rivotril information from eMC.
  • Attached the PDF information from eMC.

To Do:
  • Documents need to be moved to the document repository and made into links, but that will be another revision.
  • Also need to add rectal administration info...

Comments welcome from all.

Be well...
  #16  
Old 31-01-2011, 07:07
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Re: Clonazepam Wiki Discussion

Have moved the text in this thread to the Clonazepam Wiki Article. Hopefully it's in the correct place, and will continue to update it as time allow.

Any feedback and assistance is most welcome.

Be well...
  #17  
Old 13-02-2011, 01:33
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Re: Clonazepam Wiki Discussion

This article has been created, please continue discussion here.

Thread closed.
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