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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by europerep on January 16, 2015, at 15:21:41
Hey all, and hopefully also hey Ed ;-)...
It's been a while since I last posted, but I wanted to briefly ask a question that others here may have already looked into as well.
For about two or three years now, I've been taking amitriptyline and nortriptyline, and I'm doing much better now than before.
But I only really got to the point where I am now by deciding to abandon the conventional doses that those drugs are supplied in, and make my own customized doses. The dose intervals of 25mg (for extended release) or 10mg (for immediate release) are, in my experience, far too wide. I notice clear differences in my mood by adding or taking away a single milligram of active ingredient. I don't really want to start a debate about med sensitivity, I just see the drastic improvement I have experienced recently and I must be doing something right. (And if this is a placebo effect, then well, as long as it works I won't complain.)
For amitriptyline, making customized doses is relatively easy by using capsules filled with beads or pellets and simply counting them. But I do want to slightly fiddle with my nortriptyline now, and here it gets tricky. As far as I know, there is no nortriptyline extended release available anywhere, and the product I get here is a simply white pill, described in the marketing authorization as follows: "Other ingredients consist of pharmaceutical excipients lactose monohydrate, maize starch and magnesium stearate."
I have halved pills before without a problem, but what I want to do is to go from 10mg to something like 9mg. Is it possible to simply cut off a bit of the pill at the side, or is the active ingredient concentrated somewhere in the "core" so that this will have either no effect or make doses with little reproduceability? I do have a fine scale I could use to verify the weight if that helps, but it's of course not an analytical scale. (It measures single milligrams with a reproduceability of +/- 2mg.)
I'm sorry if this post is a bit incoherent, I'm in a hurry and I had meant to post this question for a couple of days now, so I just wanted to go ahead and post. I'd appreciate any input or experiences. Of course I know that noone here can give me a definite answer, but I'd already be happy with "it might work so it's worth a try".
If more specific information is needed, that's not a problem, just let me know.
Thanks!
ER
Posted by Phillipa on January 16, 2015, at 15:32:29
In reply to Splitting pills. Reliable or not? (@Ed and others), posted by europerep on January 16, 2015, at 15:21:41
Personally I split pills daily and not exactly. If not extended release I see no reason not to chip off a small piece of the pill. Phillipa
Posted by Zyprexa on January 16, 2015, at 22:25:55
In reply to Splitting pills. Reliable or not? (@Ed and others), posted by europerep on January 16, 2015, at 15:21:41
I split pills every day. doc says its fine. pretty sure that the active ingredient is mixed through out the pill. I even split 'er' pills. just don't crush them.
Posted by ed_uk2010 on January 17, 2015, at 13:52:35
In reply to Splitting pills. Reliable or not? (@Ed and others), posted by europerep on January 16, 2015, at 15:21:41
> Hey all, and hopefully also hey Ed ;-)
Hi!
>I don't really want to start a debate about med sensitivity, I just see the drastic improvement I have experienced recently and I must be doing something right.
There's a very large variability in the blood levels of tricyclic antidepressants in patients given the same dose, probably due to genetic differences in hepatic metabolism. It makes sense that dosage requirements for these drugs are very variable.
>As far as I know, there is no nortriptyline extended release available anywhere
I've never heard of such a product either.
>Other ingredients consist of pharmaceutical excipients lactose monohydrate, maize starch and magnesium stearate...
Some nortriptyline tablets have a thin 'film' coating. Do yours not? You've not mentioned any ingredients used to coat tablets above. Have you listed all the tablet ingredients? If you have, your tablets are not coated. Coated tablets may have ingredients such as glycerol and methylhydroxpropyl cellulose (or another similar polymer). Many manufacturers choose to add a film coating to help mask the taste of the drug. With tricyclics, film coating may also reduce the temporary numbness that occurs when the drug comes into contact with the lining of the mouth.
Lactose is a diluent. It wouldn't be possible to make 10mg of drug into a tablet without diluting it. Thorough mixing ensure even dispersion of the drug. Starch is used to bind the tablet together and to help it disintegrate quickly in the digestive tract. Magnesium stearate is a lubricant used in tablet manufacturing. Tablets are made by compressing a pharmaceutical powder under high pressure. A lubricant allows the powder to glide through the machinery.
>I have halved pills before without a problem, but what I want to do is to go from 10mg to something like 9mg. Is it possible to simply cut off a bit of the pill at the side, or is the active ingredient concentrated somewhere in the "core" so that this will have either no effect or make doses with little reproduceability? I do have a fine scale I could use to verify the weight if that helps, but it's of course not an analytical scale. (It measures single milligrams with a reproduceability of +/- 2mg.)The nortriptyline should be evenly distributed throughout the tablets unless they are film coated, in which case things are slightly more complicated because the coating is 'sprayed' onto the tablets near the end of the manufacturing process and therefore contains little drug substance. Breaking fragments off uncoated tablets may produce more accurate dosages (compared with coated tablets) because the drug is evenly distributed throughout the entire tablet. On the other hand, film coatings are extremely thin, so it probably wouldn't make any clinical difference. It's hardly important for the dose of nortriptyline to be consistent to the microgram level!
If you do break fragments off the tablets it's best to dispose of the unused portion. Keeping lots of 'bits' may be a bad idea because they could absorb moisture from the air and degrade over time.
Does this answer your Q?
Posted by europerep on January 17, 2015, at 15:15:08
In reply to Re: Splitting pills. Reliable or not? (@Ed and others), posted by ed_uk2010 on January 17, 2015, at 13:52:35
Hi Ed :)...
To answer your last question first, yes, your reply helps me a lot. I'll just address a few things you said:
> There's a very large variability in the blood levels of tricyclic antidepressants in patients given the same dose, probably due to genetic differences in hepatic metabolism. It makes sense that dosage requirements for these drugs are very variable.
Hmm, I did not know this yet, but this could indeed be an explanation. What happened was that I'd add 25mg of amitriptyline (i.e. one capsule) to my daily dose, and I'd feel better for a day or two, but the improvement then disappeared. Then I'd take the capsule away again, and now too I'd briefly feel better. So I thought, maybe the right dose for my is somewhere in between, and that's how I came to prepare my individual doses. And it really works pretty well. I'm sure at least some patients out there would benefit from an availability of a wider dose range for these drugs...
> Some nortriptyline tablets have a thin 'film' coating. Do yours not? You've not mentioned any ingredients used to coat tablets above. Have you listed all the tablet ingredients? If you have, your tablets are not coated.
Yeah, I was wondering that too. I found the same quote from the internet that I posted yesterday in the package insert, with no further information. The word "include" suggests to me that there may be other ingredients in it, but they're not specified. It happens to be a UK product, so if you want I can tell you the manufacturer's name, and you could verify that. Only if you want of course.
But I was precisely wondering whether the pills have a coating that does not contain any active ingredient. Visually there is none, both from what the tablet looks like (compared to others I had that were coated), and if you cut the tablet and then look at the inside, there are no separate layers. But there could well be two layers that just happen to have the same colour.
> Breaking fragments off uncoated tablets may produce more accurate dosages (compared with coated tablets) because the drug is evenly distributed throughout the entire tablet.
This sounds good!
> It's hardly important for the dose of nortriptyline to be consistent to the microgram level!
I had been wondering about that as well. Do you happen to know how big the allowed variations of active ingredients in pharmaceutical products are? I wouldn't be surprised if even "real" (i.e. non-manipulated) tablets would show some variation in the microgram level that are not noticeable by the patient.
> If you do break fragments off the tablets it's best to dispose of the unused portion. Keeping lots of 'bits' may be a bad idea because they could absorb moisture from the air and degrade over time.
Thanks, this advice seems reasonable as well.
> Does this answer your Q?So, yes, this is all very helpful, thanks a lot!
ER
Posted by ed_uk2010 on January 17, 2015, at 15:56:23
In reply to Re: Splitting pills. Reliable or not? (@Ed and others) » ed_uk2010, posted by europerep on January 17, 2015, at 15:15:08
Hi!
>yes, your reply helps me a lot...
Oh good.
>I'm sure at least some patients out there would benefit from an availability of a wider dose range for these drugs...
They probably would, yes. Such issues tend not to get explored a great deal because doctors prefer to think of drugs as having an effective dose range which is similar for most patients - this makes medicine easier. Such doses are usually derived from clinical trials and therefore give the prescriber an idea of what dose is likely to be suitable for most patients. This does not, of course, account for individual differences in drug metabolism, elimination and clinical response. Individual differences are much greater for some drugs than others. In general, differences in dosage requirements are most pronounced for drugs with a narrow therapeutic index (ie. a small difference between the effective and toxic blood level) where there are also large differences in metabolism and elimination between patients. Drugs such as TCAs, which rely a lot on the liver enzyme CYP2D6 for metabolism, require a particularly individual titration partly due to large differences in CYP2D6 enzyme activity - which is controlled by inherited genetic factors (but interacting drugs are also frequently relevant). On the other hand, due to differences in the way various people's brains respond to the drug, it's hard to correlate the drug level to the response.
>It happens to be a UK product, so if you want I can tell you the manufacturer's name, and you could verify that.
Sure, what is it? I'm not aware of that many different products. There's King pharma (which are film coated), NRIM pharma (not film coated) and a blister packed import called Paxtibi. I suspect your tablets are made by NRIM. Correct?
Germany, Italy, the Netherlands and Spain have accepted the NRIM product license based on the mutual recognition procedure - in this case with the UK acting as the reference member state.
Posted by ed_uk2010 on January 17, 2015, at 17:03:17
In reply to Re: Splitting pills. Reliable or not? (@Ed and others) » ed_uk2010, posted by europerep on January 17, 2015, at 15:15:08
>I wouldn't be surprised if even "real" (i.e. non-manipulated) tablets would show some variation in the microgram level that are not noticeable by the patient.
There will always be variation - no quantity can ever be exact. What's important is whether or not the differences are clinically relevant.
For pharmaceuticals, regulations are set out in the European Pharmacopoeia, the United States Pharmacopeia etc.
The rules are listed under the heading 'Uniformity of Dosage Units'. The decision to accept or reject a batch is based on a *statistical calculation*. This is because it's not possible to analyse every tablet..... the tablets are destroyed during the analytical/assay process.
Posted by europerep on January 18, 2015, at 15:17:32
In reply to Re: Splitting pills. Reliable or not? (@Ed and others), posted by ed_uk2010 on January 17, 2015, at 17:03:17
> Sure, what is it? I'm not aware of that many different products. There's King pharma (which are film coated), NRIM pharma (not film coated) and a blister packed import called Paxtibi. I suspect your tablets are made by NRIM. Correct?
Yes indeed, it's the NRIM. It's really good to hear that these are not coated, so I don't have to worry about this any longer.
> There will always be variation - no quantity can ever be exact. What's important is whether or not the differences are clinically relevant.
Of course, it's clear that no two tablets will even contain the same amount of molecules of the active ingredient. I just meant that I could imagine that there is a variation that, as far as technology is concerned, could easily be reduced, but that this would only make production more expensive without making a real difference for the patient.
> The decision to accept or reject a batch is based on a *statistical calculation*. This is because it's not possible to analyse every tablet..... the tablets are destroyed during the analytical/assay process.
Yeah, I had imagined that this would like that. What I find surprising is that, every now and then, batches of drugs *are* recalled because of excessive variation of the active ingredient. As far as I know, this is only a small part of all the recalls, but it does happen. (It happened recently here with an amitriptyline product I was taking.) Why don't they test the batch beforehand and only distribute it if the tests come out ok? That's not just easier but also so much cheaper than organizing a recall, plus of course the potential impact on patients. Do you have an idea why that is?
But I also have one more follow-up related to my initial question? Will the fact that I cut the tablet change anything about how quickly the active ingredient is released? I would assume that, since my product is an immediate release, there will be no noticeable difference, but is this indeed the case?
Thanks again! :)
Posted by ed_uk2010 on January 18, 2015, at 15:52:58
In reply to Re: Splitting pills. Reliable or not? (@Ed and others) » ed_uk2010, posted by europerep on January 18, 2015, at 15:17:32
>Yes indeed, it's the NRIM. It's really good to hear that these are not coated, so I don't have to worry about this any longer.
Glad to know my calculations were correct haha. And Yes, the drug should be evenly distributed. It's a simple tablet formulation.
>I just meant that I could imagine that there is a variation that, as far as technology is concerned, could easily be reduced, but that this would only make production more expensive without making a real difference for the patient.
True. It isn't going to make any difference whether the nortriptyline tablets contain 10mg, 9.8mg or 10.1mg etc. The amount your body absorbs isn't exactly the same every time you take a dose anyway.
The drug content of any tablet where the dose is measured in milligrams isn't too hard to keep constant. This is because thorough mixing makes the drug content of the power almost uniform before compression to form the tablets. Drugs dosed in micrograms or nanograms may require more advanced technology to ensure tabs/caps contain an accurate dose. This is because the amount of drug relative to the amount of other ingredients is very small.
>Why don't they test the batch beforehand and only distribute it if the tests come out ok?
They do test all batches before distribution. Each batch is 'released' by a QP 'qualified person' before sale to wholesalers. In some cases, a problem identified later, perhaps as a result of a complaint, will lead to further testing of a different (retained) sample from the same batch. On occasion, this identifies a small deviation from permitted criteria.
>Will the fact that I cut the tablet change anything about how quickly the active ingredient is released?No, I doubt it will make any difference at all.
Any changes in the amount of drug taken (and absorbed) is only likely to be the result of inaccurate measurement of the amount you've broken off!
Posted by ed_uk2010 on January 18, 2015, at 15:56:40
In reply to Re: Splitting pills. Reliable or not? (@Ed and others), posted by Zyprexa on January 16, 2015, at 22:25:55
>I even split 'er' pills. just don't crush them.
Some ER/modified-release tablets are designed to be split in half (and are scored). This type of tablet often relies on the drug being distributed throughout a polymer matrix which releases drug gradually.
On the other hand, other ER tablets will no longer be ER when split in half. An example is ER tablets which rely on an insolube casing containing a small hole to let the drug release gradually.... such tablets will become 'immediate release' when split.
Posted by europerep on January 19, 2015, at 15:36:23
In reply to Re: Splitting pills. Reliable or not? (@Ed and others), posted by ed_uk2010 on January 18, 2015, at 15:52:58
Thanks for the info and explanation, it's much appreciated!
Now I just have one last question relating to what you said earlier about throwing away the broken-off bits because they'd be exposed to humidity.
I certainly wouldn't want to keep or re-use those bits for future use. However, I currently always prepare my customized amitriptyline capsules for several days at the same time. (The doses I prepare are roughly 10mg per capsule, so I take one or two capsules of 25mg and make two or four custom capsules from them.) But if I do this similarly with my customized nortriptyline tablets, this might lead to the problem you described, right?
Would it be a solution to put each manipulated tablet in a small capsule so as to protect it from humidity, and then just swallow the capsule with the tablet in it? (Of course, there is also some air inside that capsule, but the exposure should probably be less.) I had actually been thinking of doing that anyway, because I remember from back when I split tablets in half that they would sometimes be a bit "crumbly". By putting them in a capsule, I wouldn't have to worry about small bits breaking off when handling the tablet.
Or should I better prepare my nortriptyline tablets one at a time? That would probably mean doing it in the evening for taking it the next morning. This would in any case not cause problems due to exposure to air and humidity, right?
Posted by ed_uk2010 on January 19, 2015, at 16:15:21
In reply to Re: Splitting pills. Reliable or not? (@Ed and others) » ed_uk2010, posted by europerep on January 19, 2015, at 15:36:23
>But if I do this similarly with my customized nortriptyline tablets, this might lead to the problem you described, right?
I don't see any reason not to prepare a few doses at once. I don't think nortriptyline is especially moisture sensitive. Maybe just make up to one week's supply at a time. I would not anticipate a problem with that.
Posted by europerep on January 19, 2015, at 16:20:29
In reply to Re: Splitting pills. Reliable or not? (@Ed and others) » europerep, posted by ed_uk2010 on January 19, 2015, at 16:15:21
> Maybe just make up to one week's supply at a time. I would not anticipate a problem with that.
Ok, cool, I definitely wasn't planning on doing more than that anyway.
I think those are all the questions I had regarding this, but if anything else comes up I'll post again. And as I said, I was slightly worried about a possible coating of my tablets, and knowing that they don't have one has certainly eased my mind a bit, so thanks a lot! :)
Posted by ed_uk2010 on January 20, 2015, at 8:56:38
In reply to Re: Splitting pills. Reliable or not? (@Ed and others) » ed_uk2010, posted by europerep on January 19, 2015, at 16:20:29
Good luck!
This is the end of the thread.
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