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methotrexate

Self-Injection Videos

How to inject methotrexate

September 12, 2017
How to inject methotrexate

Methotrexate is commonly prescribed to treat rheumatoid arthritis, psoriatic arthritis, psoriasis, as well as many other autoimmune diseases. It comes as a pill but in certain situations the medication may be more effective if it’s injected.  That being said, injectable methotrexate comes as a auto-injector pen but due to cost, often times we need to rely on the good old-fashioned method: needle, syringe, and a vial of methotrexate.  First, Dr. Farrell is going to teach us how to inject a vial of methotrexate.  In the second video, she will teach us how to inject with an auto-injector pen.

Preparing for your injection

  • Keep your medication stored in the refrigerator until use
    • Before injecting medication, take the vial out of the refrigerator.
    • Allow it to warm up to room temperature.
  • Pick a place in your house that is clean and has room for your materials (such as the kitchen table).
  • Wash your hands thoroughly with either:
    • Soap & water
    • Hand sanitizer
  • Chose an area to inject – Thigh or Stomach.
    • Chose an area that is intact and clear.
    • It should not have any of the following:
      • Cuts
      • Scrapes
      • Bruises
      • Psoriasis patches
      • If you have extensive psoriasis, inject between patches
      • Moles
      • Scars
    • Please rotate area each time you inject (shown in picture below).

Areas to inject subcutaneous medication

  • Cleanse chosen area
    • Cleanse chosen area with either of the following:
      • Alcohol swab
      • Alcohol and a cotton ball
    • Use the chosen alcohol material to “swipe” area
      • Can either use a circular motion or wipe in “strips”
      • Allow the area to dry

Injecting a methotrexate vial

Drawing the medication

  • If it is your first time using the vial, you will have to remove the plastic cap from the vial
  • Clean the top of the vial with an alcohol swab
  • Open syringe packaging and take syringe out
    • Be careful while doing this – the needle may come apart, so make sure the needle is securely on the syringe before moving on
  • Double check the dosage on your prescription.  Does your doctor want you to inject 0.5 mL? 0.6 mL?
  • Pull plunger to get air into the syringe
    • The amount of air should be half the amount of the dose that you are going to draw up (Example: if you need a dose that is 1 mL of methotrexate, draw up 0.5 mL of air)
  • Press the needle into the vial
    • Should be right into the center of the top of the vial at a 90-degree angle
  • Push the plunger to transfer the air into the vial
  • Flip the vial upside down with the needle still in
  • Pull back on the plunger to draw liquid into the syringe
    • If an air bubble appears into the syringe, push the plunger back up and try pulling out again
    • This may take a few tries before you get only medication into the syringe
  • Once you have withdrawn the dose of the medication that you need, flip the vial and take the needle out

Injecting the medicine

  • Pinch cleansed skin
  • Insert needle into the chosen area at a 45-degree angle
    • You may keep the skin pinched or let go of the skin
  • Push the plunger slowly to inject the medication
  • Once you have injected all of the medication, take the needle out of your skin

After the injection

  • Properly dispose of the entire syringe
    • NEVER recap the needle
    • Sharps Container
      • Can be purchased at your local pharmacy
      • Disposal
        • Hospitals may take full sharps containers, ask first.
        • Pharmacies and Doctors’ offices are not allowed to take used syringes or needles
  • Discard remaining materials in the trash (cap, alcohol swabs, etc.)

Injecting methotrexate with an auto-injector pen

Injecting Otrexup®

  • There will be a number “1” labeled on the auto-injector
    • Twist cap off
  • There will be a number “2” labeled on the auto-injector
    • Press with thumb to flip cap off
  • Place tip of the auto-injector on the skin at a 90-degree angle
  • Press button to release medication
    • Hold for 10 seconds
    • May feel a slight pinch and tingling as the medication goes in

Injecting Rasuvo®

  • There will be a yellow cap at the end that you will pull straight off
  • Place tip of the auto-injector on the skin at a 90-degree angle
  • Press button to release medication
    • Hold for 10 seconds
    • May feel a slight pinch and tingling as the medication goes in

After the injection

  • Properly dispose of the auto-injector.
    • Sharps Container
      • May be provided by the drug company (depending on the medication)
      • Can be purchased at your local pharmacy
      • You may use a coffee can if you are unable to attain a sharps container
      • Disposal
        • Hospitals may take sharps
        • Pharmacies and Doctors’ offices are not allowed to take used syringes or needles
  • Discard remaining materials in the trash (cap, alcohol swabs, etc.)

Credits

Jessica Farrell, PharmD.  Clinical Pharmacist, The Center for Rheumatology/Associate Professor, Albany College of Pharmacy and Health Sciences

With the help of Autumn Koniowka. Doctor of Pharmacy Candidate Class of 2018, Albany College of Pharmacy and Health Sciences, and Megan Phillips. Doctor of Pharmacy Candidate Class of 2018, Albany College of Pharmacy and Health Sciences.

A special thanks to Tammy Garren, PhD. Instructional Designer, Center for Innovative Learning, Albany College of Pharmacy and Health Sciences.

Methotrexate vial image: By Li Wa/Shutterstock

Injection site image: By British Columbia Institute of Technology (BCIT). Download this book for free at http://open.bccampus.ca [CC BY 4.0 (http://creativecommons.org/licenses/by/4.0)], via Wikimedia Commons

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.

Diseases and Conditions

How much alcohol is safe with methotrexate?

April 26, 2017
Is it safe to drink while taking methotrexate?

Can I drink alcohol when I take methotrexate?  This is one of the most often asked questions I’m asked in clinic when starting methotrexate.  I also suspect it is one of the reasons people sometime decline treatment with methotrexate.  This is a shame, because methotrexate the cornerstone medication for rheumatoid arthritis.

You would think the answer to this question is obvious.  Alcohol can cause liver failure and cirrhosis.  Methotrexate can also cause liver inflammation and fibrosis/cirrhosis.  So combining the two doesn’t sound like such a hot idea.  It turns out the answer to the question isn’t so black and white.

Yes, alcohol can cause liver failure, however, not everyone who drinks alcohol gets cirrhosis.  It tends to happen when someone drinks excessively for years.  The same goes for methotrexate.  Not everyone who takes methotrexate gets liver inflammation.

The real question is, how MUCH alcohol is safe to take with methotrexate?  Shockingly there was little if any data addressing this question until recently.  How much alcohol is too much?  How much alcohol is likely safe?

Science to the rescue!  A recent study from the UK specifically addressed this question¹.  But before I get into that, let’s quickly review what a standard unit of alcohol actually is.  “I drink alcohol socially” simply isn’t going to cut it.  “Social” is highly variable!


What is a standard unit of alcohol?

This depends on the country you’re talking about.  Every country defines a unit of alcohol differently.  Since I’m writing based from the US, I define a unit of alcohol as follows:

“NIH standard drink comparison” by the National Institutes of Health is in the public domain in the United States.  This file has been identified as being free of known restrictions under copyright law, including all related and neighboring rights.

Moreover, each country has their own definition for the maximum amount of alcohol per week.  Some countries are more permissive than others.  In the US, defines low risk drinking for women as no more than 3 drinks on a single day and no more than 7 drinks per week.  Men can drink no more than 4 drinks on a single day and no more than 14 drinks per week².

Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate

Researchers in the UK recently looked into this matter.  As I alluded to, our current guidelines actually offer no specific guidance about alcohol and methotrexate.  In the UK, “patients taking methotrexate should limit their alcohol intake to well within the UK national recommendations”… whatever that means.  The American College of Rheumatology offers similar non-specific guidance.  When I was training, some mentors would have a strict “no alcohol” policy and some would say, a glass of wine or two per week should be okay.

The aim of the recent study was to quantify the risk of alcohol consumption on hepatotoxicity (liver damage) in a contemporary group of methotrexate users with rheumatoid arthritis, in a large national primary care database.

Methods

The researchers recruited people from the Clinical Practice Research Datalink (CPRD) which is a large database of information gathered by primary care providers.  They looked at all patients identified as having rheumatoid arthritis and starting methotrexate after 1987 up until Feb 2016.  People were included if their liver enzymes were measured at least six times per year.

The researchers want to measure any episode of liver inflammation (transaminitis) defined as a level that was three times the upper limit of normal.  This was called the primary definition of transaminitis.  Since we know that persistently elevated liver inflammation can lead to liver fibrosis, the researchers were also interested in identifying people that that have three back-to-back levels that were above the upper limit of normal.  This was called the secondary definition of transaminitis.

Alcohol consumption was measured first by seeing whether the person drinks alcohol, yes or no.  Then the person’s alcohol consumption was categorized:

  1. Mild: 1-7 units per week
  2. Moderate: 8-14 units per week
  3. Moderate-high: 15-21 units per week
  4. High: > 21 units per week

Results

The researchers identified 44 586 people but only included 11 839 people in the study.  The people that were excluded typically were a little younger, were female, and tended to drink no alcohol or very little alcohol.

Using the primary definition of transaminitis, there were 530 first episodes in 47 090 person-years.  That’s about 11.26 per 1000 person-years.  This rate was similar between drinkers of alcohol and non-drinkers of alcohol.  There was no increased risk in the occurrence of transaminitis in drinkers compared with non-drinkers.  But this is pulling all the data together.  What about people who drank mildly vs moderately vs high?

After analyzing the data ever further, the researchers found, unsurprising, that the rate of transaminitis increased with increasing levels of alcohol consumption.  Drinking mild to moderate amounts of alcohol was not associated with transaminitis.  Drinking more than 21 units of alcohol per week tended to be associated with transaminitis.

Alcohol consumption below 14 units per week was associated with a very low probability (0.93%) of having clinically important risk of transaminitis.  Alcohol consumption in excess of 14 units per week was associated with increasing risk of transaminitis.  More specifically, the risk was 33% with moderate-high consumption (15 – 21 units weekly) and 81% with high (>21 units weekly) consumption.

When the researchers used the secondary definition of transaminitis, i.e., 3 or more consecutive episodes of increased liver enzymes above the upper limit of normal, they found similar data: Mild = 0.01%, moderate-high = 8%, and high 17%.

Limitations

No study is perfect.

First, the data came from a primary care database.  This means, it was the PCP or rather the general practitioner that was responsible for coding the diagnosis appropriately, not a rheumatologist.  That being said, some misclassification may have occurred inadvertently.

Another issue was that the amount of amount of alcohol consumption was self-reported.  Most people tend to under report their alcohol consumption, so we can kind of assume that the levels of alcohol reported by the people in the study were actually a lot more than stated.

Another limitation included the fact that many people were excluded because their liver enzymes were measured less than 6 times per year.  Things get a little muddled up here.  People that have their blood tested less often statistically have a decreased chance of having an abnormal test simply because they get tested less.  Then again, having your blood tested 6 times a year is a bit much, unless that person has risk factors that put them at increased risk of developing liver problems.

An important limitation is the fact that the dose of methotrexate was not included.  There could be an increased risk of hepatotoxicity if someone were to take 25 mg of methotrexate weekly versus someone who takes 10 mg.

It’s also unclear whether these results are generalizable to other autoimmune diseases.  Methotrexate is also used to treat psoriasis and psoriatic arthritis.  The study only included people with rheumatoid arthritis.  People with rheumatoid arthritis and psoriasis are not the same.  People with psoriasis tend to have more liver problems in general.  For example, they tend to develop fatty liver.  So the risk of hepatotoxicity with alcohol could be different.

Lastly, some people say that measuring liver function tests (AST and ALT) may be insufficient to actually assess long-term damage from methotrexate because some people develop liver fibrosis without having transaminitis.  The problem with the studies that look at methotrexate and liver fibrosis are for the most part, dated and most looked at people with psoriasis.  As I mentioned, people with psoriasis tend to have more liver problems than people with rheumatoid arthritis.  It’s also important to note that since the 80’s, we’ve changed the way we prescribe methotrexate as well as changed the way we check labs.  Measuring liver function tests, NOT performing serial liver biopsies to monitor methotrexate toxicity, remains current best practice.

On a side note, liver function tests is kind of misnomer because the AST and ALT actually don’t measure liver function.  They measure liver inflammation.

Conclusion

According to this study modest amounts of alcohol consumption when taking methotrexate may not be as harmful as once though.  I would like to remind you that the information provided today does not constitute medical advice.  Please talk to your doctor.  Everyone’s health is unique.  Please leave comments below!

References

  1. Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis.2017 Mar 23. pii: annrheumdis-2016-210629. doi: 10.1136/annrheumdis-2016-210629. [Epub ahead of print]
  2. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics
Diseases and Conditions

What are the risks vs. benefits of biologic therapy?

March 8, 2017

Some of you may recall one of my previous posts where I attempted to dispel some of the myths commonly associated methotrexate.  Don’t get me wrong, I frequently use methotrexate.  It is considered gold standard for the treatment of rheumatoid arthritis.  And this is despite the armada of new fancy medications coming onto the market.  The American College of Rheumatology doesn’t call it the gold standard for nothing.

But sometimes it isn’t enough.

It’s estimated that about 30% of people achieve either remission or very minimal disease activity with methotrexate alone.  That leaves the other 70%.  Maybe this includes you?  In this situation, your rheumatologist may either recommend you to combine methotrexate with another conventional disease modifying anti-rheumatic drug (DMARD) or either to combine it with a biologic DMARD.  The decision is very complex and will vary from person-to-person and from rheumatologist-to-rheumatologist.  Were there issues with the ability to tolerate the medication, allergies, other medical conditions, insurance coverage, safety profile concerns, etc?  And then there’s just style.

DMARDs

In the best of situations, ALL people diagnosed with rheumatoid arthritis should be started on a DMARD as quickly as possible.  For those who don’t really know me, the tone of this statement is very uncharacteristic of me.  I loathe dogma and authoritarian statements in general.  But when it comes to DMARDs and rheumatoid arthritis, people that receive these medications as soon as possible do better and have less joint damage.  It’s important to achieve remission or have very minimal disease activity as soon as possible and as long as possible.

So what is a DMARD? For a medication to be considered a DMARD it has to change the course of the disease, for the better:), for at least one year.  There should be improvement in either physical function, decreased swelling, or slowing/prevention of joint damage.

To understand why your doctor may want to start a biologic medication, it’s important to understand what is meant by a conventional vs. a biologic DMARD.

I would say there are two main differences between conventional DMARDs and biologic DMARDs: mechanism of action and cost.  Conventional DMARDs do NOT directly target a specific type of inflammation.  Biologics do.  This means that biologics are a lot more molecular complex.  This also means that they are A LOT more expensive.  Even in countries like Canada, where the single payer system has the ability to negotiate prices with pharmaceutical companies, the price is still very high.  I could on and on with this subject, but I’ll leave that for another post.

Conventional DMARDs

  • Often used
    • Hydroxychloroquine
    • Methotrexate
    • Leflunomide
    • Sulfasalazine
  • Not really used
    • Azathioprine
    • Mycophenolate, sometimes used for rheumatoid arthritis affecting the lungs
    • Cyclophosphide, used for life or organ threatening disease
    • Cyclosporine
    • Gold injections

Biologic DMARDs

  • Tumor necrosis factor inhibitors
    • Etanercept
    • Adalimumab
    • Golimumab
    • Certolizumab pegol
    • Infliximab
  • Interleukin-6 inhibitors
    • Tocilizumab
  • Co-stimulation inhibitors
    • Abatacept
  • JAK inhibitors
    • Tofacitinib
  • B cell depletion
    • Rituximab

There are other medications that are coming down the pipeline, but these are the ones that are FDA approved and commercially available for the treatment of rheumatoid arthritis.  There are other biologic medications like belimumab, apremilast, ustekinumab, and secukinumab that are used for other diseases like systemic lupus erythmatosus, psoriatic arthritis, and ankylosing spondylitis.

Triple therapy vs. methotrexate + biologic

Generally triple therapy refers to the simultaneous use of methotrexate + sulfasalazine + hydroxychloroquine for the treatment of rheumatoid arthritis.  A Cochrane meta-analysis recently found that triple therapy typically is just as effective as methotrexate + a biologic or tofacitinib alone.  So why is your doctor proposing going to a biologic medication instead of going to triple therapy?  It certainly would be cheaper.

This is where I would say is one of the potential benefits of biologics: the ability to tolerate treatment long-term.  Let’s put things into perspective.  When you take an antibiotic, you may end up with some GI discomfort, diarrhea, some nausea, etc.  You receive 7 days worth of treatment, the infection is gone, it usually takes a few more days for things to settle down, but then it’s done.  When it comes to the vast majority of rheumatic conditions like rheumatoid arthritis, some form of medication is consistently needed to keep the disease in remission. If you stop, the disease flares.  Don’t get me wrong, there are exceptions.  Sometimes the disease goes into permanent remission or “burns out”.  This is rare and definitely is not the rule.

The problem with triple therapy is that it tends to be very difficult to tolerate long-term.  Most people could tolerate a few weeks, but we’re talking years, decades, lifetime.  Many people stop one or more of the medications without telling their doctor, others take them sporadically.  Basically, there’s a lot of non-compliance with treatment when people receive triple therapy.

It isn’t necessarily because those people are irresponsible.  It’s that the medicines are making them feel sicker than their actual disease!

Simply put, biologics tend to be a lot easier to tolerate long-term and to bout SOME can be used as monotherapy i.e., you don’t need to combine with methotrexate.

Onset of action

I wouldn’t say that this is necessarily the most important factor when making a decision to go with a biologic instead of sticking to conventional DMARDs but I guess it could help tip the balance in certain situations.  In general biologic DMARDs tend to work a little more quickly that conventional.  This greatly varies from biologic-to-biologic.  Generally conventional DMARDs taking between 3 – 6 months to fully work.  It tends to be closer to the 3 month mark.  For most biologics it can take up to 3 months.  Certain ones like abatacept can take up to 6 months as well.

Cost

Most biologics cost over $ 1 100 per month.  Mind you, hardly anyone actually pays $ 1,100 per month.  Before starting a biologic medication, you doctor’s office will obtain authorization from your insurance company prior to prescribing the medication.  When the medication is authorized, your doctor will send it to your prescription mail-order company, and then it will be mailed to you.  Co-pays vary from $5 a script to a few hundred dollars in extreme cases.  It really depends on your insurance coverage.  It’s very important to keep your doctor but also your doctor’s medical secretary and if your doctor is extra lucky, your doctor’s patient advocate, appraised of all changes to your insurance.  It can mean the difference between a $5 co-pay and a second mortgage.  Most pharmaceutical companies have patient assistance programs.  Some are better than others… and some are better advertised than others.

Conventional DMARDs are a lot cheaper.  For example, methotrexate comes in 2.5 mg tablets.  20 tablets cost a little over $25.  This is the price if you had no insurance and were paying completely out of pocket.  Someone taking oral methotrexate will typical take between 24 to 40 tablets per month.  For most people this is doable even without any insurance.

Conversely, if you were receiving etanercept and had no insurance, your out of pocket cost would be about $3,500 per month.  Again, your doctor’s team will work to have the medication covered, but it’s still something to think about.

Method of delivery

This may be a non-issue for many people but it may be for some.  Most biologics need to either be injected or infused.  So far, only tofacitinib (rheumatoid arthritis) and apremilast (psoriatic arthritis) are taken orally.  There are pros and cons for both injections and infusions but generally, if your needle phobic, this may be a problem.  Infusions are time consuming because you need to come to the clinic to receive the infusion.  They typically last between an hour to half a day depending on the medication.  Some are dosed every month others every 8 weeks.  Rituximab is every 6 months but this is an exception.  Most injections are either given every week or every other week.  Some are a lot less frequent like ustekinumab, but again this is an exception.

Conversely, all the conventional DMARDs are oral except for cyclosphosphamide and gold.  I’ve never prescribe cyclophosphamide for rheumatoid arthritis… ever.  First, we simply do not encounter many people with life-threatening complications caused by rheumatoid arthritis anymore because the vast majority of people with the condition are treated with DMARDs very early into their disease.  Second, there are many other medications on the market that are a whole like better.  Don’t get me wrong, there are certain very serious indicated clinical situations.  Just wrote an order for it last week… my first in a year and it wasn’t for RA!

Infection risk

One of the big differences between conventional DMARDs and biologics is the infection risk.  Biologic medications generally are a lot more immunosuppressive than conventional DMARDs.  Again there are exceptions.  For example, abatacept is generally thought to have less of an infection risk.

I have to stress that this does not mean that people taking biologics get a ton of infections.  But it becomes extra important to keep up with routine vaccinations, adhere to proper hand washing, and try to stay away from high risk situations as much as possible.  It may also not be such a great idea to be on a biologic if you are prone to getting infections.  Let’s face it, no one wants 10 sinus infections in one year.  It also may not be such a great idea to be one some of these biologics if you have very serious lung problems.  I probably will try to avoid most biologics if someone has severe COPD requiring extra oxygen.  Pneumonia could be life-threatening in this situation.

Another important noteworthy point, certain biologics can re-activate dormant infections such as tuberculosis, hepatitis B+C, and zoster.  It’s important to screen for both tuberculosis and hepatitis B+C prior to initiation of therapy.   You may need to start therapy for these latent infection prior to treatment with biologics.  For zoster also known as shingles, you may benefit from the shot one month prior to treatment with biologics.  The shingles shot is a live vaccine and should NOT be given while taking a biologic medication.  Like I said, you need to wait a month.  Please contact your rheumatologist for more information.

Miscellaneous

There are a few other items of concern but these vary from medication to medication irrespective of whether that medication is a conventional DMARD or a biologic.  The following are items to consider when choosing the most appropriate medications.

  • History of hepatitis C
  • History of HIV
  • History of a demyelinating disease like multiple sclerosis
  • History of severe congestive heart failure
  • History of lymphoma or leukemia
  • History of melanoma
  • History of a solid cancer within the last 5 years (e.g., breast cancer)
  • History serious liver disease
  • History of a serious kidney disease
  • History of serious lung disease
  • History of serious diverticulitis or bowel perforation
  • History of gastric bypass surgery
  • History of macular degeneration
  • History of organ transplant
  • Allergy history
  • Current medications.  Are there any possible drug interactions? (e.g., azathioprine and allopurinol should not be combined)

Having one of these does NOT mean you cannot take any biologic medication safely.  It simply means that certain ones may not be such a good idea.  For example, tumor necrosis inhibitors should not be taken by people suffering from multiple sclerosis.

Conclusion

I hope this helps clarify a few concerns that you may have had regarding biologic medications.  Maybe I’ve caused you to think about things you had not thought about before?  Choosing the best course of therapy can be very complex.  There are so many things to think about and the down stream effects could be very serious.

Open communication and knowledge are key!

References

Rheumatology Secrets 3rd edition

Hazlewood GS, et al. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis. Cochrane Database Syst Rev. 2016 Aug 29;(8):CD010227. doi: 10.1002/14651858.CD010227.pub2.

https://www.drugs.com/price-guide/methotrexate

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