DRUG ACTION AND RLS

Jacquelyn Bainbridge, Pharm.D., FCCPProfessor

Pei Shieen Wong, Pharm.D., BCPSUniversity of Colorado Anschutz Medical Campus,

Skaggs School of Pharmacy and Pharmaceutical Sciences,Department of Clinical Pharmacy and Department of Neurology

QUESTION

­ Where do you get most of your information about medications?

a. Doctor/Physician’s Assistantb. Nursec. Pharmacistd. Internet – RLS websitee. Family/Friendf. Internet – Other websites

HOW DRUGS AND THE BODY INTERACT

vPharmacokinetics:•What the body does to the drug (liberation, absorption, distribution, metabolism, excretion)

vPharmacodynamics:•What the drug does to the body (treats disease, side effects, etc.)

LIBERATIONvThe release of the drug from its dosage form• Extended release formulations release a small amount of the drug over a long period of time

ABSORPTION

vThe movement of a drug into the bloodstream

vDrug can be delivered via tablets, patches, injections etc.

vFactors that affect absorption:•Food, pH, other medications, or disease

vTmax- the time after administration of a drug when the maximum plasma concentration is reached

METABOLISM

vThe chemical conversion of drugs into compounds that are easier to eliminate

vCertain organs, such as the liver, possess enzymes that metabolize drugs. These metabolites may be inactive or have a pharmacologic effect of their own

vSome medications can cause these enzyme to work more efficiently, therefore eliminating the drug more quickly (enzyme induction)

vOthers can slow the enzymes down resulting in the drug staying longer in the body (enzyme inhibition)

EXCRETION/ELIMINATION

vThe removal of the substances from the body

vOrgans involved•Kidney, lungs, intestines

vHalf life- the time required for serum concentrations to decrease by one-half after absorption and distribution are complete

HALF-LIFE

vIt takes approximately 5 half lives to completely remove a drug from the body

vExample: 100 mg of Drug X with a half life of 5 hours­ After 5 hours, 50 mg is left (50% gone)­ After 10 hours, 25 mg is left (75% gone)­ After 15 hours, 12.5 mg is left (87.5% gone)­ After 20 hours, 6.25 mg is left (93.75% gone)­ After 25 hours, 3.125 mg is left (96.875% gone)

HALF-LIFE

0 1 2 3 4 5

STEADY STATE

vThe situation where the overall intake of a drug is in equilibrium with its elimination

vIt takes approximately 4-5 half lives to reach steady state

HALF-LIFE AND DOSING

vHalf life is also used to determine how often a drug needs to be taken

vDrug X Half life: 5 hours

vWant max steady state concentration of 20mg/L and a minimum steady state of 10mg/L

vMinimum concentration is ½ of the maximum, which is one half life, due to drug accumulation this medication would most likely be dosed, depending on the drug, every 12 hours (every 2 to 3 half lives)

vUsually, medications with a longer half-life are dosed less frequently

vDrugs that are designed to be extended release are not interchangeable with immediate release preparations

QUESTION

Have you been on combination therapy, with a dopamine agonist in conjunction with another drug with a different mechanism of action?

a. Yesb. Noc. Not sure

RLS TREATMENT: DOPAMINERGICS

vRequip® (ropinirole)•0.25mg daily week 1 (typical starting dose for RLS) and increase to relief of symptoms (max dose 3 mg/daily)

vTake 1-3 hours before bedtime • (Half life: 6 hrs, Tmax: 1 hr)

vRequip® XL – once-a-day dosage form of ropinirolevAbsorption-High fat meal can delay Tmax by 2.5 hoursvMetabolized by the liver (interactions)•Warfarin-may increase INR•Ciprofloxacin-may increase ropinirole exposure•Anti-psychotics-decrease effectiveness of anti-psychotic

vFDA approved for RLS and both are available as generic

DOPAMINERGICS

vMirapex® (pramipexole)•Generic or Brand name• 0.125mg-1.5mg daily for RLS

vTake 2-3 hours before bedtime • (Half life: 8 hrs, Tmax: IR: 2 hrs, ER: 6 hrs)

vMirapex ER - considered for severe RLS, given once dailyvAbsorption- Food can delay Tmax by 1-2 hoursvDose adjustments in those with kidney problemsvFDA approved for RLS

DOPAMINERGICSvSinemet® (carbidopa/levodopa)•25/100mg IR given 30 to 60 minutes before bedtime and may repeat once (if awaken within 2 hours)•50/200mg CR 1-2 tabs 1 hour before bedtime

vControlled Release (CR) may be best in RLS•Half life: 1-2 hrs, Tmax: IR: 30 min, CR: 2 hrs

vAbsorption- Food can delay/reduce absorption•Can take with low protein snack to avoid GI issues

vMetabolism- Liver•Numerous drug interactions. Consult with a pharmacist before starting.

vNot FDA approved for RLS

DOPAMINERGICS

vNeupro ®Patch (Rotigotine)•1-3mg daily for RLS•Patch size 5,10,15 cm2

vHalf life: 5-7 hours, Tmax: 15-18 hrs, detected in the serum at 3 hrsvDrug is slowly released throughout the dayvAbsorption- Food has no effectvNo dose adjustments for liver/kidney problemsvFDA approved for RLS

NEURONTIN ® (GABAPENTIN)

v300-800 mg before bedtime (half life: 5-7 hrs, Tmax: 2hrs)•Can add morning and afternoon doses

vAbsorption- Food can increase rate/extent of absorption•Avoid taking with antacids (separate by 2 hours)

vDose adjustments in those with kidney problemsvNaproxen may reduce effectivenessvNot FDA approved for RLS

Non-Dopaminergics

HORIZANT ®(GABAPENTIN ENACARBIL)

vProdrug of gabapentinvExtended release tablet designed to last 24 hoursvModerate to severe primary RLS• 600 mg once daily with food at 5PM (terminal half life 5-6 hours of gabapentin)• 1200 mg had no additional benefit

vNot interchangeable with other gabapentin productsvAbsorption- Food can delay the time to maximum blood concentration and increase amount of drug available to the body • Tmax: 7 hrs

v Dose adjustments in those with kidney problemsv FDA approved for RLS

Non-Dopaminergics

LYRICA ® (PREGABALIN)

v50-450 mg 30-45 min before bedtime

v> 450-600 mg divided at 2 pm and before bedtime•(Half life: 6 hrs, Tmax: 1.5hrs)

vAbsorption- Food can increase Tmax to 3 hrs•Avoid taking with antacids (separate by 2 hours)

vDose adjustments in those with kidney problemsvNaproxen may reduce effectivenessvNot FDA approved for RLS

Non-Dopaminergics

TEGRETOL/CARBATROL ® (CARBAMAZEPINE)

v600-1,500 mg a day (divided into 2 or 3 doses)• (Half life: 2-9 hrs, Tmax: 3-13hrs)

vAbsorption- Food has no effect

vMetabolism- Liver•Numerous drug interactions. Consult with a pharmacist before starting• Induces its own metabolism – therefore the dose is increased gradually

v Dose adjustments in kidney diseasev Not FDA approved for RLS

v Additionally opioids are listed in the guidelines

Non-Dopaminergics

AUGMENTATIONvMain complication of long-term dopaminergic treatment of RLS• Sinemet, Mirapex, Requip• Neupro patch lower rate of augmentation• Case reports of occurrence with tramadol

vDefined as worsening of RLS symptoms that occurs after starting a medication to treat RLS

vGenerally occurs within the first six months of starting therapy

vSymptoms occur earlier in the day, at least two hours earlier than prior to the initiation of drug therapy

vTemporal relationship exists between:• ↑ daily medication ↑ symptom intensity • ↓ daily medication ↓ symptom intensity

vSensations spread to previously uninvolved parts of the body

vRLS symptoms while awake occur for the first time or are worse than before

AUGMENTATION TREATMENT

vFirst consider/remove other factors•Example: changes in lifestyle, iron deficiency,

vAdjusting the timing or dose

vSwitching to a different medication class

vDrug holiday

vCombination of agents with different mechanisms of action

QUESTION

If you have taken Neupro®, was it prior to the product withdrawal/reformulation?

a. Yesb. Noc. Not sure

NEUPRO ®PATCH (ROTIGOTINE)

v1-3mg patch once daily• 1 mg patch: 1 inch in diameter (2.25

cm)• 2mg patch : 1 ¼ inches (3.15 cm)• 3 mg patch : 1 ½ inches (3.85 cm)

v Rotate site each day to avoid irritation• Don’t use same site for 14 days

NEUPRO ®PATCH (ROTIGOTINE)

vPrecautions•Apply to clean, dry, healthy skin (do not apply to red, irritated, or injured skin)•Do not place patch underneath tight clothing or waistband• If you need to shave the area - do so 3 days prior•Avoid creams, lotions, ointments, oils and powders to the skin area where the patch will be placed

vWarnings•Sulfite sensitivity – not sulfonamide or sulfate sensitivity•Seen more frequently in asthma patients

NEUPRO ®PATCH (ROTIGOTINE)

vOpen the pouch and pull the patch outvHold it with protective liner on topvBend the edges away from you to open up the “s” shaped cut vPull off half of the protective liner vDO NOT touch the sticky side

NEUPRO ®PATCH (ROTIGOTINE)

vApply to the chosen area vPRESS firmly for 30 seconds with your hand (you need the heat from you hand to activate the adhesive)vDO NOT use any other heat sources (ie., hair dryer)vWash your hands with soap and water after handling the patchvDo not touch your eyes before washing your handsvDispose of the patch by folding the sticky side inwards before discarding in the trashvKeep the medication away from children or pets

NEUPRO ®PATCH (ROTIGOTINE)

vCommercial Plans - Tier 3, unrestricted

vMedicare Part D will require a prior authorization• Prior authorization may not be required in the future

vMedicaid-varies by each state• CO/UT-$3

vCopay card available at www.neupro.com• Will cover up to $65 resulting in a copay of $10 for most commercial plans• Also can be used for cash paying customers ($65 savings)

• Good for 12 months

vThis information changes on a regular basis and may vary by state

NEUPRO ®PATCH (ROTIGOTINE)

vPatient Assistance Program• Provide Neupro® to qualifying patients at a reduced price• Government-funded insurance programs are excluded from this patient assistance • Program will begin Monday August 6th

• www.Neupro.com

QUESTION

If you have taken any medication via patch (for pain, or nicotine cessation, etc.) did you have any of the following:

a. Skin REACTION due to the medicationb. Skin IRRITATION due to the patch/ adhesive

CONCLUSION

vRLS is a common, under diagnosed treatable condition that can have significant negative effects on quality of life

vMedications for RLS should be taken as prescribed and follow the pattern of the symptoms

vDrug interactions can occur with prescription and over the counter medications

vAlways talk to your health care practitioner and pharmacist about all the medications you are taking or have question about

RESTLESS LEGS SYNDROME FOUNDATION

DRUG ACTIONS AND RLS

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