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Pitfalls in the Management of Hypothyroidism: Is it Adherence (the patient), Change in Medication (the Doctor or Pharmacist), or other Factors? Optimizing Patient Care

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Title: Pitfalls in the Management of Hypothyroidism: Is it Adherence (the patient), Change in Medication (the Doctor or Pharmacist), or other Factors? Optimizing Patient Care


1
Pitfalls in the Management of Hypothyroidism Is
it Adherence (the patient), Change in Medication
(the Doctor or Pharmacist), or other Factors?
Optimizing Patient Care
James V. Hennessey MD Associate Professor of
Medicine Harvard Medical School
2
Disclosures
  • I have provided consultative services on thyroid
    hormone therapy topics in the past year to
  • Akrimax Pharmaceuticals
  • AbbVie Pharmaceuticals

3
Pre Test True or False?
  • A. Oral Levothyroxine (LT4) results in goal TSH
    levels more than 95 of the time.
  • B. Poor medication adherence seldom is observed
    in the course of clinical practice.
  • C. Ingestion of levothyroxine with a meal
    enhances absorption and the consistency of TSH
    outcomes.
  • D. If designated as interchangeable, LT4 products
    will differ by less than 1.

4
Room for Improvement Prevalence of Under- and
Overdosage with Levothyroxine
38
22
5
17
16
28
Somwaru, 2009
Okosieme, 2011
Diez, 2002
Ross JCEM.19907164-769. Parle Br J Gen Pract.
199343107. Canaris Arch Intern Med.
2000160526. Hollowell JCEM. 200287489. Diez
J Gerontol. 2002 57A(5)M315. Somwaru JCEM. 2009
941342. Okosieme QJ Med. 2011 104395.
5
Clinical Outcomes on LT4
  • 17,684 patients on LT4 in Tayside Scotland
  • 85.6 women, mean age 60.3 W, 61.8 Men
  • Outcome measures, median F/U 4.5 years
  • 2,144 episodes of CV disease
  • 357 episodes of dysrhythmia
  • 562 osteoporotic fractures
  • Subjects categorized by weighted TSH status
  • Normal (0.4-4.0) 61.7 - High (gt4.0) 11.2
  • Suppressed (lt0.03) 6.1 - Low (lt0.4) 21.1

Flynn RW et al. 2010 JCEM 95(1)gt186-93
6
Cardiovascular Admission or Death
AHR 1.37
AHR cited plt0.05
AHR 1.8
Flynn RW et al. 2010 JCEM 95(1)gt186-93
7
Dysrhythmia Admission or Death
AHR 1.8
AHR 1.6
AHR cited plt0.05
Flynn RW et al. 2010 JCEM 95(1)gt186-93
8
Fracture Related Admission or Death
AHR 1.8
AHR cited plt0.05
AHR 2.0
Flynn RW et al. 2010 JCEM 95(1)gt186-93
9
Risks of Under- and Overdosage with Levothyroxine

Atrial fibrillation
Excessive Thyroxine Therapy
Bone loss
CV mortality
Impaired cognition
Inadequate Thyroxine Therapy
10
Many Factors Contribute to Treatment Success
Patient and Physician Variables Play Most
Important Role
Variability due to Human Factors Patient-related
Physician-related
Interproduct Variability

11
Case 1
  • 43-year-old man presents for annual exam
  • Diagnosed with primary hypothyroidism 2 years ago
    with a TSH of 21.88 mU/L, FT4 0.6 (0.8-1.8 ng/dl)
  • At 25 yo diagnosed with bipolar disorder
  • Patient is on quetiapine and fluoxetine as
    maintenance therapy for bipolar disorder
  • LT4 therapy titrated over the past 2 years to
    current dose of 375 mcg/day
  • TSH level has never been brought under control
    with levels ranging from 20.1 37.2 mU/L

12
Case 1
(2)
43-year-old man
  • Recent lab test results
  • TSH 32.5 mU/L (0.5 4.1 mU/L)
  • FT4 0.8 ng/dL (0.8 1.8 ng/dL)
  • Patient denies non-compliance, however has been
    known to have compliance issues with his
    anti-psychotic medications in the past
  • Blood count, liver, and renal function tests are
    normal
  • Celiac disease has been ruled out through a
    gastroduodenoscopy
  • What can the problem be?

13
Patient Factors Affecting Treatment Success or
Failure
  • Patient adherence with treatment regimen

Lip DJ, et al. Neth J Med. 20042(4)114-118.
14
Poor Medication Adherence A Common Cause of
Treatment Failure Across All Disease States
33 of respondents report being nonadherent
often, or very often
Why patients dont take meds (in general for
all disease states)
33
Population on Medication ()
often or very often
Lip DJ, et al. Neth J Med. 20042(4)114-118.
HarrisInteractive. Available at
http//www.harrisinteractive.com/news/allnewsbydat
e.asp?NewsID904. Last Accessed on December, 14,
2006.
15
Poor Medication Adherence A Common Cause of
Treatment Failure Across All Disease States
  • Steps to Improve Patient Adherence
  • Inform the patient of the effects of not
    following treatment regimen
  • Avoid unnecessary changes in treatment regimens
  • Pharmacy follow-up can improve adherence by gt30
  • Strategies for Patients
  • Use a daily pill box (end of the week 7 pills for
    QD dosing)
  • Set up a routine eg, put pills next to
    toothbrush or alarm clock
  • Set reminders on cell phones or watches
  • Notes on the refrigerator

1. Lip DJ, et al. Neth J Med. 20042(4)114-118.
HarrisInteractive. Available at
http//www.harrisinteractive.com/news/allnewsbydat
e.asp?NewsID904. Last Accessed on December, 14,
2006. 2. Lee JK et al. JAMA. 2006 Dec
6296(21)2563-71. Epub 2006 Nov 13.
16
Patient Factors Affecting Treatment Success or
Failure
  • Patient adherence with treatment regimen
  • Dietary interference with absorption

Lip DJ, et al. Neth J Med. 20042(4)114-118.
17
Optimizing LT4 Rx Fasting
76
with TRH Suppression
0
Wenzel KW Dtsch Med Wochenschr 1986
111(36)1356-1362
18
Effective of FDA Standard Breakfast on LT4
Absorption
  • Single dose, randomized, 3 way crossover study in
    48 healthy adult (60 F) volunteers
  • 600 mcg LT4 under fasting or fed conditions
  • Treatments separated by 35 day washout
  • Breakfast 950 calories eggs, bacon, toast,
    hash browns and milk.
  • Sampling of T4 and T3 done before and at
    intervals up to 48 hours after ingestion.

Lamson MJ et al. 2004 Thyroid 14876
19
Reduction of Corrected T4 PK
of Fasting T4 AUC
38
40
40
48
Lamson MJ et al. 2004 Thyroid 14876
20
Timing of LT4 Administration
  • 65 hypothyroid subjects rendered euthyroid
    ingesting therapeutic LT4 doses
  • Randomized 3, 8-wk X-over periods, same LT4
  • Fasting state 1 hour before breakfast (BB)
  • Bedtime at least 2 hours after last meal (HS)
  • With breakfast (WB)
  • Calcium, FeSO4, MVI etc. with meals (not WB)
  • Evaluation of TFTs after each 8 week period
  • Fasting (0800) TSH, FT4, Total T3

Thien-Giang B-H et al. 2009 JCEM 94(10)3905-3912
21
Same Dose LT4 Timing Results
P lt 0.001
_
P lt 0.001
_
_
Mean TSH mIu/ml (95 CI)
_
_
P lt 0.026
_
WB
HS
BB
Thien-Giang B-H et al. 2009 JCEM 94(10)3905-3912
22
Variability of TSH Outcomes
Thien-Giang B-H et al. 2009 JCEM 94(10)3905-3912
23
Change in TSH vs. Fasting (BB)
35
55
Thien-Giang B-H et al. 2009 JCEM 94(10)3905-3912
24
LT4 Rx Fasting vs. with a Meal
  • 45 1? hypothyroid patients (40 W) LT4 Rxd
  • Included if TSH 0.5 3.5 mIu/L
  • Using one of 2 LT4 brands
  • Excluded serious chronic illnesses, medications
    known to interfere with LT4
  • Randomized to 90 treatment periods
  • LT4 ingestion Fasting after overnight fast
  • 60 minutes prior to breakfast
  • LT4 ingestion with breakfast
  • At the beginning of meal

Silva Perez CL et al. 2013 Thyroid 23(7)779-784
25
Impact of Breakfast on TSH
plt0.05

(mIu/L)
(ng/dL)
Silva Perez CL et al. 2013 Thyroid 23(7)779-784
26
TSH gt 3.5 mIu/L Fasting 14.3 Breakfast
23.8
Preference for LT4 Fasting
40.5 Breakfast 33.3 No Preference
26.2
B gt 2.0 F lt 2.0 15 cases
B lt 2.0 F gt 2.0 3 cases
Silva Perez CL et al. 2013 Thyroid 23(7)779-784
27
Physician Factors Affecting Treatment Success or
Failure
  • Patient adherence with treatment regimen
  • Dietary interference with absorption
  • Drug interactions

Lip DJ, et al. Neth J Med. 20042(4)114-118.
28
Lack of Response Can be Caused by Iatrogenic
Factors
Impaired Absorption Increased Clearance Increased Demand Most Common
Dietary fiber (bread) Phenobarbital Pregnancy Nonadherence
Bile acid sequestering agents Phenytoin Weight gain
Sucralfate Carbamazepine
Proton-pump inhibitors Rifampicin
H2 blockers
Ferrous sulfate
Aluminum hydroxide antacids Calcium salts
Soy
Herbal remedies
Small bowel disorders
Rangan S, Tahrani A, Macleod A, et al. Postgrad
Med J. 2007 83(e3) Green WL. AAPS Journal.
20057(1)E54-E58
29
Medication Interactions
Impaired absorption Increased Metabolism (Clearance)
Aluminum Hydroxide Antacids Axitinib, Bosutinib, Crizotinib
Calcium Carbonate, Sucralfate Dasatinib, Erlotinib, Imitinib
Bile Acid Binding Resins Lapatinib, Nilotinib, Pazopanib
Sodium Polystyrene Sulfonate Sorafenib, Sunitinib, Vandetanib
Colesevlam, Didanosine Barbiturates, Carbamazepine
Chromium Picolinate, Sevelamer Phenytoin
Magnesium Citrate, FeSO4 Rifampins
Lanthanum, Orlistat, Raloxifene
Epocrates Drug Resource Accessed 31 May 2013 _at_
2200
30
Patient Factors Affecting Treatment Success or
Failure
  • Patient adherence with treatment regimen
  • Dietary interference with absorption
  • Drug interactions
  • Pregnancy
  • Gastrointestinal disease or surgery
  • Liver or heart disease
  • Other factors

Lip DJ, et al. Neth J Med. 20042(4)114-118.
31
Adequate Patient Monitoring Can Lead to Fewer ADEs
  • N363 patients (from retrospective chart reviews)
  • 56 received satisfactory monitoring (guideline
    compliant)
  • A total of 12 patients (3) in the study
    experienced adverse drug events (ADEs)
  • 1 of well-monitored patients experienced ADEs
  • 6 of poorly monitored patients experienced ADEs
  • LT4-related ADEs included
  • Depressive symptoms returned
  • Unstable angina
  • Atrial fibrillation
  • Palpitations
  • 9 of these ADEs were classified as preventable

Stelfox HT, et al. J Eval Clin Pract.
200410525-530.
32
Duration of Rx and Adequate Control
N 655 LT4 treated patients
80
With Adequate Control
Years
20
of Patients
Diez JJ 2002 J Gerontol 57A(5)M315-M320
33
Duration of Rx to Optimal Control
Percentage of Patients With Adequate Control 50
Years
of Patients
Diez JJ 2002 J Gerontol 57A(5)M315-M320
34
Status of Hypothyroid RX (gt65 yrs)
  • 339 subjects on TH
  • 26 on T4/T3
  • Overall Status
  • 41 Low TSH
  • 42.8 Euthyroid
  • 16.2 High TSH
  • Risk for Low TSH
  • Lower weight
  • 65 ? risk/ 10 kg
  • Diabetes

LT4 vs. T4/T3 NS Difference
Somwaru et al. 2009 JCEM 941342-1345
35
Adequacy of Thyroid Hormone Replacement in a
General Population
  • General practice audit of 11 practices caring for
    1037 patients in a hypothyroidism registry
  • Rated adequacy of LT4 replacement therapy
  • Adequate TSH 0.4- 4.0 mU/l
  • Over replaced TSH lt 0.4 mU/l
  • Under replaced TSH gt 4.0 mU/l

Okosieme OE et al. 2011 Q J Med. 104395-401
36
Adequacy of Replacement
TFTs evaluated lt 12 months ago 88.1 of
participants Appropriate dose adjustments made
81 of participants
62.8
37.2
19.8
17.4
Okosieme OE et al. 2011 Q J Med. 104395-401
37
Risk of Inadequate Replacement
  • Under Replacement
  • Risk Factor Odds Ratio (CI)
  • Male Gender 2.85 (1.86-4.38)
  • Younger Age 0.88 (0.80-0.98)
  • Per 10 year increase
  • Over Replacement
  • Risk Factor Odds Ratio (CI)
  • Longer Rx Duration 1.06 (1.01-1.10)
  • L-thyroxine Dose 1.73(1.49-2.01)

Okosieme OE et al. 2011 Q J Med. 104395-401
38
Case 2
  • 55-year-old man with a 20-year history of
    hypothyroidism presents for his annual exam
  • Has had NO change in his non-thyroid medications
  • Patients chief complaint is loss of energy
  • Patient has been successfully treated with 150
    mcg/day LT4 for many years TSH 0.4-2.5 mU/L
  • Test results show TSH level to 8.1 mU/L
  • What may have happened here?

39
FDA STABILITY DATA
  • 1987-94 58 adverse drug experience reports
    (ADER) associated with the potency of LT-4
    products
  • 47 ADERs subpotency
  • 2 hopitalizations
  • 9 ADERs superpotency
  • 2 hospitalizations
  • 2 ADERs inconsistent TFTs
  • 58 Total ADERs reported triggered action!!!!

Federal Register Vol. 62, No. 15743535-8, 14 Aug
1997
40
Pharmacovigilance Surveys
  • Surveys requesting information on potential
    adverse events (AEs) in thyroid hormone treated
    patients. Sent by e-mail to members of AACE,
    ATA, TES, frequent LT4 and Extract Rxers
  • 1,536 survey responses recorded
  • 971 (63.2) NO Problems noted
  • 556 (36.8) noted adverse outcomes
  • 335 LT4 Rxers completed AE surveys

Hennessey et al. 2010 Endocrine Practice
16(3)357-370
41
Survey Adjustments
  • 335 LT4 Rxers completed AE surveys
  • 22 duplicate reports (6.6)
  • 12 considered non compliant (3.6)
  • 44 using interfering medications (13.1)
  • 4 patients reported to be pregnant (1.2)
  • 28 cases with unstable LT4 doses (8.4)
  • 2 cases reported by patients (0.6)
  • 24 cases Sxs only NO TSH change (7.2)
  • 198 cases for further evaluation (59.1)

Hennessey et al. 2010 Endocrine Practice
16(3)357-370
42
TSH Values in AE patients
  • Indication for LT4 therapy
  • Goiter/ nodules (0.5)
  • Hypothyroidism (89.4)
  • Thyroid Cancer (10.1)

with TSH
Figure 1
Hennessey et al. 2010 Endocrine Practice
16(3)357-370
43
TSH Changes Thyroid Ca
N 20
of Patients
Figure 2
Hennessey et al. 2010 Endocrine Practice
16(3)357-370
44
TSH Changes Hypothyroidism
N 177
of Patients
Figure 3
45
Survey Results
  • Was type of LT4 changed prior to AE?
  • Yes 177/198 (89.4)
  • 177 reports had details on source change
  • Brand to generic n156/177 (88.1)
  • Brand to another brand n12/177 (6.8)
  • Generic to brand n9/177 (5.1)
  • Total 177/177
    (100)

Hennessey et al. 2010 Endocrine Practice
16(3)357-370
46
Survey Adverse Events
  • If type of LT4 was changed, who did it?
  • Pharmacy withOUT MD knowledge
  • 153/167 (91.6)
  • Pharmacy with MD or MD office knowledge
  • 13/167 (7.8)
  • Did the change in LT4 type result in SAE?
  • YES 54/198 (27.3)
  • Urgent clinic visit n13 ER visit n1
  • Missed work n17 Other n23

Hennessey et al. 2010 Endocrine Practice
16(3)357-370
47
Conclusions
  • In 1997 FDA took action after receiving 58
    adverse drug experience reports (ADER) on the
    potency of LT-4 products
  • By 2007 we received 198 AE reports
  • AEs indicate both super and subpotency
  • 96.3 of AEs associated with change in LT4 source
    by reporting health care professional
  • Following these switches, 27.3 had SAE
  • Missed work, urgent ER/clinic visits, other
    events (Cancer recurrence, Congenital Hypo Rx off)

Hennessey et al. 2010 Endocrine Practice
16(3)357-370
48
FACT
  • Products that differ by 12.5 can be considered
    bioequivalent and therefore interchangeable under
    current FDA criteria.

Blakesley V et al. Thyroid 200414191-200.
Johnson, SB. Endogenous Substance Bioavailability
and Bioequivalence Levothyroxine Sodium Tablets.
Data presented at FDA ACPS Meeting March 13,
2003 Rockville, MD. Available at
www.fda.gov/ohrms/dockets/ac/03/briefing/3926b2.ht
m
49
Equivalence of 4 AB-2 Levothyroxine
Formulations
Ratios (Synthroid vs generic) of least-squares
ANOVA. All 90CI (80-125)
112.5
109
BX
103
AUC 0-48 Hours ( Ref)
100
100
100
AB-1
Predicted difference 12.5 9 3
Http//www.accessdata.fda.gov/scripts/cder/drugsat
fda/index.cfm 17 May 2005
50
The Clinicians Response
  • A difference of 12.5 is equivalent to a dose
    increase.

25
300
75
50
150
88
100
112
125
137
175
200
12
12
10
10
Green WL. AAPS Journal. 20057(1)E54-E58
51
Bioequivalent Products Approved LT4 Drugs
Product
Manufacturer
TE Rating
Unithroid Stevens AB1
Levothyroxine sodium Mylan AB1
Levoxyl Jones AB1
Synthroid Abbott AB1
     
Synthroid Abbott AB2
Levothyroxine sodium Mylan AB2
Levo-t Alara (Sandoz) AB2
Unithroid Stevens AB2
Levothyroxine sodium Genpharm AB2
     
Levoxyl Jones AB3
Levo-t Alara (Sandoz) AB3
Unithroid Stevens AB3
Levothyroxine sodium Mylan AB3
Levothyroxine sodium Genpharm AB3
     
Thyro-tabs/Levothroid Lloyd AB4
Levothyroxine sodium Mylan AB4

Food and Drug Administration Web site. Approved
Drug Products with Therapeutic Equivalence
Evaluations. Available at http//www.fda.gov/cder
/orange/obannual.pdf Last accessed Jan 7, 2008.
52
MD PharmD Factors Affecting Treatment Success
or Failure
  • Patient adherence with treatment regimen
  • Dietary interference with absorption
  • Drug interactions
  • Pregnancy
  • Gastrointestinal disease or surgery
  • Liver or heart disease
  • Differences in Bioavailability

Lip DJ, et al. Neth J Med. 20042(4)114-118.
53
Professional Guidance
Singer Solution
  • June 24, 2004 statement from
  • American Thyroid Association
  • Endocrine Society
  • American Association of Clinical Endocrinologists
  • Physicians should
  • Alert patients that preparation may be switched
    at pharmacy
  • Encourage patients to ask to remain on the same
    preparation at every pharmacy refill
  • Make sure patients understand the need to have
    their TSH retested and dosing readjusted every
    time their levothyroxine preparation is switched

Available at http//www.thyroid.org/professionals/
advocacy/04_06_24_fda.html Accessed 9-20-04
54
Case
  • 38 year old fitness instructor consults with her
    physician for heat intolerance, irritability and
    frequent bowel movements.
  • She uses a wide range of organic supplements
    which she has carefully selected to balance her
    body function, mood and metabolism.
  • On physical exam her pulse rate is 112 BPM
  • She looks anxious
  • TSH is lt0.01, FT4 is 0.07(lo), TT3 level is
    178(nl)

55
T4 and T3 Content in Supplements
  • 10 commercially available thyroid support
    dietary supplements
  • T4 and T3 content analyzed
  • Using HPLC
  • Calculated TH doses that would be administered as
    per directions

Kang GY et al. 2013 Thyroid 23 (10)1233-37
56
Kang GY et al. 2013 Thyroid 23 (10)1233-37
57
T4 and T3 Content in Supplements
  • 10 commercially available thyroid support
    dietary supplements
  • T4 and T3 content analyzed
  • Using HPLC
  • Calculated TH doses that would be administered as
    per directions
  • The majority of Thyroid Support supplements
    contained T4, T3 or both some in doses higher
    than prescribed in practice.

Kang GY et al. 2013 Thyroid 23 (10)1233-37
58
Recent Guideline Recommendations
  • 32.1 Iodine supplementation including kelp should
    not be used to manage hypothyroidism in iodine
    sufficient areas.
  • 32.2 Kelp and seaweed should not be used to treat
    iodine deficiency in pregnancy.
  • 33 Selenium should not be used to prevent or
    treat hypothyroidism.
  • 34 Advise that thyroid support remedies may
    contain iodine or sympathomimetics and may be
    adulterated by LT3 or LT4.

Garber et al. Thyroid 2012 22(12)1200-1235
59
MD PharmD Factors Affecting Treatment Success
or Failure
  • Patient adherence with treatment regimen
  • Dietary interference with absorption
  • Drug interactions
  • Pregnancy
  • Gastrointestinal disease or surgery
  • Liver or heart disease
  • Differences in Bioavailability
  • Iodine, dietary and nutraceutical supplements

60
Steps to Take to Ensure Optimal Patient Outcomes
  • Patients should be maintained on one LT4 brand
  • By writing the prescription dispense as
    written, the substitution of one LT4 product for
    another can be prevented
  • Confirm the LT4 brand the patient is taking at
    each visit
  • Tell patients to obtain serum TSH 6 - 8 weeks
    after LT4 dose or brand changes
  • Consider brand substitution among the list of
    explanations for deviation of the TSH from the
    therapeutic goal range

Singer et al. JAMA. 1995273808-812.
61
Post Test True or False?
  • A. Oral Levothyroxine (LT4) results in goal TSH
    levels more than 95 of the time.
  • B. Poor medication adherence seldom is observed
    in the course of clinical practice.
  • C. Ingestion of levothyroxine with a meal
    enhances absorption and the consistency of TSH
    outcomes.
  • D. If designated as interchangeable, LT4 products
    will differ by less than 1.

62
Summary Poor Control Considerations
  • Compliance
  • Monitoring Communication
  • Interference of food intake
  • Interfering medications
  • Duration of therapy
  • Weight, Gender, Age
  • Substitution of LT4 preparations

63
Internet References
  • American Association of Clinical Endocrinologists
    www.aace.com
  • American Thyroid Association www.thyroid.org
  • Thyroid Manager www.thyroidmanager.org
  • Thyroid Today www.thyroidtoday.com
  • National Cancer Institute www.cancer.gov (search
    thyroid)
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