# Presentation: 199948

## Concerns regarding Dispensing Practices and Bioequivalence of Levothyroxine 

- Leonard Wartofsky, M.D.
- Washington Hospital Center
- President Elect, The Endocrine Society

- Joint Public Meeting onEquivalence of Levothyroxine Sodium Products Monday, May 23, 2005Washington, DC Co-Sponsored by the Food and Drug Administration and
- the American Thyroid Association, The Endocrine Society,
- and the American Association of Clinical Endocrinologists

## Narrow Therapeutic Range (NTR) Drugs

**2. FDA Guidance: Levo.Sodium Tablets—*****In Vivo***** Pharmacokinetic and BA Studies. December, 2000.**

- “...those containing certain drug substances that are subject to therapeutic drug concentration monitoring   and/or where product labeling indicates a narrow therapeutic range designation” 1,2
- Levothyroxine sodium is a compound with a narrow therapeutic range with small differences between therapeutic and toxic doses
- Requires careful dose titration, monitoring
- In this regard, L-T4 is like other NTI drugs:
**Warfarin**
**Digoxin**
**Phenytoin**

## Switching LT4 Products

- Legality of switching is state-dependent
- Prescribers often not informed of switch 	unless mandated by state regs
- Pharmacies not honoring prescribed L-T4
- Products switched commonly when refilled
- More calls by pharmacists to prescribers

## L-T4 Switching:  Issues

- Switching branded L-T4 for generic L-T4 is done frequently
- The switch is confusing to patients
- ~18% of patients discontinue medicationupon receiving a different brand
- ~30% of patients do not know which brand they are taking

## State Regulations on Interchange 

_**Orange Book State**_**: **Pharmacist permitted to interchange only  therapeutically equivalent products as determined by the FDA’s  Approved Drug Products With Therapeutic Equivalence Evaluations  (i.e. “Orange Book”).
_**Individual Determination/ Formulary**_**:** Those states with a statutory or regulatory authority to make individual interchange decisions by product and issue a state-wide formulary.
**VA, MA, NJ are positive formulary states, products on formulary can be substituted****	**
_**Professional Judgment State**_**:** A licensed pharmacist is empowered to use professional judgment to make determinations on interchangeable pharmaceuticals.

##  Regulatory Interchange by States

## Switching:  Impact on Physicians

- More office visits by patients
- Need to justify reimbursement for additional TSH testing
- Patients presenting with ill-defined symptoms
- More calls to and from pharmacists

## Switching: Impact on Patients

- Potentially symptomatic until retitrated
**“****Doctor, I don’t feel good.”**
- Inconvenience and time for office visits
- Cost of extra TSH testing
- Increased risk for adverse effects of either under- or overdosage

## Question

- How can physicians maintain control of their patient’s TSH levels when pharmacists are liberally switching non-equivalent L-T4 preparations?

## FDA Guidance (2000)

- Drug substitution may lead to:
- “Suboptimal response and hypothyroidism”
- “Toxic manifestation of hyperthyroidism such as cardiac pain, palpitation, or cardiac arrhythmia...”
- “In patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium may be hazardous.”

## Switching L-T4 Products

- 	When L-T4 prescription is switched,
- 	1) Will repeat TSH testing be reimbursed ?
- 	2) What is impact of switching on TSH?
-    3) How often is TSH testing and re-titration of	 L-T4 dosage actually done ?

## Medicare reimburses for TSH testing up to two times a year in clinically stable patients.

- Testing may be covered up to two times a year in clinically stable patients; more frequent testing may be reasonable and necessary for patients whose thyroid therapy has been altered or in whom symptoms or signs of hyperthyroidism or hypothyroidism are noted. 								 (Federal Register  66(226), Nov. 23, 2001, Rules and Regulations)

## Effect of Switching on TSHPharmetrics study 1

- 7/10 patients not retested by 3 mos post switch
- In 3/10, TSH measured before and 3 mos after switch of one brand for another
- Pre-switch  TSH = 2.39; Post-switch TSH = 3.32
- 47% of patients had change of > 1.0 mU/L
- 25% of patients had change of > 2.0 mU/L
- Mean increase = 0.93 mU/L
- This variation is > individual range 2
- Significant change = 0.75 mU/L  (NACB) 3

- Insurance claims database of 50 managed healthcare plans; ~36,000 patients given L-T4 prescriptions on stable dosage
- Andersen S, et al  J Clin Endocrinol Metab 2002; 87: 1068-1072
- Baloch Z et al,  Thyroid 2003; 13:3-126.

## Adequacy of retesting and Dosage Re-titration (Stelfox et al. J Eval Clin Pract 2004;10:525-30) 

- 400 outpatients at PBBH on L-T4 evaluated for occurrence of minimal recommended monitoring
- Only 56% received recommended tests for follow visits, surveillance, and TSH testing
- Adverse drug events were more common in 44% of patients not receiving adequate monitoring

## What is the cost of LT4 product switching? 

- Drug acquisition costs
- Impact of loss of euthyroid state
- Increased expense for third-party payers and individuals
- Need for more frequent monitoring / TSH
- Increased provider visits
- Development of nonspecific symptoms may not be recognized as thyroid-related
- Impact on patient time, quality of life
- Cost impact of complications

## FDA Bioequivalence Standards Should Distinguish a 12.5% Dose Difference 

- Current FDA recommendations to determine bioequivalence
- may not be sufficiently sensitive to detect small differences

-  Small differences in dosage have significant clinical impact, both on safety and efficacy

## Potential Medical Consequences of Levothyroxine Substitution

## Imprecise Thyroxine DosingVulnerable Populations

- Patients with (or at risk of) cardiac disease
- Patients with (or at risk of) osteoporosis
- Elderly patients
- Pregnant women
- Thyroid cancer patients
- Children

## What might be the adverse consequences of LT4 ‘switching’ in patients who:
have thyroid cancer ?
are elderly with underlying CV disease ?
are pregnant ?

**have thyroid cancer ?**
**are elderly with underlying CV disease ?**
**are pregnant ?**

- Potential Consequences of LT4 Substitution

## Thyroid Cancer:  Overall survival improved with TSH suppression (All Stages)

- P=0.0002

**Normal - elevated**

**Low normal - normal**

**Undetectable – low normal**

**Jonklaas et al, in prep.**

- TSH

## Consequences of Mild Hypothyroidism Fetal Death

- Fetal death rate 4x greater with high TSH** **

**Rate of Fetal Death and Thyroid Deficiency**

**Maternal                                                                      **
**TSH **_**>**_**6 mU/L**

**       ****.9%**

**1**

**0**

**2**

**3**

**4**

**5**

**Maternal                                                                     **
**TSH <6 mU/L**

**(P<0.001)**

**3.8%**

**Allan WC, et al. *****J Med Screen.***** 2000;7:127-130.**

**Notes:**
This study determined that hypothyroid pregnancies result in a higher percentage of fetal deaths.

Only 0.9% of euthyroid women experienced fetal death after 16 weeks of pregnancy.
3.8% of women with a TSH 6 mU/L suffered this consequence.
Among women with TSH elevations 10mU/L, the percentage of fetal death rose to 8.1%.
Other complications did not increase as a result of hypothyroidism.

Since TSH testing was done in this study during the second trimester of pregnancy, it has been concluded that thyroid function testing must be done during the first trimester of pregnancy and that all pregnant women must be tested and, if found to be hypothyroid, be treated immediately to prevent these outcomes.

## Consequences of Mild Hypothyroidism Fetal Brain Development

- Averaged 7 points lower on IQ testing*

**IQ Scores of ********85**

**Children of Mothers with**
**Untreated Hypothyroidism**

**Control**
**Children**

**5**

**0**

**10**

**15**

**20**

**25**

**(P<0.005)**

**19%**

***Full-scale Wechsler Intelligence Scale for Children.   **

**Haddow JE, et al. *****N Engl J Med*****. 1999; 341:549-555.**

**5%**

**Notes:**
Children aged 9 to 11 were tested for intelligence, attention, language, reading ability, school performance, and visual-motor skills. It was found that children of untreated hypothyroid women averaged 7 points lower on IQ tests than the control children. In addition, 19% of children in this group scored 85 or lower on IQ tests, as compared with 5% among control children. According to the Weschsler Scale, IQ below 85 is subnormal, probably leading to poor intellectual development and limited job prospects.

Background information on the Weschler Scale for the presenter:  
  85-99 IQ	Low Normal 
  100-114	Upper Normal
  115-129	Bright
  130-144	Gifted
  145-159	Highly Gifted
  160+ 	Profoundly Gifted

## SNAP POLL QUESTIONNAIRE TO MEMBERS OF AACE & ATA

- 1. Pharmacists substitute my prescriptions for a specific brand of levothyroxine, even when instructed to dispense as written:								__ Never    __ Rarely        __ Often                                   (if often, how often?:__daily__weekly_monthly)
- 2.  Patients under consistent good control on a specific brand of levothyroxine and present with either symptoms of thyroid excess or deficiency or TSH levels out of expected range and are found to have been switched to a different brand or generic preparation:				__ Never     __ Rarely      __ Often		         (if often, how often?: __daily __weekly _monthly)

## SNAP POLL QUESTIONNAIRE TO MEMBERS OF AACE & ATA

- 1. Pharmacists substitute my prescriptions for a specific brand of levothyroxine, even when instructed to dispense as written:
- Never __ 75    (7.1%)
- Rarely__323  (30.7%)
- Often __ 655	  (62.2%)
- How often? 	     Daily     _188_					          Weekly     _267_ 					  Monthly    _200_

## SNAP POLL QUESTIONNAIRE TO MEMBERS OF AACE & ATA

- 2.  Patients under consistent good control on a specific brand of levothyroxine and present with either symptoms of thyroid excess or deficiency or TSH levels out of expected range and are found to have been switched to a different brand or generic preparation:
- Never     24   ( 2.3%)
- Rarely   259  (25.0%)
- Often     751  (72.6%)
- How often?:     Daily       _120__	_					   Weekly    _296_				 	   Monthly   _335_

## SNAP POLL QUESTIONNAIRE TO MEMBERS OF AACE & ATA

- 3.  I support more stringent bioequivalence standards for L-T4 products.			  Yes  1013       No  22       No Opinion  32     	  **(94.9%)**
- 4.  I support stronger policies that would limit a pharmacists’ ability to override physician orders for a specific branded product.							    Yes  1024        No   25     No Opinion  14	 **(96.3%)**

## Conclusions - 1

- L-T4 is the synthetic version of an endogenous hormone that has a narrow therapeutic index.
- Physicians carefully titrate L-T4 using small dosage changes & measuring TSH.
- Small dosage changes result in significant TSH changes, the parameter used by physicians.
- Because of significant risks associated with minor overtreatment or undertreatment, LT4 products that differ in bioavailability by as little as 10% may place patients at risk.

## Conclusions - 2

- Switching products after patient stabilized causes loss of desired level of thyroid function
- Clinicians see little evidence of therapeutic equivalence of  L-T4 products
- Switching increases chance of adverse outcomes
- Switching increases physician, pharmacist workload without economic benefit
- Large chains encourage or mandate switching
- Generic L-T4 does not = Generic L-T4
- We need better methods to determine equivalence of NTI drugs like L-T4 to minimize impact of switching

## Conclusions - 3

- Current FDA recommendations to determine bioequivalence are not sufficiently sensitive to detect small differences
- The impact of switching is not being routinely detected by appropriate TSH monitoring
- Small differences in dosage are important & have significant clinical impact on efficacy, safety, and patient risk
- The current state of affairs is frustrating to physicians, unnecessarily expensive & wasteful of resources, and does not serve the health needs of the public.