Cases in Primary Care

1. Cases in Primary Care Lauren Foy, D.O. APN Pharmacology Update March 28, 2014

2. Identify the appropriate treatment for hypothyroidism, including appropriate medication dosing & monitoring • Appropriately prescribe & monitor statins, including differentiating between moderate & high intensity statins according to the 2013 ACC/AHA hyperlipidemia guidelines • Appropriately prescribe and manage antiviral treatment for shingles, including length of treatment and choice of agent Objectives

3. 45 year old female presents to the office • CC: “I want my thyroid checked” • ROS: +fatigue, constipation, dry skin, steady weight gain over last few years • FHx: +thyroid disorder (mom, MGM) • PE: unremarkable, no thyromegaly or nodules palpated • Labs: TSH 7.5, FT4 <0.01 Case 1

4. Dx: Hypothyroidism • Treatment: start thyroid replacement medication & monitor response • What dose of levothyroxine do I start? • How frequently do I need to recheck the thyroid? And which labs do I need to monitor? • What are the adverse effects? Case 1, continued

5. Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. • Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-stimulating hormone, TSH, from the anterior pituitary. • TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, L-thyroxine (T4) and L-triiodothyronine (T3), by the thyroid gland. • Circulating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretion. • When serum T3 and T4 levels increase, TRH and TSH secretion decrease. • When thyroid hormone levels decrease, TRH and TSH secretion increase. Thyroid Physiology

6. Thyroid Physiology, continued

7. Thyroid Physiology, continued

8. Active ingredient: synthetic crystalline L-3,3’,5,5’-tetraiodothyronine sodium salt [Levothyroxine (T4) sodium] • Synthetic T4 is identical to that produced in the human thyroid gland Levothyroxine

9. Synthetic form of thyroxine (T4), an endogenous hormone secreted by the thyroid gland • T4 converted to its active metabolite, L-triiodothyronine (T3) • Thyroid hormones (T4 and T3) then bind to thyroid receptor proteins in the cell nucleus and exert metabolic effects: • control of DNA transcription and protein synthesis • involved in normal metabolism, growth, and development • promotes gluconeogenesis, increases utilization and mobilization of glycogen stores • stimulates protein synthesis • increases basal metabolic rate Mechanism of Action

10. Repletion of T4 via daily levothyroxine dose exerts feedback to hypothalamus, restores homeostasis Via oral replacement with synthetic T4 Mechanism of Action Decreased T4 secretion in hypothyroidism

11. Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80% • Majority of the levothyroxine dose is absorbed from the jejunum and upper ileum • T4 absorption is increased by fasting • T4 absorption is decreased in malabsorption syndromes, and by certain foods such as soybean infant formula. Absorption may also decrease with age. • Dietary fiber decreases bioavailability of T4. Absorption

12. T4 is slowly eliminated • The major pathway of thyroid hormone metabolism is through sequential deiodination. • Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. • The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. • Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3, which are arefurther deiodinated to diiodothyronine. • Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation. Metabolism

13. Thyroid hormones are primarily eliminated by the kidneys. • A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. • Approximately 20% of T4 is eliminated in the stool. • Urinary excretion of T4 decreases with age. Elimination

14. Adults: ~1.7 mcg/kg/day • usual doses are ≤200 mcg/day (range: 100-125 mcg/day [70 kg adult]) • doses ≥300 mcg/day are rare • consider poor compliance, malabsorption, and/or drug interactions • Elderly patients may require <1 mcg/kg/day • >50 years without cardiac disease or <50 years with cardiac disease: Initial: 25-50 mcg/day • adjust dose by 12.5-25 mcg increments at 6- to 8-week intervals as needed • >50 years with cardiac disease: Initial: 12.5-25 mcg/day • adjust dose by 12.5-25 mcg increments at 4- to 6-week intervals (many clinicians prefer to adjust at 6- to 8-week intervals) Dosing

15. Walmart $4 list & Walgreens (Prescription Savings Club; $10 for #30) • Levothyroxine 25mcg tab • Levothyroxine 50mcg tab • Levothyroxine 75mcg tab • Levothyroxine 88mcg tab • Levothyroxine 100mcg tab • Levothyroxine 112mcg tab • Levothyroxine 125mcg tab • Levothyroxine 137mcg tab • Levothyroxine 150mcg tab • Levothyroxine 175mcg tab* • Levothyroxine 200mcg tab* Cost-Conscious Options

16. No dose adjustment provided in manufacturer’s labeling Dose Adjustment in Renal or Hepatic Impairment

17. Hypersensitivity to levothyroxine sodium or any component of the formulation • Acute MI • Thyrotoxicosis of any etiology • Uncorrected adrenal insufficiency Contraindications

18. Elderly do not have a change in serum thyroxine(T4) associated with aging; however, plasma T3 concentrations are decreased 25% to 40% in the elderly. • There is not a compensatory rise in thyrotropin(TSH) suggesting that lower T3 is not reacted upon as a deficiency by the pituitary • This indicates a slightly lower than normal dosage of thyroid hormone replacement is usually sufficient in elderly patients than in younger adult patients • TSH must be monitored closely: • insufficient thyroid replacement (elevated TSH) is a risk for coronary artery disease • excessive replacement (low TSH) may cause signs of hyperthyroidism and excessive bone loss Geriatric Considerations

19. Pregnancy category A • Endogenous thyroid hormones minimally cross the placenta • Levothyroxine has not been shown to increase the risk of congenital abnormalities. • Uncontrolled maternal hypothyroidism may result in adverse neonatal outcomes (eg, premature birth, low birth weight, and respiratory distress) and adverse maternal outcomes (eg, spontaneous abortion, pre-eclampsia, stillbirth, and premature delivery) • To prevent adverse events, normal maternal thyroid function should be maintained prior to conception and throughout pregnancy. • Levothyroxine is considered the treatment of choice for the control of hypothyroidism during pregnancy. • Due to alterations of endogenous maternal thyroid hormones, the levothyroxine dose may need to be increased during pregnancy and the dose usually needs to be decreased after delivery. Safety in Pregnancy

20. Cardiovascular: Angina pectoris, cardiac arrest, cardiac arrhythmia, congestive heart failure, flushing, hypertension, increased pulse, myocardial infarction, palpitations, tachycardia • Central nervous system: Anxiety, choking sensation (Levoxyl), emotional lability, fatigue, headache, heat intolerance, hyperactivity, insomnia, irritability, myasthenia, nervousness, pseudotumorcerebri (children), seizure (rare) • Dermatologic: Alopecia, diaphoresis • Endocrine & metabolic: Menstrual disease, weight loss • Gastrointestinal: Abdominal cramps, diarrhea, dysphagia (Levoxyl), gag reflex (Levoxyl), increased appetite, vomiting • Genitourinary: Infertility • Hepatic: Increased liver enzymes • Hypersensitivity: Hypersensitivity (to inactive ingredients; symptoms include urticaria, pruritus, rash, flushing, angioedema, GI symptoms, fever, arthralgia, serum sickness, wheezing) • Neuromuscular & skeletal: Decreased bone mineral density, slipped capital femoral epiphysis (children), tremor • Respiratory: Dyspnea • Miscellaneous: Fever Adverse Effects

21. In adult patients with primary hypothyroidism: • Serum TSH levels alone may be used to monitor therapy • Frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization. • For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage of levothyroxine changed: • Serum TSH concentration should be measured after 8-12 weeks. • When the optimum replacement dose has been attained: • Clinical and biochemical monitoring may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the patient’s status • Physical examination and a serum TSH measurement be performed at least annually Monitoring

22. The Levothyroxine in Levothyroxine sodium tablets, USP is intended to replace a hormone that is normally produced by your thyroid gland. Generally, replacement therapy is to be taken for life, except in cases of transient hypothyroidism, which is usually associated with an inflammation of the thyroid gland (thyroiditis). • Take Levothyroxine sodium tablets, USP as a single dose, preferably on an empty stomach, one-half to one hour before breakfast. Levothyroxine absorption is increased on an empty stomach. • Levothyroxine sodium tablets, USP may rapidly disintegrate. It is very important that you take the tablet with a full glass of water. • It may take several weeks before you notice an improvement in your symptoms. • Notify your physician if you experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. • Notify your physician if you become pregnant while taking Levothyroxine sodium tablets, USP. It is likely that your dose of Levothyroxine sodium tablets, USP will need to be increased while you are pregnant. Patient Instructions

23. TSH is the most reliable guide for evaluating adequacy of thyroid replacement dosage • Monitor TSH every 6-8 weeks until normalized; 8-12 weeks after dosage changes; every 6-12 months throughout therapy • Decreased dosing recommended in elderly/cardiac patients • Start low, go slow! Summary

24. 53 year old male • CC: “annual exam” • ROS: 10-point negative • FHx: CAD, father (MI @67); HLD, mother • PE: unremarkable • Labs: FLP, AST/ALT, FBS ordered Case 2

25. FLP • LDL: 190 • HDL: 35 • TG: 175 • AST/ALT: WNL • FBS: 88 Case 2, continued

26. Dx: hyperlipidemia • Treatment: start statin, diet/exercise • What medication do I start? And at which dose? • What labs do I need to monitor? • What are the side effects? • Are there important interactions to worry about? Case 2, continued

27. Physiology of HLD

28. 2013 ACC/AHA Cholesterol Guidelines

29. Beneficial in patients with dyslipidemias for both primary and secondary prevention of coronary heart disease Statins

30. Statins vs Other Agents

31. Mechanisms by which lipid-lowering therapy (particularly with statins) is beneficial are incompletely understood • Lowering of low density lipoprotein (LDL) concentration is associated with regression of atherosclerosis • Observed benefit of (particularly statin) therapy begins within months after its initiation • Makes regression an unlikely cause at this early stage • Other mechanisms thought to be involved include: • plaque stabilization • reduction of inflammation • reversal of endothelial dysfunction • decreased thrombogenicity • Reduction in monocyte adhesion to the endothelium, reduced oxidative modification of LDL, and increases in mobilization and differentiation of endothelial progenitor cells • potential benefits from lipid lowering Mechanism of Benefit

32. HMG CoA reductase (hydroxymethylglutaryl CoA reductase) inhibitors • competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol biosynthesis • occupy a portion of the binding site of HMG CoA, blocking access of this substrate to the active site on the enzyme Mechanism of Action

33. Cholesterol Synthesis(simplified!)

34. (Livalo) (Crestor) Statin Properties

35. Dosage Comparison

36. Chronic kidney disease presents an additional challenge for the selection of a statin • Atorvastatin and fluvastatin do NOT require dose adjustment • statins of choice in patients with severe renal impairment • If statins other than atorvastatin or fluvastatin are used, pravastatin may be safer than other statins • Dose adjustment is warranted with other statins in patients with severe kidney disease (CrCl less than 30 mL/min) Dosing in Patients with CKD

37. Patients with chronic liver disease who require a statin because of high cardiovascular risk, suggest complete abstinence from alcohol and the use of pravastatin at a low dose. • If the LDL-C remains elevated, combined therapy with a bile acid sequestrant may allow such patients to achieve their LDL-C target • Statins are contraindicated in patients with progressive liver disease • Patients who simply have baseline elevations in aminotransferases do not appear to be at increased risk when prescribed a statin Dosing in Patients with Chronic Liver Dz

38. In 2012, the US FDA revised its labeling information on statins to only recommend liver function testing prior to initiation of statin therapy and to only repeat such testing for clinical indications • check baseline aminotransferase levels prior to initiating statin therapy • do NOT routinely monitor these levels in patients on statins • recommend changing medications or lowering the statin dose in patients who are found to have an alanine aminotransferase (ALT) level more than three times the upper limit of normal that is confirmed on a second occasion Monitoring

39. 2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013): • Lipid panel (total cholesterol, HDL, LDL, triglycerides): Baseline lipid panel; fasting lipid profile within 4-12 weeks after initiation or dose adjustment and every 3-12 months (as clinically indicated) thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose. • Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (ie, ALT); measure hepatic function if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy. • CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue). • Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation. • If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy. Manufacturer recommendations: • Liver enzyme tests at baseline and repeated when clinically indicated. Upon initiation or titration, lipid panel should be analyzed at intervals of 4 weeks or more. Monitoring

40. Hypothyroidism as potential cause of dyslipidemia • Suggest checking a TSH level prior to initiating statin therapy • Hypothyroidism may predispose patients to statin-induced myopathy • Concerns have been raised that Asians may have greater responses to low doses of statins than Caucasians • Prescribing information for rosuvastatin recommends starting therapy at a lower initial dose in Asians than in other groups, given observed differences in pharmacokinetics • There is no strong evidence supporting such an approach with other statins. Other Considerations

41. 1% to 10%: • Cardiovascular: Chest pain (4%) • Central nervous system: Headache (2% to 6%), fatigue (4%), dizziness (1% to 3%) • Dermatologic: Rash (4%) • Gastrointestinal: Nausea/vomiting (7%), diarrhea (6%), heartburn (3%) • Hepatic: Transaminases increased (>3x normal on two occasions: 1%) • Neuromuscular & skeletal: Myalgia (2%) • Respiratory: Cough (3%) • Miscellaneous: Influenza (2%) <1%: • Allergy, alopecia, appetite decreased, dermatitis, dry skin, edema, fever, flushing, insomnia, lens opacity, libido change, muscle weakness, neuropathy, paresthesia, pruritus, sexual dysfunction, taste disturbance, tremor, urticaria, vertigo Postmarketing and/or case reports: • Amnesia (reversible), anaphylaxis, angioedema, cholestatic jaundice, cirrhosis, cognitive impairment (reversible), confusion (reversible), cranial nerve dysfunction, dermatomyositis, erythema multiforme, ESR increase, fulminant hepatic necrosis, gynecomastia, hemolytic anemia, hepatitis, hepatoma, lupus erythematosus-like syndrome, memory disturbance (reversible), memory impairment (reversible), myopathy, pancreatitis, peripheral nerve palsy, polymyalgia rheumatica, positive ANA, purpura, rhabdomyolysis, Stevens-Johnson syndrome, vasculitis Additional class-related events or case reports: • Angioedema, blood glucose increased, cataracts, depression, diabetes mellitus (new onset), dyspnea, eosinophilia, erectile dysfunction, facial paresis, glycosylated hemoglobin (Hb A1c) increased, hypersensitivity reaction, immune-mediated necrotizing myopathy (IMNM), impaired extraocular muscle movement, impotence, interstitial lung disease, leukopenia, malaise, memory loss, ophthalmoplegia, paresthesia, peripheral neuropathy, photosensitivity, psychic disturbance, skin discoloration, thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, transaminases increased, vomiting Adverse Effects

42. Hepatic Dysfunction • Muscle Injury • Renal Dysfunction • Behavioral & Cognitive • Cancer • DM Adverse Effects

43. Clinical studies of statins have demonstrated a 0.5 to 3.0 percent occurrence of persistent elevations in aminotransferases in patients receiving statins • Primarily occurred during the first three months of therapy and is dose-dependent Hepatic Dysfunction

44. Options in patients with aminotransferase elevations (more than three times the upper limit of normal; confirmed on repeat testing) • Use of a different statin (particularly pravastatin) • Dose reduction • Alternate day therapy Mgmt of Statin Intolerance due to LFT elevation

45. Development of muscle toxicity remains a concern with the use of the statins • Myopathicsyndromes associated with statins span a spectrum of complaints ranging from myalgias to myositis to overt rhabdomyolysis, which may be associated with acute renal failure from myoglobinuria • Muscle injury is uncommon with statin therapy alone • Frequency of 2 to 11 percent for myalgias, 0.5 percent for myositis, and less than 0.1 percent for rhabdomyolysis • Muscle symptoms usually begin within weeks to months after starting statins • Myalgias, weakness, and serum CK concentrations usually return to normal over days to weeks after drug discontinuation • Pravastatin and fluvastatin appear to have less intrinsic muscle toxicity. • Enhanced susceptibility to statin-associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, and hypothyroidism. • Patients can experience statin-induced myalgiaswithout an elevation in serum creatine kinase (CK) concentration • Clinical judgment is necessary in interpreting elevated CK levels in patients on statins • In the absence of clinical symptoms, a CK level >10 times the ULN that is felt to be due to a statin indication for discontinuing the medication • Patients should drink large quantities of fluids to facilitate renal excretion of myoglobin. After the CK and/or myoglobin have returned to baseline, patients may be tried on a statin less likely to cause muscle toxicity (as above) with careful monitoring. Muscle Injury

46. If a patient requires a statin and experiences muscle toxicity (other than rhabdomyolysis) with a statin other than pravastatin or fluvastatin, once symptoms have resolved off statin therapy, it is reasonable to consider a trial of pravastatin or fluvastatin with careful monitoring • Patients with a history of statin-induced rhabdomyolysis should generally NOT be treated with another statin (including pravastatin and fluvastatin), because of the risk of recurrence • In some cases, it may be reasonable to retry statin therapy after the resolution of an acute reversible event that contributed to muscle toxicity (eg, undetected hypothyroidism, acute renal failure, biliary obstruction, use of other medications that increase statin levels) Mgmt of Statin Intolerance 2/2 Muscle Injury

47. Statins appear to be able to cause proteinuria through tubular inhibition of active transport of small molecular weight proteins • Have been a number of reports to the FDA about proteinuria with statins, particularly in patients receiving rosuvastatin or simvastatin • it is believed that proteinuria with statins is a benign finding Renal Dysfunction

48. Case reports of patients developing severe irritability and aggression associated with the use of statins • not known whether the statin use caused these symptoms • very rare idiosyncratic reactions of this sort could be missed in controlled trials • Concerns have been raised about cognitive dysfunction and memory loss associated with statin use • Review of adverse events reported to the FDA between November 1997 - February 2002 found 60 reports of patients who had memory loss associated with statins • apparently high rate of reports with lipophilic statins (simvastatin and atorvastatin; 36 & 23 patients affected respectively) compared with hydrophilic statins (pravastatin; 1 patient) does suggest a possible biologic effect • If an individual patient appears to have memory loss associated with lipophilic statin therapy (simvastatin, lovastatin, atorvastatin, or fluvastatin) and has a strong indication for lipid lowering therapy, it would be reasonable to attempt treatment with a more hydrophilic statin (pravastatin or rosuvastatin) Behavioral/Cognitive

49. Preclinical studies found that very high-dose statin therapy increased the risk of liver tumors in rodents • Meta-analyses of randomized trials have shown no effect of statins on cancer incidence or cancer mortality Cancer

50. Experimental evidence has been conflicting about whether statins as a group improve glucose metabolism or whether some statins show beneficial effects while others show harmful effects • A 2011 meta-analysis of five randomized trials (N = 32,752) found an increased risk of incident diabetes with intensive statin therapy compared with moderate statin therapy (OR 1.12, CI 1.04-1.22) • Translates into approximately one additional case of diabetes for every 500 patients treated with intensive rather than moderate statin therapy. • Appears likely that statin therapy confers a small increased risk of developing diabetes • Risk is slightly greater with intensive statin therapy than moderate statin therapy. As would be expected, given the evidence from clinical trials that statins reduce CV events in patient with diabetes both randomized trials and observational studies suggest that the beneficial effects of statins on CV events and mortality outweigh any increased risk conferred by promoting the development of diabetes Diabetes Mellitus