Continuing Education Activity

Tafamidis is an oral medication for treating cardiomyopathy and peripheral neuropathy due to transthyretin amyloidosis (ATTR). It is a transthyretin stabilizer and has been shown to reduce disease progression and mortality significantly. This activity will highlight the current indications, mechanism of action, dosage, contraindications, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) of tafamidis in a clinical setting pertinent for healthcare team members in the management of patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) or peripheral neuropathy (ATTR-PN).

Objectives:

• Describe the mechanism of action of tafamidis.
• Review the available formulations and dosage of tafamidis.
• Identify the adverse events of tafamidis in clinical practice.
• Outline the importance of collaboration and coordination in an interprofessional health team to improve patient outcomes when receiving tafamidis.

Indications

Tafamidis is an innovative drug used to treat certain forms of ATTR amyloidosis (Transthyretin). ATTR amyloidosis is due to transthyretin (prealbumin) misfolding, which becomes unstable and deposits within the extracellular space of mainly cardiac tissue and nerves.[1] It is of two types: the wild or senile type (ATTRwt) and the variant type (ATTRv), also known as hereditary or familial type. ATTRwt amyloidosis presents in elderly males with a predominant cardiac phenotype: Whereas the ATTRv amyloidosis mainly presents as sensorimotor peripheral neuropathy, specifically in patients with V30M mutation.[2]

However, in the United States, a predominantly cardiac phenotype is seen due to the high prevalence of V122I mutation (3.5%) in the African American population.[3] Previously, the treatment was mainly supportive in both types of ATTR amyloidosis, with the liver transplantation being reserved for the ATTRwt form.[4] However, the prognosis is improving with the availability of effective targeted therapies, including TTR stabilizers (tafamidis, diflunisal) and silencers (patisiran, inotersen).

In the multinational ATTR-ACT study, 441 patients with cardiomyopathy (24% ATTRv and 76% ATTRwt) were randomized to receive either tafamidis 80mg or tafamidis 20mg or a placebo once daily for 30 months.[5] Compared to placebo, tafamidis led to significantly lower all-cause mortality (42.9% vs. 29.5%; hazard ratio= 0.70) and cardiovascular hospitalizations (0.7 per year vs. 0.48 per year; relative risk ratio= 0.68). It also reduced the decline in 6-min walk distance and health status score. In May 2019, the FDA approved tafamidis to treat ATTR cardiomyopathy (ATTR-CM) of both wild and hereditary types to reduce cardiovascular hospitalizations and mortality. Patients in NYHA class IV were not included in the study, and those with NYHA class III had increased cardiovascular hospitalizations compared to placebo. Therefore, it is prudent to start the treatment early while the patient is still in NYHA class I or II to improve long-term survival.[6] Cardiomyopathy associated with ATTRv has a poor prognosis compared with ATTRwt, but tafamidis showed a similar reduction in mortality and hospitalizations in both types.[7]

In November 2011, tafamidis was approved by the European Medicines Agency (EMA) to treat ATTR amyloidosis to delay neurological progression in patients with stage 1 polyneuropathy.[8] Subsequently, it has received approval in more than 40 countries. In 2016, the first European consensus on transthyretin familial amyloid polyneuropathy recommended tafamidis as the standard of care in stage 1 ATTR-PN (polyneuropathy), replacing the liver transplantation.[9] Early diagnosis of ATTR-PN and treatment are essential to achieve the most significant benefits.[10] In the pivotal placebo-controlled Fx-005 study, including patients with early familial ATTR polyneuropathy, the disease progression in the tafamidis group did not differ significantly.[11]

In 2019, the FDA granted tafamidis priority review, fast track, and breakthrough therapy designations to treat the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM). In addition, tafamidis and tafamidis meglumine also obtained orphan drug designation, which provides incentives for developing drugs for rare diseases.[12] The FDA has not approved tafamidis to treat ATTR polyneuropathy based on insufficient evidence of clinical efficacy.

Mechanism of Action

Tafamidis is disease-modifying transthyretin (TTR) kinetic stabilizer for treating transthyretin amyloidosis (ATTR amyloidosis).[12]

Transthyretin (TTR) is a soluble, tetrameric protein synthesized and secreted by the liver. Conformational change can occur in TTR either spontaneously with age (ATTRwt) or genetic abnormality (ATTRv), leading to destabilization and dissociation into monomers.[13] These monomers misfold and deposit in the extracellular space of tissues as insoluble amyloid fibrils, impairing their normal functioning. Tafamidis, a selective stabilizer of TTR, selectively binds to the thyroxine-binding sites and kinetically stabilizes the TTR tetramer.[14] By slowing the dissociation into monomers, the rate-limiting step of amyloid formation, tafamidis slows the disease progression in both cardiomyopathy and peripheral neuropathy.[13]

Pharmacokinetics (manufacturer's labeling)

• Absorption: Peak concentration is observed within 4 hours after dosing. No clinically meaningful differences in the pharmacokinetics of tafamidis are marked concerning high fat/calorie food intake.

• Distribution: The apparent volume of distribution(Vd) of tafamidis meglumine is 16 liters and 18.5 liters for tafamidis. Tafamidis predominantly binds to TTR. Plasma protein binding of tafamidis is high(>99% in vitro).

• Metabolism: Glucuronidation has been observed in clinical studies. However, the metabolism of tafamidis is not comprehensively understood.

• Excretion: The mean half-life of tafamidis is 49 hours, and the clearance of tafamidis meglumine is approximately 0.228 L/h and 0.263 L/h for tafamidis. Consequently, after multiple tafamidis dosing, drug accumulation is approximately 2.5-fold times greater than administration of a single dose. Approximately 22% of the dose is recovered in urine (primarily as the glucuronide metabolite). Approximately 59% of the dose is recovered in feces (primarily as the unchanged drug).

Administration

Tafamidis is administered orally and is currently available as soft capsules in the following two strengths:

• Tafamidis meglumine 20 mg capsules (equivalent to 12.2 mg of tafamidis free acid)
• Tafamidis free acid 61 mg capsules

Dosage in ATRR cardiomyopathy (FDA-approved indication): The recommended dose is either tafamidis meglumine 80 mg (four capsules of 20 mg) or tafamidis 61 mg (single capsule) orally once daily.[13] Doses of 80 mg tafamidis meglumine and 61 mg tafamidis are bioequivalent, but they can not be substituted per mg.[15] The capsules should be swallowed whole and can be taken with or without food. The manufacturer promotes the 61 mg capsule more because of single capsule dosing, preventing patients from self-adjusting the 20mg capsules. Dosage in ATTR peripheral neuropathy (non-FDA-approved indication): The recommended dose is 20 mg of tafamidis meglumine orally once daily.[10]

Specific Patient Populations (according to manufacturer's labeling)

• Hepatic Impairment: There are no significant differences in tafamidis in patients with mild hepatic impairment (Child-Pugh score of 5 to 6). Patients with moderate hepatic impairment (Child-Pugh score 7 to 9) have decreased systemic exposure and increased clearance of tafamidis, but these patients have low TTR levels than healthy subjects. Consequently, the exposure of tafamidis relative to the amount of TTR is sufficient to maintain the stabilization of the TTR tetramer in these patients. The significance of severe hepatic impairment on tafamidis is not known.

• Renal Impairment: No clinically significant differences in the pharmacokinetics of tafamidis are observed in patients with renal impairment. But therapeutic benefit has not been established with impaired renal function (eGFR<25 mL/min/1.73 m2) based on 2022 AHA/ACC/HFSA guidelines.[16]

• Pregnancy Considerations: Preclinical studies indicates that tafamidis may cause fetal harm when administered to a pregnant woman. In animal reproductive studies, administration of tafamidis to pregnant rabbits resulted in adverse effects on development (embryofetal mortality and fetal malformation) at a dosage approximately nine times the human exposure (AUC) at the maximum recommended human dose (MRHD). In addition, postnatal mortality and growth retardation were observed in offspring of pregnant rats administered tafamidis meglumine approximately two times the MRHD-based on body surface area (mg/m2). Limited human data on tafamidis use in pregnant women have not identified major congenital disabilities or miscarriage, but more research is still needed. Hence, advise pregnant women of the potential risk to a fetus and consider pregnancy planning and prevention.

• Breastfeeding Considerations: Currently, there is no data regarding the presence of tafamidis in human milk and its effect on the breastfed infant. However, in pregnant and lactating female rats radioactivity study revealed that tafamidis meglumine is transferred to milk after oral administration. Animal studies also suggest the potential for serious adverse drug reactions in the breastfed infant. Consequently, advise patients that breastfeeding is not recommended during treatment with tafamidis.

Adverse Effects

In the 30-month ATTR-ACT study, the frequency of adverse events was similar in the tafamidis 20 mg, tafamidis 80 mg, and the placebo groups.[5] However, data from long-term follow-up and clinical practice settings in ATTR-PN show the following adverse events:[10][17]

• Headache 
• Urinary tract infection 
• Peripheral edema 
• Upper abdominal pain, flatulence, diarrhea
• Influenza, pneumonia
• Acute cardiac failure
• Pain in extremity, myalgia
• Punctate keratitis
• Vaginal infection
• Laboratory abnormalities: altered neutrophil and lymphocyte count, increased liver function test and blood urea nitrogen, increased prothrombin time, reduced serum thyroxine levels

Fecal incontinence and renal impairment may infrequently lead to treatment discontinuation. Severe adverse events are infrequent, with only one reported case of treatment-related pericardial effusion. One case of sudden death related to tafamidis was seen in a small Japanese study.[18] However, no mortality due to tafamidis has been reported in more extensive studies.

Contraindications

There is no absolute contraindication to the use of tafamidis except hypersensitivity to the active substance (tafamidis or tafamidis meglumine) or any inactive ingredients present in the capsule. Tafamidis is not recommended during pregnancy or breastfeeding, and for women of childbearing potential not using contraception. Safety and effectiveness have not been established in pediatric patients.

Due to sorbitol in the capsules, it should not be given to patients with hereditary fructose intolerance. As mentioned in pharmacokinetics, tafamidis can be initiated in patients with mild to moderate renal and hepatic impairment; caution is recommended in severe hepatic impairment. Tafamidis should not be given in patients with liver transplants and should be discontinued after liver transplants. Tafamidis should not be given in patients with NYHA class IV symptoms, 6-minute walk distance <100 m, and severe renal dysfunction (estimated glomerular filtration rate < 25 ml per minute per 1.73 m^2) as these patients were not studied in the ATTR-ACT trial.[5]

Drug Interactions: Dose adjustment may be required when used with substrates of breast cancer resistant protein (BCRP) transporter (e.g., methotrexate, rosuvastatin, imatinib). Avoid the combination of tafamidis with alpelisib, berotralstat, cladribine, ubrogepant, pazopanib, rimegepant, or topotecan.

Monitoring

The success of ATTR amyloidosis treatment with tafamidis is monitored and assessed by echocardiograms, cardiac magnetic resonance imaging (MRI), and scintigraphy with bone tracers to diagnose infiltrative cardiomyopathy.[13] There are no specific recommendations but based on the available trial data; the following parameters need to be monitored periodically:[10][19]

• Liver function test (LFT)
• Renal function test (RFT)
• Complete blood count (CBC)
• Thyroid function test 
• Prothrombin time
• Biomarkers of heart failure (NT-proBNP and Troponin I)
• Electrocardiogram (EKG)-  Low voltage in the limb leads and/or a pseudo-infarct pattern in the precordial leads.[20]
• Changes in echocardiography measures from baseline such as left ventricular ejection fraction (LVEF), interventricular wall thickness, left ventricular stroke volume, and global longitudinal strain (as mentioned in the appendix)[5]
• Quality of life as measured by the KCCQ-OS (Kansas city cardiomyopathy questionnaire-overall summary) and six-minute walk test (6MWT)[5]

Toxicity

In clinical studies, tafamidis has been administered at a dose of 80 mg and for up to 111 months without any significant adverse events. A single dose of tafamidis of 480 mg in healthy volunteers did not show any adverse event except mild hordeolum in one patient. Two patients, during clinical trials, accidentally took 160 mg of tafamidis without any adverse event. Moreover, administering a very high dose of tafamidis in dogs (476 fold the clinical dose of 80 mg tafamidis meglumine) had no apparent adverse events. Thus, the risk of overdose in humans is extremely low. However, clinicians should give standard supportive measures in case of overdose.

Enhancing Healthcare Team Outcomes

Cardiomyopathy associated with ATTR amyloidosis (ATTR-CM) is debilitating and has a median survival of only 2 to 6 years.[21] Early diagnosis is critical because of the recent availability of targeted treatment, which is more effective when instituted early in the disease course. Due to unclear clinical benefits, tafamidis currently has FDA approval only for ATTR-CM and not ATTR-PN. Delay in diagnosis and treatment mainly occurs due to fragmented knowledge among the healthcare professionals regarding clinical suspicion, availability of non-invasive diagnostic modalities, disease course and prevalence, genotypic heterogeneity, and use of targeted treatment.[22]

An interprofessional team is critical for diagnosing, managing symptoms, optimizing nutrition, treating with tafamidis, monitoring cardiac function, and managing the adverse effects of the treatments. Therefore, an integrated interprofessional healthcare team is required, including primary care physicians, cardiologists, neurologists, hematologists, pathologists, radiologists, nursing staff, and pharmacists. Due to non-specific clinical presentation, a high degree of clinical suspicion is necessary from clinicians. The disease is usually suspected based on symptoms, electrocardiogram (ECG), echocardiography, cardiac biomarkers, or magnetic resonance imaging (MRI). Suspected cases of cardiac amyloidosis should undergo screening for monoclonal protein to rule out AL amyloidosis (light chain), followed by myocardial scintigraphy or cardiac biopsy as needed.[23] 

Consultation with a hematologist is necessary in case of mild or doubtful elevations of serum-free light chains. The involvement of a nuclear medicine expert is essential because scintigraphy by 99mtechnetium compound is the mainstay of an early and non-invasive diagnosis of ATTR-CM. In case of any doubt, endomyocardial biopsy and evaluation by an experienced pathologist remain the gold standard of diagnosis. Genotyping is essential after diagnosis as a TTR variant requires genetic counseling from the family members. Neurological consultation may be necessary if there is suspicion of neurological involvement, particularly in the ATTRv type.

The treating physicians and nursing staff must understand that these patients do not tolerate antihypertensive and heart failure medications. They do not offer any clinical benefit and instead can cause symptomatic hypotension. The nursing staff must give supportive treatment in consultation with the cardiologists until more definitive treatment is initiated. Tafamidis is currently the most expensive cardiovascular medication, with a yearly cost of $225,000. Therefore, clinicians must start it only after explaining the cost and expected benefit to the patient in consultation with the pharmaceutical company and the medical insurer. An integrated multidisciplinary program is required, along with a dedicated pharmacist, to ensure the availability and affordability of tafamidis.[24] Once a clinician decides to start tafamidis, the nurse can counsel the patient on dosage and administration and monitor the clinical response in collaboration with the healthcare team. The nursing staff and pharmacist should also counsel regarding the potential harm of this drug during pregnancy, breastfeeding, and caution in women of childbearing potential. Despite an excellent safety profile of tafamidis, care is necessary by the physician, nurse, and pharmacist to monitor for rare adverse events.

Clinicians can advise all patients on tafamidis therapy of the availability of the Transthyretin Amyloidosis Outcome Survey (THAOS) registry and their voluntary participation.[25] The principal aim of this THAOS survey is to understand pathophysiology, disease characteristics, and emerging treatment options for amyloidosis by studying a large and heterogeneous patient population. A long-term study can help develop new treatment guidelines and recommendations, optimizing patient care and safety.[17] Thus, it must be emphasized that collaboration and coordination between the interprofessional team consisting of clinicians, specialists, nursing, and pharmacists are required to improve the outcomes of the patient.[26] [Level 2]