Tafamidis

Usage

Tafamidis is prescribed for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) in adults. This condition involves the buildup of amyloid protein deposits in the heart, leading to heart failure. It is also used to treat transthyretin amyloid polyneuropathy (ATTR-PN) to delay peripheral neurologic impairment.

Tafamidis’s pharmacological classification is a transthyretin stabilizer.

It works by binding to transthyretin, stabilizing the tetrameric form of the protein and preventing its dissociation into monomers, which can then aggregate into amyloid fibrils and deposit in tissues, causing organ damage.

Alternate Names

Tafamidis is also known as tafamidis meglumine (the meglumine salt form).

Brand names: Vyndaqel, Vyndamax.

How It Works

Pharmacodynamics: Tafamidis stabilizes transthyretin tetramers, preventing their dissociation into monomers. This stabilization inhibits the formation of amyloid fibrils that cause damage to organs, particularly the heart and peripheral nerves.

Pharmacokinetics:

• Absorption: Tafamidis is administered orally and is absorbed relatively quickly. Steady-state is typically reached within two weeks.
• Metabolism: Tafamidis is mainly excreted unchanged in the feces. A small portion undergoes glucuronidation in the liver. It does not induce or inhibit CYP3A4 enzymes.
• Elimination: Primarily fecal excretion of unchanged drug. The elimination half-life is approximately two days.

Mode of Action: Tafamidis selectively binds to the thyroxine-binding sites of transthyretin. This binding stabilizes the tetrameric structure of the protein and prevents its breakdown into monomers, thus inhibiting amyloid fibril formation.

Receptor binding, enzyme inhibition, or neurotransmitter modulation: Tafamidis’s primary mechanism is transthyretin stabilization. While in vitro studies have shown inhibition of the efflux transporter BCRP (breast cancer resistant protein), as well as OAT1 and OAT3 (organic anion transporters) at the 61 mg/day dose, its main clinical effect is related to transthyretin binding.

Elimination pathways: Primarily fecal excretion of unchanged drug; a small portion is metabolized via glucuronidation in the liver, with metabolites excreted in urine.

Dosage

Standard Dosage

Adults:

• Tafamidis meglumine (Vyndaqel): 80 mg (four 20 mg capsules) orally once daily.
• Tafamidis (Vyndamax): 61 mg (one capsule) orally once daily. Vyndamax and Vyndaqel are not interchangeable on a per-mg basis.

Children: The safety and effectiveness of tafamidis have not been established in pediatric patients.

Special Cases:

• Elderly Patients: No dose adjustment is necessary.
• Patients with Renal Impairment: No dose adjustment is necessary.
• Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild to moderate impairment. Caution is advised in severe hepatic impairment, and use is not recommended in patients with severe hepatic impairment.
• Patients with Comorbid Conditions: Individualized assessment is required.

Clinical Use Cases

Tafamidis’s indicated use is for the chronic management of ATTR-CM and ATTR-PN. It is not indicated for acute conditions such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Dosage adjustments may be needed in patients with severe hepatic dysfunction.

Side Effects

Common Side Effects

While generally well-tolerated, diarrhea has been reported in post-marketing surveillance. Clinical trial data show similar adverse event rates in tafamidis and placebo groups.

Rare but Serious Side Effects

Hypersensitivity reactions (skin rash, itching or hives, swelling of the face, lips, or tongue). One isolated case report of pericardial effusion possibly related to treatment exists.

Long-Term Effects

Long-term effects are still being investigated.

Adverse Drug Reactions (ADR)

Clinically significant ADRs requiring immediate intervention are rare, including hypersensitivity reactions.

Contraindications

Hypersensitivity to tafamidis or any component of the formulation.

Drug Interactions

• BCRP substrates: Dose adjustment may be required when co-administered with substrates of the breast cancer resistance protein (BCRP) transporter (e.g., methotrexate, rosuvastatin, imatinib). Rosuvastatin exposure increases approximately 2-fold following multiple doses of tafamidis 61 mg.

• OAT1 and OAT3 substrates: Dose adjustments may be required when co-administered with substrates of OAT1 and OAT3 organic anion transporters (e.g., NSAIDs, diuretics like furosemide).

• Avoid combination with: alpelisib, berotralstat, cladribine, ubrogepant, pazopanib, rimegepant, or topotecan.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Tafamidis is not recommended during pregnancy and should be avoided in women of childbearing potential not using highly effective contraception due to potential fetal harm based on animal studies. Contraception should be continued for one month after stopping treatment.
• Breastfeeding: Tafamidis should not be used during breastfeeding. Animal studies demonstrate drug excretion in milk with potential risk to newborns/infants.

Drug Profile Summary

• Mechanism of Action: Transthyretin stabilizer. Binds to transthyretin, preventing its dissociation and the formation of amyloid fibrils.
• Side Effects: Generally well-tolerated; diarrhea reported post-marketing. Hypersensitivity reactions possible.
• Contraindications: Hypersensitivity.
• Drug Interactions: BCRP, OAT1 and OAT3 substrates.
• Pregnancy & Breastfeeding: Not recommended in pregnancy or breastfeeding.
• Dosage: Vyndaqel: 80 mg (four 20 mg capsules) once daily; Vyndamax: 61 mg once daily.
• Monitoring Parameters: Monitor for signs of hypersensitivity or other adverse events. Cardiac function should be assessed regularly.

Popular Combinations

Tafamidis is typically used as monotherapy for ATTR-CM and ATTR-PN. Concomitant medications to manage symptoms of heart failure or polyneuropathy may be used as needed.

Precautions

• Assess for hypersensitivity, hepatic impairment, and renal function.
• Patients should not be pregnant or breastfeeding. Women of childbearing potential should use contraception during treatment and for one month after discontinuation.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Tafamidis?

A: Adults: Vyndaqel: 80 mg (four 20 mg capsules) orally once daily. Vyndamax: 61 mg (one 61 mg capsule) orally once daily. Pediatric use is not established.

Q2: How does Tafamidis work?

A: Tafamidis binds to and stabilizes transthyretin, preventing its dissociation into monomers, the building blocks of amyloid fibrils.

Q3: What are the common side effects of Tafamidis?

A: Tafamidis is generally well-tolerated. Diarrhea has been reported post-marketing. Clinical trial data show comparable side effects between tafamidis and placebo.

Q4: Is Tafamidis safe during pregnancy?

A: No. Tafamidis is not recommended during pregnancy based on animal studies. Contraception is needed during and for one month after treatment.

Q5: Can Tafamidis be used in patients with renal impairment?

A: Yes, no dosage adjustment is necessary for patients with renal impairment.

Q6: Are there any significant drug interactions with Tafamidis?

A: Yes, Tafamidis can interact with substrates of BCRP (e.g., methotrexate, rosuvastatin, imatinib) and OAT1 and OAT3 transporters. Dosage adjustments of interacting drugs might be required. Certain other drugs like alpelisib and berotralstat should be avoided in combination with tafamidis.

Q7: What is the difference between Vyndaqel and Vyndamax?

A: Vyndaqel contains tafamidis meglumine, while Vyndamax contains tafamidis. They are not interchangeable on a per-mg basis. Vyndaqel is dispensed as 20 mg capsules, with 80 mg (four capsules) being the standard dose. Vyndamax is dispensed as 61 mg capsules, with one capsule being the standard dose.

Q8: Can Tafamidis cure ATTR-CM?

A: No, Tafamidis does not cure ATTR-CM, but it slows the progression of the disease and reduces cardiovascular-related hospitalizations and mortality.

Q9: How should I monitor patients on Tafamidis?

A: Monitor for signs of hypersensitivity or other adverse events. Regular assessment of cardiac function is crucial, potentially including echocardiography, ECG, and biomarkers like NT-proBNP. Additionally, monitor for peripheral neuropathy in patients with ATTR-PN.