Dofetilide

The dosing of Dofetilide is highly individualized and is determined by a healthcare provider based on two critical factors: the patient's renal function (calculated creatinine clearance) and their heart's electrical response (the QT interval) as measured on an electrocardiogram (ECG).

For adults with normal kidney function (Creatinine Clearance > 60 mL/min), the standard starting dose is 500 mcg taken twice daily.

If the patient has moderately impaired kidney function, the dose must be reduced to prevent the drug from building up to dangerous levels:

• Creatinine Clearance 40-60 mL/min: 250 mcg twice daily.
• Creatinine Clearance 20-39 mL/min: 125 mcg twice daily.
• Creatinine Clearance < 20 mL/min: Dofetilide is contraindicated (must not be used).

The safety and effectiveness of Dofetilide in pediatric patients (children under the age of 18) have not been established. Clinical trials for Dofetilide primarily focused on adult populations. Therefore, Dofetilide is not currently approved for pediatric use. Healthcare providers will typically explore other antiarrhythmic options or procedures for children with heart rhythm disorders.

Renal Impairment

As noted above, renal function is the primary determinant of Dofetilide dosing. Healthcare providers calculate a patient's Creatinine Clearance (CrCl) using the Cockcroft-Gault formula. If kidney function declines during treatment, the dose may need to be lowered or the medication stopped entirely. Routine blood tests to monitor kidney function are mandatory for anyone taking this medication.

Hepatic Impairment

Since only about 20% of Dofetilide is metabolized by the liver, mild to moderate hepatic (liver) impairment typically does not require a dose adjustment. However, the drug has not been extensively studied in patients with severe hepatic impairment, so healthcare providers use extreme caution in this population.

Elderly Patients

Elderly patients are more likely to have decreased kidney function, even if their blood creatinine levels appear normal. Healthcare providers are particularly careful when calculating the initial dose for patients over 65 and will monitor their renal function and ECGs closely throughout treatment.

Taking Dofetilide correctly is essential for maintaining a stable heart rhythm and avoiding dangerous side effects.

• Consistency is Key: Take Dofetilide exactly as prescribed, usually twice a day (approximately every 12 hours).
• With or Without Food: Dofetilide can be taken with or without food. However, you should choose one way and stay consistent.
• Swallow Whole: Capsules should be swallowed whole with a full glass of water. Do not crush, chew, or open the capsules, as this can affect how the drug is absorbed.
• Storage: Store the medication at room temperature, away from excessive moisture and heat. Keep the bottle tightly closed.
• Hospital Initiation: You will be required to stay in the hospital for the first 3 days (5 or 6 doses) of treatment. This allows doctors to monitor your heart rhythm constantly and adjust the dose if your 'QT interval' (a specific part of your heartbeat) becomes too long.

If you miss a dose of Dofetilide, do not take the missed dose. Simply wait and take your next scheduled dose at the regular time. Never take two doses at once to make up for a missed one. Taking a double dose significantly increases the risk of a life-threatening arrhythmia. If you miss multiple doses, contact your healthcare provider immediately, as you may need to be re-hospitalized to safely restart the medication.

An overdose of Dofetilide is a medical emergency. The primary risk of overdose is a life-threatening heart rhythm called Torsades de Pointes, which can lead to ventricular fibrillation and cardiac arrest.

Signs of Overdose include:

• Severe dizziness or fainting
• Palpitations (feeling like your heart is racing or skipping beats)
• Extreme fatigue
• Seizures

If an overdose is suspected, call 911 or your local emergency services immediately. Treatment in an emergency setting usually involves continuous ECG monitoring, correcting electrolyte imbalances (like potassium and magnesium), and potentially using medications or a temporary pacemaker to manage the heart rate.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking Dofetilide without direct medical guidance, as stopping the drug can cause your AFib to return.

While Dofetilide is generally well-tolerated when dosed correctly, some patients may experience side effects as their body adjusts to the medication. Common side effects reported in clinical trials include:

• Headache: This is the most frequently reported side effect. It is usually mild to moderate and may diminish over time. Patients should discuss safe over-the-counter pain relief options with their doctor.
• Chest Pain (Angina): Some patients may feel pressure or discomfort in the chest. While this can be a side effect of the drug, it must always be evaluated by a doctor to rule out other heart issues.
• Dizziness: Feeling lightheaded or unsteady is common, especially when moving from a sitting to a standing position. This is often related to changes in heart rhythm or blood pressure.

These side effects occur in a smaller percentage of patients but are still significant enough to monitor:

• Nausea and Diarrhea: Gastrointestinal upset can occur. If these symptoms are severe or lead to dehydration, they can affect electrolyte levels, which is dangerous for patients on Dofetilide.
• Insomnia: Difficulty falling or staying asleep has been reported by some patients.
• Respiratory Symptoms: This may include an increased cough, shortness of breath (dyspnea), or symptoms resembling a common cold (flu syndrome).
• Back Pain: General musculoskeletal pain in the back or limbs.
• Rash: Some patients may develop a mild skin rash or itching.

Rare but documented side effects include:

• Syncope (Fainting): A sudden loss of consciousness, which often indicates a significant change in heart rhythm.
• Paresthesia: A 'pins and needles' or tingling sensation in the hands, feet, or face.
• Liver Enzyme Elevations: Rare cases of asymptomatic increases in liver function tests.

> Warning: Stop taking Dofetilide and call your doctor or emergency services immediately if you experience any of these serious symptoms. These may indicate a life-threatening heart rhythm disturbance.

• Torsades de Pointes: This is a specific type of ventricular tachycardia (fast heart rhythm) that can be fatal. Symptoms include sudden, severe dizziness, fainting, or a feeling that the heart is 'flopping' in the chest.
• Ventricular Arrhythmias: Any new or worsening irregular heartbeat that feels different from your original AFib.
• Severe Bradycardia: An abnormally slow heart rate (usually below 50 beats per minute) that causes extreme tiredness or weakness.
• Angioedema: While rare, swelling of the face, lips, tongue, or throat, or difficulty breathing, requires immediate emergency care.

Dofetilide does not typically cause 'cumulative' toxicity like some other antiarrhythmics (such as amiodarone, which can affect the lungs and thyroid over time). However, the long-term risk associated with Dofetilide is the persistent risk of proarrhythmia (the drug causing a new arrhythmia). As patients age, their kidney function naturally declines. If the Dofetilide dose is not adjusted to match this decline, the risk of serious side effects increases significantly over time. Regular, lifelong monitoring of renal function and ECGs is required for as long as a patient is on the drug.

The FDA has issued a Black Box Warning for Dofetilide, which is the most serious type of warning. The warning states that to minimize the risk of induced arrhythmia, Dofetilide must be initiated (or re-initiated if it was stopped) in a setting where there is continuous ECG monitoring and specialized staff who can calculate creatinine clearance and monitor the QT interval. Patients must stay in this facility for a minimum of three days. This warning exists because the risk of Torsades de Pointes is highest during the first few days of treatment. Statistics show that approximately 2-3% of patients may experience this serious arrhythmia during the initiation phase, necessitating immediate medical intervention.

Report any unusual symptoms, no matter how minor they seem, to your healthcare provider immediately. What might seem like a simple stomach bug can lead to electrolyte imbalances that make Dofetilide dangerous.

Dofetilide is a high-alert medication. Because it works by altering the electrical properties of the heart, it has a narrow 'therapeutic window'—meaning the difference between a helpful dose and a dangerous dose is very small. Patients must be committed to strict adherence to the dosing schedule and regular laboratory monitoring. You must never share this medication with others, and you should ensure that all your healthcare providers (including dentists and specialists) know you are taking Dofetilide.

FDA Black Box Warning Summary: Dofetilide must be initiated in a facility that can provide continuous electrocardiographic (ECG) monitoring and cardiac resuscitation for a minimum of three days. This is required to minimize the risk of Torsades de Pointes, a potentially fatal heart rhythm. Healthcare providers must accurately calculate the patient's creatinine clearance (kidney function) before the first dose and monitor the QT interval closely after each of the first several doses. If the QT interval increases too much, the dose must be reduced or stopped.

• QT Prolongation: This is the primary concern with Dofetilide. The drug naturally lengthens the QT interval (the time it takes for the heart to electrically reset). If the QT interval becomes too long (typically over 500 milliseconds), the risk of a fatal arrhythmia becomes unacceptably high.
• Electrolyte Imbalance: Low levels of potassium or magnesium in the blood significantly increase the risk of Dofetilide-induced arrhythmias. Conditions that cause electrolyte loss—such as severe diarrhea, vomiting, or the use of certain diuretics (water pills)—must be reported to a doctor immediately.
• Heart Failure: Patients with severe heart failure may be at a higher risk for certain side effects, although Dofetilide is often preferred over other antiarrhythmics in patients with stable heart failure because it does not weaken the heart's pumping strength (it has no negative inotropic effect).
• Liver and Kidney Health: Because the kidneys remove most of the drug from the body, any decline in kidney health can lead to toxic levels of Dofetilide. While liver metabolism is a smaller factor, severe liver disease requires cautious monitoring.

If you are prescribed Dofetilide, your medical calendar will include several mandatory tests:

1. 1ECG (Electrocardiogram): Used to measure the QT interval. This is done multiple times during hospital initiation and periodically during follow-up visits.
2. 2Renal Function Tests: Blood tests (Creatinine and BUN) to calculate how well your kidneys are filtering the drug. These are usually performed every 3 to 6 months.
3. 3Electrolyte Panel: To ensure potassium and magnesium levels are within the optimal range. This is often done alongside renal function tests.

Dofetilide itself does not typically cause sedation. However, because it can cause dizziness or fainting (especially if the heart rhythm changes), you should be cautious when driving or operating heavy machinery until you know how the medication affects you. If you feel lightheaded, stop the activity and contact your doctor.

Alcohol should be used with extreme caution. Alcohol can cause dehydration and affect electrolyte balance, both of which increase the risks associated with Dofetilide. Additionally, excessive alcohol is a known trigger for atrial fibrillation (sometimes called 'Holiday Heart Syndrome'), which may counteract the benefits of the medication.

Do not stop taking Dofetilide abruptly unless directed by your doctor. While there isn't a 'withdrawal syndrome' like with some medications, stopping Dofetilide will likely cause your heart to go back into atrial fibrillation or flutter. If you must stop the drug because of a side effect or for a medical procedure, your doctor will provide a specific plan. If you are off the drug for more than two days, you may need to be re-hospitalized to safely restart it.

> Important: Discuss all your medical conditions, especially any history of kidney disease or other heart problems, with your healthcare provider before starting Dofetilide.

Certain drugs block the removal of Dofetilide from the body or further prolong the QT interval, creating a dangerous situation. The following medications are strictly contraindicated with Dofetilide:

• HCTZ (Hydrochlorothiazide): Often found in blood pressure medications. It increases Dofetilide blood levels and depletes potassium.
• Verapamil: A common calcium channel blocker. It can significantly increase the peak levels of Dofetilide in the blood.
• Cimetidine (Tagamet): An over-the-counter acid reducer. It interferes with the renal transport of Dofetilide.
• Trimethoprim (often in Bactrim): An antibiotic that blocks the kidney's ability to excrete Dofetilide.
• Ketoconazole: An antifungal medication that inhibits the CYP3A4 enzyme and renal transport.
• Prochlorperazine (Compazine): Used for nausea; it can increase Dofetilide levels.
• Dolutegravir: An HIV medication that increases Dofetilide exposure.
• Megestrol: Used for appetite stimulation; it can increase Dofetilide levels.

Taking any of these with Dofetilide can lead to toxic levels and fatal arrhythmias.

• Other Antiarrhythmics: Drugs like amiodarone, sotalol, or quinidine should generally be stopped and allowed to clear the body (washout period) before starting Dofetilide, as they also affect heart rhythm.
• Certain Antibiotics: Erythromycin and clarithromycin can increase Dofetilide levels by inhibiting the CYP3A4 enzyme.
• Antidepressants: Some SSRIs and tricyclic antidepressants can prolong the QT interval, adding to Dofetilide's effect.

• Digoxin: While often used together for heart rate control, both drugs can affect heart conduction, requiring careful ECG monitoring.
• Grapefruit Juice: Grapefruit is a known inhibitor of the CYP3A4 enzyme. While the effect on Dofetilide is moderate, it is generally recommended to avoid large amounts of grapefruit juice to prevent unnecessary increases in drug levels.

Aside from grapefruit, there are no specific dietary restrictions like dairy or high-fat meals. However, maintaining a consistent diet is important to keep electrolyte levels stable. Avoid 'fad diets' that might cause rapid changes in potassium or magnesium levels.

• St. John's Wort: This herb can 'speed up' the metabolism of many drugs. While it might lower Dofetilide levels (reducing efficacy), it is best avoided to keep drug levels predictable.
• Magnesium and Potassium Supplements: These should only be taken under a doctor's direction. While adequate levels are needed, excessively high levels can also be dangerous.
• Licorice Root: Real licorice can cause the body to lose potassium, which is dangerous for Dofetilide patients.

Dofetilide does not typically interfere with common laboratory tests, such as blood sugar or cholesterol panels. However, it is essential that the laboratory and your doctor use the Cockcroft-Gault formula to calculate your kidney function, rather than just looking at the 'eGFR' typically reported on lab sheets, as the eGFR may not be accurate for Dofetilide dosing.

For each major interaction, the mechanism usually involves either the CYP3A4 enzyme in the liver or the cationic transport system in the kidneys. When these pathways are blocked, Dofetilide levels rise, leading to QT prolongation and the risk of Torsades de Pointes. Management always involves avoiding the combination or, in rare cases, a significant dose reduction and intensive monitoring.

> Important: Tell your doctor about ALL medications, including over-the-counter drugs, vitamins, and herbal products, before starting Dofetilide.

There are several situations where the risks of Dofetilide far outweigh any potential benefits. In these cases, the drug must NEVER be used:

• Congenital or Acquired Long QT Syndromes: If a patient already has a long QT interval (over 450 milliseconds) before starting the drug, Dofetilide will push that interval into a dangerous range, making a fatal arrhythmia almost certain.
• Severe Renal Impairment: Patients with a calculated Creatinine Clearance of less than 20 mL/min cannot filter the drug out of their system. This leads to rapid toxic buildup.
• Concurrent use of Contraindicated Drugs: If a patient must take verapamil, HCTZ, cimetidine, trimethoprim, or the other drugs listed in the interactions section, they cannot take Dofetilide.
• Known Hypersensitivity: Anyone who has had a severe allergic reaction to Dofetilide or any of its capsule components.

In these cases, a healthcare provider will perform a careful risk-benefit analysis:

• Low Potassium or Magnesium: These must be corrected before the first dose of Dofetilide is given.
• Recent Heart Attack: Patients who have had a myocardial infarction within the last 2-4 weeks are usually not started on Dofetilide until their heart has stabilized.
• Severe Liver Disease: Due to the lack of data in this population.
• Pregnancy: The risks to the fetus must be weighed against the mother's need for rhythm control.

There is no known cross-sensitivity between Dofetilide and other classes of drugs like sulfonamides or penicillins. However, patients who have had 'proarrhythmic' reactions to other Class III antiarrhythmics (like Sotalol) are at a much higher risk of having the same reaction to Dofetilide and are usually not considered good candidates for the drug.

> Important: Your healthcare provider will evaluate your complete medical history, including your baseline ECG and kidney function, before determining if Dofetilide is safe for you.

Dofetilide is classified by the FDA as Pregnancy Category C. This means that animal studies have shown some adverse effects on the fetus, but there are no adequate, well-controlled studies in humans. In animal studies, Dofetilide was associated with structural abnormalities and increased fetal death when given at doses higher than the human equivalent. Dofetilide should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus. It is not recommended for use in women of childbearing age who are planning to become pregnant unless rhythm control is absolutely essential and other options have failed.

It is not known whether Dofetilide is excreted in human milk. However, because many drugs are excreted in milk and because of the potential for serious adverse reactions in nursing infants (specifically heart rhythm issues), a decision should be made whether to discontinue nursing or discontinue the drug. In most cases, if a mother requires Dofetilide, healthcare providers recommend using infant formula to ensure the baby's safety.

As previously mentioned, Dofetilide is not approved for use in children. The electrical system of a child's heart and their kidney function change rapidly as they grow, making the strict dosing requirements of Dofetilide difficult to manage safely. Conditions like supraventricular tachycardia (SVT) in children are typically treated with other medications or catheter ablation procedures.

Clinical trials included a significant number of patients over 65. While the drug is effective in the elderly, this population is at a higher risk for side effects because kidney function naturally declines with age. Furthermore, elderly patients are often taking multiple medications (polypharmacy), increasing the risk of drug-drug interactions. Doctors are extremely cautious when calculating the dose for geriatric patients and will often start with a lower dose if there is any doubt about kidney function.

Renal impairment is the most critical factor in Dofetilide safety. For patients with a CrCl between 20 and 60 mL/min, the dose must be reduced (either 250 mcg or 125 mcg BID). For those with a CrCl below 20 mL/min, the drug is prohibited. Dofetilide is not significantly removed by hemodialysis, so patients on dialysis cannot safely use this medication.

While no specific dose adjustment is required for mild to moderate liver disease (Child-Pugh Class A or B), the drug should be used with caution. The liver is responsible for about 20% of the drug's clearance, and if liver function is severely impaired, this could lead to higher-than-expected blood levels. There is no data for patients with Child-Pugh Class C (severe) hepatic impairment.

> Important: Special populations require individualized medical assessment and more frequent monitoring to ensure the safe use of Dofetilide.

Dofetilide is a 'pure' Class III antiarrhythmic agent according to the Vaughan-Williams classification system. Its molecular mechanism is highly specific: it binds to and blocks the KCNH2 (hERG) potassium channels in the heart. These channels are responsible for the $I_{Kr}$ (rapid delayed rectifier) potassium current. By inhibiting this current, Dofetilide slows down the exit of potassium ions from the heart cells during Phase 3 of the cardiac action potential. This results in a prolongation of the action potential duration and the effective refractory period in both the atria and the ventricles. Essentially, it keeps the heart cells in a 'resting' state for a longer period, preventing the rapid, chaotic electrical signals of AFib from re-triggering the heart too soon.

The primary pharmacodynamic effect of Dofetilide is the prolongation of the QT interval on the ECG. This effect is dose-dependent—the more drug in the system, the longer the QT interval. There is a direct relationship between the plasma concentration of Dofetilide and the increase in the QT interval. Dofetilide does not have any significant effect on the heart rate or blood pressure in most patients, nor does it affect the conduction velocity (the speed at which the signal travels).

| Parameter | Value |

|---|---|

| Bioavailability | >90% |

| Protein Binding | 60% - 70% |

| Half-life | ~10 hours |

| Tmax | 2 - 3 hours |

| Metabolism | CYP3A4 (approx. 20%) |

| Excretion | Renal 80% (60-70% unchanged) |

• Molecular Formula: $C_{19}H_{27}N_{3}O_{5}S_{2}$
• Molecular Weight: 441.56 g/mol
• Solubility: Very slightly soluble in water; soluble in 0.1 M HCl.
• Structure: Dofetilide is a methanesulfonamide derivative. Its structure allows it to fit specifically into the pore-forming region of the $I_{Kr}$ potassium channel.

Dofetilide is a Class III antiarrhythmic. Other drugs in this class include Sotalol, Amiodarone, and Ibutilide. However, Dofetilide is unique because it is more selective for the $I_{Kr}$ channel than amiodarone (which affects multiple channels) or sotalol (which also has beta-blocking properties).