Istradefylline: Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Istradefylline represents a significant milestone in the treatment of certain neurological disorders. The drug was approved by the United States Food and Drug Administration (USFDA) on August 27, 2019; after over two decades of rigorous preclinical and clinical research, this medication offers hope for individuals with Parkinson's disease (a neurodegenerative disorder that affects movement). The approval of Istradefylline marked a significant advancement in Parkinson's disease therapy, particularly for individuals experiencing motor complications despite standard treatment with Levodopa.

Motor fluctuations, characterized by periods of involuntary movements (dyskinesia) or immobility (off episodes), can significantly impact the quality of life for Parkinson's patients. Istradefylline offers a new approach to managing these fluctuations, providing relief and improving overall motor function. Clinical trials have demonstrated the efficacy of Istradefylline in reducing "off time", periods when the medication's effects wear off and symptoms return, while also decreasing the need for additional Levodopa doses. Additionally, studies have shown improvements in motor function and activities of daily living among patients receiving Istradefylline compared to those on a placebo.

Drug Group

Istradefylline belongs to the drug class known as adenosine receptor antagonists. Adenosine receptor antagonists are a class of drugs that block the action of adenosine at its receptors in the body. Adenosine, a naturally existing molecule, contributes to multiple physiological functions, such as controlling heart rate, blood circulation, and neurotransmitter discharge in the brain.

Indications

Istradefylline is prescribed as an additional treatment alongside Levodopa or Carbidopa for adult patients with Parkinson's disease (PD) who encounter 'off' episodes.

Dosage Forms and Available Strengths

Istradefylline is typically available in tablet form, with varying strengths, such as 20 mg (milligrams) and 40 mg.

For Patients

What Is the Parkinson’s Disease?

Parkinson's disease is a neurodegenerative condition impacting movement functions. It is characterized by symptoms such as tremors (involuntary and rhythmic movements), rigidity, bradykinesia (slow movements), and impaired balance and coordination. Parkinson's disease results from the degeneration of brain cells responsible for producing Dopamine, resulting in disturbances in the brain's ability to control movement. At present, there is no known cure for Parkinson's disease. Treatments such as medications, surgery, and physical therapy have the potential to assist in symptom management and enhance the quality of life for individuals living with the condition.

What Are the Clinical Uses of Istradefylline?

Istradefylline is used alongside Levodopa or Carbidopa to manage "off" episodes in Parkinson's disease.

What Is the Dosage of the Istradefylline?

Istradefylline is typically taken orally at a starting dose of 20 mg (milligrams) once daily. Depending on a person's response and tolerance, the dosage may be raised to 40 mg once daily. Initial dose adjustment is unnecessary. Istradefylline can be taken with or without food.

How Is Istradefylline Administered?

Istradefylline is typically administered orally in the form of tablets, which are swallowed with water. The tablets are usually taken once daily, with or without food, as directed by a healthcare professional.

What Are the Side Effects of Istradefylline?

Istradefylline can cause serious side effects, such as:

• Uncontrolled sudden movements (dyskinesia) may become worse or more frequent. It is necessary to tell the doctor if this happens.

Hallucinations and other symptoms like:

• Feeling overly suspicious or paranoid.

• Disorientation.

• Believing in things that are not real (delusions).

• Aggressive behavior.

• Seeing or hearing things that are not real (hallucinations).

• Agitation, confusion, or increased activity (mania).

Unusual urges, like:

• Gambling urges.

• Increased sexual urges.

• Strong urges to spend money.

• Binge eating refers to consuming large amounts of food within a short period.

Common side effects of Istradefylline include uncontrolled movements, dizziness, constipation, nausea (vomiting sensation), hallucinations, and insomnia (lack of sleep). These are not all possible side effects, so if you experience anything unusual, contact the doctor immediately or report it to the FDA.

What Are the Things to Inform the Doctor Before Taking Istradefylline?

Before starting Istradefylline, inform the healthcare provider about:

• Any history of abnormal movements or dyskinesia.

• Reduced liver function.

• Smoking habits.

• Pregnancy or any plans for pregnancy, such as Istradefylline, may harm unborn babies.

• Breastfeeding or plans for breastfeeding, as it is unclear if Istradefylline passes into breast milk.

• Also, disclose all medications one takes, including prescriptions, over-the-counter (OTC) drugs, vitamins, and herbal supplements. Interaction between Istradefylline and other medications can lead to side effects or altered effectiveness. When starting new treatments, keep a list of the medications to share with the healthcare provider and pharmacist.

Dietary Considerations

None, unless specified by the doctor.

Missed Dose

If a dose of Istradefylline is missed, take it when remembered. If it is close to the next dose, skip it. Avoid doubling doses. If unsure, seek guidance from the healthcare provider or pharmacist.

Overdose

• Human Experience: Limited clinical experience exists regarding overdosage with Istradefylline. In one clinical trial, a patient consumed six tablets (equivalent to 120 mg, three times the maximum recommended dose) of Istradefylline along with alcoholic beverages. This resulted in hallucinations, agitation, and worsening dyskinesia.

• Management of Overdose: No specific antidotes for Istradefylline overdosage are known. If an overdose occurs, discontinue Istradefylline treatment and provide supportive care as needed. Considering Istradefylline's long half-life (approximately 83 hours) and the potential involvement of multiple drugs, consult a certified poison control center for current guidance and advice.

Storage and Handling

Keep at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit); for excursions, the temperature can range between 15 and 30 degrees Celsius (59 to 86 degrees Fahrenheit). Ensure that children, pets, or others cannot access the medication.

Disposal:

The drug must be discarded safely by contacting the nearest local garbage authority or pharmacist to give it away in a take-back program. However, if this option is unavailable, one can discard the drug by following FDA (Food and Drug Administration) guidelines and protocols for safe disposal.

For Doctors

Description:

Istradefylline is an adenosine receptor antagonist with a xanthine derivative structure. It is a light yellow-green crystalline powder. Each tablet, for oral use, contains 20 mg or 40 mg of Istradefylline along with inactive ingredients. These include crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polyvinyl alcohol. The film coating consists of hypromellose, lactose monohydrate, polyethylene glycol 3350, titanium dioxide, triacetin, and dyes such as red and yellow. Carnauba wax is used for polishing.

Dosing Considerations:

• Dosage Adjustment with Strong CYP3A4 Inhibitors: When Istradefylline is used with strong CYP3A4 inhibitors, the maximum recommended dosage is 20 mg once daily.

• Dosing with Strong CYP3A4 Inducers: Avoid using Istradefylline with strong CYP3A4 or Cytochrome P450 3A4 inducers.

• Dosage Adjustment in Patients with Hepatic Impairment: For patients with moderate hepatic impairment (Child-Pugh B), the highest advised dose is 20 mg taken once daily. Close monitoring for adverse reactions is necessary. Istradefylline is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

• Dosage Adjustment for Tobacco Smokers: For individuals who consume 20 or more cigarettes daily (or an equivalent amount of another tobacco product), the recommended dosage is 40 mg once daily.

Warnings and Precautions

The warnings and precautions are:

• Dyskinesia: Istradefylline with Levodopa can cause or worsen dyskinesia, which refers to abnormal, involuntary movements often associated with certain medications or neurological conditions. It occurred in 15 percent of patients on Istradefylline 20 mg, 17 percent on Istradefylline 40 mg, and 8 percent on placebo. One percent of patients on Istradefylline discontinued due to dyskinesia.

• Hallucinations or Psychotic Behavior: Patients with major psychotic disorders should not use Istradefylline due to the risk of worsening psychosis (loss of contact with reality). Hallucinations occurred in two percent with Istradefylline 20 mg, six percent with Istradefylline 40 mg, and three percent with placebo. One percent of Istradefylline 40 mg was discontinued due to hallucinations.

• Impulse Control or Compulsive Behaviors: Patients on Istradefylline and other Parkinson's medications may experience intense urges like gambling, increased sexual activity, spending money, or binge eating. In trials, one patient on Istradefylline 40 mg developed an impulse control disorder. Some urges stopped when the dose was reduced, or the medication was stopped. Specialists or doctors should ask about new or increased urges and consider dose adjustment or discontinuation if needed.

What Are the Pharmacological Actions of Istradefylline?

Pharmacodynamics: Istradefylline (40 mg or 160 mg once daily for 14 days) was assessed at a QTc interval. Results showed no clinically significant QTc interval prolongation or correlation between QTc changes and Istradefylline concentrations.

Mechanism of Action: The exact way Istradefylline works to treat Parkinson's disease is not fully understood. However, studies conducted in test tubes (in vitro) and in animals (in vivo) have shown that Istradefylline is an antagonist for adenosine A2A receptors.

Pharmacokinetics:

• Istradefylline shows dose-proportional pharmacokinetics, reaching a steady state within two weeks of once-daily dosing.

• The time to reach peak concentration (Tmax) under fasting conditions is around four hours.

• Food intake increases exposure to Istradefylline but does not significantly affect clinical outcomes.

• It exhibits high plasma protein binding and has a large apparent volume of distribution.

• Elimination occurs primarily through metabolism, with minimal excretion in urine.

• Smoking reduces systemic exposure to Istradefylline.

• Istradefylline has minimal effects on drug-metabolizing enzymes and transporters.

Non-clinical Toxicity

• Carcinogenesis: Research in mice and rats revealed no signs of cancer, even at high doses.

• Mutagenesis: Istradefylline did not cause mutations in tests.

• Impairment of Fertility: High doses reduced fertility and sperm motility in rats, while lower doses had no effect on reproduction.

• Animal Toxicology: Long-term use in rats led to brain vessel mineralization. No similar effects were seen in mice or dogs.

What Are the Contraindications of Istradefylline?

None.

What Are the Drug Interactions of Istradefylline?

When Istradefylline is taken with certain drugs:

• Strong CYP3A4 Inhibitors: Taking Istradefylline with drugs like Ketoconazole can increase Istradefylline levels in the body. The maximum recommended dosage of Istradefylline with these drugs is 20 mg once daily.

• Strong CYP3A4 Inducers: Avoid taking Istradefylline with drugs like Rifampin as they can decrease Istradefylline levels in the body.

• CYP3A4 Substrates: Istradefylline may affect the levels of drugs metabolized by CYP3A4, like Atorvastatin. Monitor for increased adverse reactions when taking these drugs with Istradefylline.

• P-glycoprotein (P-gp) Substrates: Taking Istradefylline with drugs like Digoxin can increase the levels of these drugs in the body. Monitor for increased adverse reactions when taking these drugs with Istradefylline.

Clinical Studies

Because clinical trials occur in diverse conditions, comparing adverse reaction rates between drug trials is inaccurate and might not reflect real-world rates. In studies of Istradefylline for Parkinson’s disease, 734 patients on stable Levodopa therapy participated in four 12-week trials. The majority were Asian, and about half were male, with an average age of 65. Discontinuation due to side effects was low, around five to six percent, with dyskinesia being the most common reason.

The most common side effects observed with Istradefylline were dyskinesia, dizziness, constipation, nausea, hallucinations, and insomnia, with frequencies higher than those on placebo. For instance, dyskinesia affected around 15 to 17 percent of patients on Istradefylline, compared to 8 percent on placebo. Other less common adverse effects included changes in appetite, increased blood markers, upper respiratory tract inflammation, and a rash.

Additionally, post-approval use outside the United States has reported an increase in libido as an adverse reaction to Istradefylline. However, its frequency is not reliably estimated due to voluntary reporting and uncertain population size.

Use in Specific Populations

Pregnancy and Lactation:

• There is limited data on the risks of using Istradefylline during pregnancy, but animal studies suggest potential harm, including teratogenic effects.

• Use during pregnancy should be avoided unless the benefits outweigh the risks.

• It is unknown if Istradefylline is present in human breast milk, but it is detected in the milk of lactating rats at high concentrations.

• Consideration of the maternal clinical need for Istradefylline and potential risks to the infant is advised during lactation.

Other Important Points:

• Contraception Recommendation: Contraception is recommended for women of childbearing potential using Istradefylline.

• Pediatric Guidelines: The safety and efficacy of Istradefylline have not been established in pediatric patients. Therefore, it should be used with caution.

• Renal Impairment: Dosage adjustment is unnecessary for patients with mild to moderate renal impairment.

• Hepatic Impairment: For individuals with moderate hepatic impairment, the highest advised dosage is 20 mg per day, taken once. Avoid Istradefylline use in patients with severe hepatic impairment.

• Tobacco Smokers: Tobacco smokers may require a higher dosage of Istradefylline for efficacy due to decreased systemic exposure.