Idebenone

Usage

• Idebenone is prescribed for Leber’s Hereditary Optic Neuropathy (LHON) to improve visual impairment in adolescents and adults. It is also used for Friedreich’s ataxia, Duchenne Muscular Dystrophy (DMD) (specifically to slow the decline of respiratory function in patients not currently taking glucocorticoids), and Alzheimer’s disease, although evidence for the latter two is not as strong.
• Pharmacological classification: Antioxidant.
• Mechanism of action: Idebenone is a synthetic analog of coenzyme Q10, acting as a potent antioxidant and electron carrier within the mitochondria. It bypasses complex I in the electron transport chain, facilitating electron transfer and improving cellular energy production, which is particularly relevant in mitochondrial disorders like LHON.

Alternate Names

• 6-(10-Hydroxydecyl) ubiquinone, Hydroxydecyl ubiquinone.
• Brand Name: Raxone.

How It Works

• Pharmacodynamics: Idebenone acts as an antioxidant, scavenging free radicals and protecting cells from oxidative stress. In LHON, it improves mitochondrial function, particularly in the eye, and this may help restore some lost vision. In Friedreich’s Ataxia, it aims to reduce damage to the nervous system and the heart. In DMD, it aims to slow the decline of respiratory function.
• Pharmacokinetics: Idebenone is readily absorbed orally, with increased bioavailability when taken with food. It undergoes extensive first-pass metabolism, primarily via quinone reduction by NADH-quinone oxidoreductase and oxidation to QS10 by CYP enzymes or alcohol dehydrogenase. It is metabolized in the liver and excreted in the urine, where its metabolites can cause a harmless reddish-brown discoloration (chromaturia).
• Mode of action: Idebenone facilitates electron transfer in the mitochondrial electron transport chain, bypassing the dysfunctional complex I commonly affected in LHON. This improves ATP production and reduces oxidative stress, which contributes to neuronal cell death.
• Elimination pathways: Hepatic metabolism and renal excretion. The major metabolites in plasma are idebenone conjugates (glucuronides and sulfates), QS10, QS6, and QS4, as well as their corresponding phase II metabolites.

Dosage

Standard Dosage

Adults:

• LHON, DMD: 900 mg/day, administered as 300 mg three times daily with food.
• Alzheimer’s disease: 90–120 mg three times daily.

Children:

• LHON: Not established for children under 12. Limited data exist for adolescents aged 12-17, where 900 mg/day has been used in trials, but no official recommendation exists.
• DMD: Approved for children aged 10 and older not taking glucocorticoids. Dosage is 900 mg/day (300 mg three times daily) with food.
• Friedreich’s ataxia: Pediatric dosage is calculated based on weight, up to a maximum equivalent to the adult dose.

Special Cases:

• Elderly Patients: No specific dose adjustment is required for LHON or DMD.
• Patients with Renal Impairment: Caution is advised. No specific dose adjustment recommendations are available due to lack of studies.
• Patients with Hepatic Dysfunction: Caution is advised. No specific dose adjustment recommendations are available due to lack of studies.
• Patients with Comorbid Conditions: Exercise caution in patients with blood disorders or a history of seizures.

Clinical Use Cases

Idebenone is not indicated for use in these clinical settings:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations (e.g., status epilepticus, cardiac arrest)

Dosage Adjustments

• Dosage adjustments are not well-defined for renal or hepatic impairment. Exercise caution and monitor patients closely.

Side Effects

Common Side Effects

• Nasopharyngitis (common cold)
• Cough
• Diarrhea
• Back pain

Rare but Serious Side Effects

• Liver enzyme elevations
• Allergic reactions

Long-Term Effects

• Not well-established. Data from controlled clinical trials extending beyond 6 months (for LHON) or 12 months (for DMD) are limited.

Adverse Drug Reactions (ADR)

• Allergic reactions, including skin rash.
• Elevated liver enzymes.

Contraindications

• Hypersensitivity to idebenone or any of its excipients.

Drug Interactions

• CYP3A4 substrates (e.g., alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids): Co-administration may increase exposure to these drugs, requiring caution and potential dose adjustments.
• P-glycoprotein (P-gp) substrates (e.g., dabigatran etexilate, digoxin, aliskiren): Idebenone may inhibit P-gp, potentially increasing exposure to these substrates.
• Anticoagulants (e.g., warfarin): Close monitoring of INR levels is necessary.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Not established. Limited animal data suggest no adverse effects on fertility or reproduction. However, adequate human data are lacking, so it is generally avoided during pregnancy unless the potential benefit outweighs the risk.
• Breastfeeding: Not established. Idebenone may be excreted in breast milk. Avoid use during breastfeeding unless deemed essential by the physician.

Drug Profile Summary

• Mechanism of Action: Mitochondrial antioxidant and electron carrier, bypassing complex I dysfunction.
• Side Effects: Nasopharyngitis, cough, diarrhea, back pain, allergic reactions (rare), liver enzyme elevations (rare).
• Contraindications: Hypersensitivity.
• Drug Interactions: CYP3A4 and P-gp substrates, anticoagulants.
• Pregnancy & Breastfeeding: Not recommended unless essential.
• Dosage: 900 mg/day (300 mg TID with food) for LHON and DMD in adults. 90-120 mg TID for Alzheimer’s disease. Pediatric dosage is not well-established for most indications.
• Monitoring Parameters: Visual acuity (LHON), respiratory function (DMD), liver enzymes, signs of allergic reactions.

Popular Combinations

• No specific, routinely recommended combinations exist. Treatment is typically with idebenone monotherapy.

Precautions

• General Precautions: Monitor for allergic reactions and liver enzyme elevations.
• Specific Populations: Avoid in pregnancy and breastfeeding unless deemed essential by the physician. Caution in renal and hepatic impairment. No established pediatric dosage for LHON under 12.
• Lifestyle Considerations: Alcohol consumption should be avoided as it may exacerbate side effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Idebenone?

A: For LHON and DMD in adults, 900 mg/day, divided into three 300 mg doses taken with meals. For Alzheimer’s, 90-120 mg three times daily. Pediatric dosing varies depending on the indication and is not established for all conditions.

Q2: What are the common side effects of Idebenone?

A: The most frequent side effects are nasopharyngitis, cough, diarrhea, and back pain.

Q3: How should Idebenone be administered?

A: Orally with food. Tablets should be swallowed whole and not crushed or chewed.

Q4: Are there any specific monitoring parameters for patients taking Idebenone?

A: Monitor for allergic reactions and liver enzyme elevations. For LHON, visual acuity should be tracked. For DMD, respiratory function should be followed.

Q5: Is Idebenone safe to use during pregnancy or breastfeeding?

A: It’s generally avoided during pregnancy and breastfeeding due to the lack of sufficient safety data in humans. Only use if the potential benefit outweighs the risk, as determined by the physician.

Q6: Does idebenone interact with any other medications?

A: Yes. It can interact with CYP3A4 substrates, P-gp substrates, and anticoagulants like warfarin. Provide a thorough medication history to identify potential interactions.

Q7: What is the mechanism by which idebenone improves vision in LHON?

A: It bypasses the dysfunctional complex I in the mitochondrial electron transport chain, enhancing energy production and reducing oxidative stress in the eye.

Q8: Can idebenone cure LHON?

A: No. Idebenone does not cure LHON, but it can improve visual function in some patients.

Q9: How long should treatment with idebenone continue for LHON?

A: Treatment is usually continued for at least one year, and potentially longer in patients who demonstrate a positive response, until a sustained plateau of one year is reached.

Q10: Is idebenone effective for all patients with LHON?

A: No. While some patients experience vision improvement, others may not respond to treatment.