Endoxifen

Usage

Endoxifen is primarily indicated for the acute treatment of manic episodes, with or without mixed features, associated with Bipolar I disorder. It is classified as an antimanic agent and a selective estrogen receptor modulator (SERM). It may also be used off-label as an adjuvant treatment for breast cancer, though this is not its primary FDA-approved indication. It works by inhibiting protein kinase C (PKC), an enzyme implicated in the overactive intracellular signaling seen in bipolar mania, and modulating brain chemicals like serotonin, norepinephrine, and dopamine. It acts as an anti-estrogen in breast cancer treatment.

Alternate Names

Endoxifen is the most common and internationally recognized name. It is an active metabolite of Tamoxifen. A brand name under which it is marketed is Zonalta.

How It Works

Pharmacodynamics: Endoxifen primarily exerts its antimanic effects through the inhibition of PKC, thus normalizing the balance of neurotransmitters in the brain. It’s SERM properties come from its interaction with estrogen receptors in various tissues.

Pharmacokinetics:

• Absorption: Endoxifen is well-absorbed orally and peak plasma concentrations are generally reached within 4 to 7 hours of administration.

• Metabolism: Unlike its prodrug, Tamoxifen, which requires metabolic activation by CYP2D6, Endoxifen is directly active. It is mainly metabolized in the liver.

• Elimination: Primarily excreted via the biliary route and undergoes enterohepatic circulation.

Mode of Action: Endoxifen acts by competitively binding to the catalytic domain of PKC, which inhibits the enzyme activity and downstream signaling, resulting in decreased neuronal excitability and thus modulating mood. It’s antiestrogenic effects are based on its competition with estrogen for receptor binding, leading to changes in gene expression in estrogen-sensitive tissue like breast tissue.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Endoxifen inhibits PKC activity and indirectly modulates serotonergic, noradrenergic and dopaminergic neurotransmission. It binds to estrogen receptors, exhibiting antagonistic properties in some tissues (e.g., breast) and agonistic properties in others (e.g., bone).

Elimination Pathways: The major route of elimination is through the feces, with a small portion eliminated in the urine. It is metabolized in the liver via CYP3A4.

Dosage

Standard Dosage

Adults:

The standard dose is 8 mg orally once daily for Bipolar I disorder. It can be administered with or without food. Some sources suggest a potential increase to 16 mg/day based on clinical response and tolerability, specifically for bipolar disorder. For breast cancer treatment, doses up to 160 mg have been studied.

Children:

Safety and effectiveness in children have not been established. Use is not recommended.

Special Cases:

• Elderly Patients: Safety and effectiveness in geriatric patients have not been established. However, dosage adjustment is not routinely recommended.

• Patients with Renal Impairment: Careful monitoring is advised, though specific dosage modifications aren’t clearly defined.

• Patients with Hepatic Dysfunction: Caution is advised as Endoxifen is metabolized in the liver, but no formal dosage guidelines exist.

• Patients with Comorbid Conditions: Consider individual patient factors such as other medications and comorbidities when determining appropriate dosing.

Clinical Use Cases

Endoxifen’s clinical use is primarily focused on the treatment of manic episodes in Bipolar I disorder. It’s role in intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations isn’t established, and not normally part of treatment algorithms in these settings.

Dosage Adjustments

Dosage adjustments should be made based on the patient’s clinical response and tolerability. Consider renal and hepatic function, concomitant medications (especially CYP2D6 and CYP3A4 inhibitors), and genetic polymorphisms affecting drug metabolism.

Side Effects

Common Side Effects

Headache, nausea, vomiting, insomnia, increased sleepiness (somnolence), abdominal discomfort, diarrhea, and restlessness.

Rare but Serious Side Effects

Though rare, potential serious side effects based on Tamoxifen’s profile include thromboembolic events (deep vein thrombosis, pulmonary embolism), uterine malignancies (endometrial cancer, uterine sarcoma), ocular disturbances (corneal changes, retinal vein thrombosis), and hepatic abnormalities (hepatitis, hepatic necrosis).

Long-Term Effects

Potential long-term effects, extrapolated from Tamoxifen’s profile, include increased risk of endometrial cancer, uterine sarcoma, and thromboembolic events with prolonged use.

Adverse Drug Reactions (ADR)

Serious ADRs would require discontinuation of Endoxifen and immediate medical attention. These may include severe allergic reactions, signs of thromboembolism, uterine bleeding, vision changes, and signs of liver dysfunction.

Contraindications

Known hypersensitivity to endoxifen or Tamoxifen; concomitant use with coumarin-type anticoagulants; history of deep vein thrombosis or pulmonary embolism; pregnancy; breastfeeding.

Drug Interactions

• CYP450 Interactions: Endoxifen is metabolized by CYP3A4. Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) may increase Endoxifen concentrations, while inducers (e.g., rifampin, phenytoin) may decrease levels.

• Coumarin-type anticoagulants: Increased risk of bleeding.

• CYP2D6 inhibitors: While Endoxifen itself isn’t metabolized by CYP2D6, it is important to note that this enzyme is essential for the conversion of Tamoxifen to Endoxifen. Thus, concomitant use with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion) should be avoided if Endoxifen is being considered after discontinuation of Tamoxifen.

• Other Potential Interactions:

  • Alcohol: May increase drowsiness and dizziness.
  • Grapefruit juice: May inhibit CYP3A4 metabolism and thus increase endoxifen levels.

Pregnancy and Breastfeeding

Endoxifen is contraindicated in pregnancy and breastfeeding due to potential fetal harm and the potential for drug accumulation in breast milk.

Drug Profile Summary

• Mechanism of Action: PKC inhibitor, SERM.
• Side Effects: Headache, nausea, insomnia, abdominal discomfort, hot flashes, vaginal bleeding.
• Contraindications: Hypersensitivity, concurrent coumarin anticoagulants, pregnancy, breastfeeding.
• Drug Interactions: CYP3A4 inhibitors and inducers, coumarin anticoagulants, CYP2D6 inhibitors.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 8 mg orally once daily for bipolar disorder.
• Monitoring Parameters: Monitor mood, liver function tests, complete blood counts, and signs for thromboembolic events with long-term use.

Popular Combinations

Data on popular combinations of Endoxifen with other drugs is limited, however it has been used in combination with other mood stabilizers for treating Bipolar I disorder.

Precautions

• General Precautions: Screen for allergies, history of thromboembolic events, liver and renal function before starting therapy.
• Pregnant Women and Breastfeeding Mothers: Contraindicated.
• Children and Elderly: Safety and efficacy not established.
• Lifestyle Considerations: Avoid alcohol. Caution patients about potential for drowsiness and impact on ability to drive.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Endoxifen in Bipolar I disorder?

A: The standard recommended dosage is 8 mg orally once daily.

Q2: How does Endoxifen work in bipolar disorder?

A: It primarily acts as a protein kinase C (PKC) inhibitor, modulating neurotransmitter balance in the brain.

Q3: What are the common side effects of Endoxifen?

A: Common side effects include headache, nausea, vomiting, insomnia, increased sleepiness, abdominal discomfort, diarrhea, and restlessness.

Q4: Is Endoxifen safe to use during pregnancy?

A: No, Endoxifen is contraindicated during pregnancy due to the risk of fetal harm.

Q5: Can Endoxifen be used with other mood stabilizers?

A: While limited data exists on combined use, it has been used in clinical practice along with other mood stabilizers in some instances. Careful monitoring is essential if combining treatments.

Q6: Does Endoxifen interact with any other medications?

A: Yes, it can interact with coumarin-type anticoagulants, CYP3A4 inhibitors and inducers, some antidepressants, and grapefruit juice.

Q7: What should patients be monitored for when taking Endoxifen?

A: Patients should be monitored for mood changes, liver function, complete blood count parameters, and any signs or symptoms of thromboembolic events.

Q8: Is there a specific antidote for Endoxifen overdose?

A: No specific antidote exists for Endoxifen overdose. Treatment is supportive and based on managing presenting symptoms.

Q9: What is the role of CYP2D6 in relation to Endoxifen?

A: While endoxifen itself isn’t directly metabolized by CYP2D6, this enzyme is crucial for converting Tamoxifen into its active metabolite, Endoxifen. Therefore, co-administration of potent CYP2D6 inhibitors with Tamoxifen can reduce its efficacy.

Q10: What should a patient do if they miss a dose of Endoxifen?

A: Take the missed dose as soon as it is remembered. However, if it’s close to the time for the next dose, skip the missed dose and return to the regular dosing schedule. Do not double the dose.