Ambrisentan + Tadalafil

Usage

• Ambrisentan + Tadalafil is prescribed for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adults. This combination therapy aims to improve exercise ability and delay clinical worsening of PAH. It is also used to reduce the risks of disease progression and hospitalization for worsening PAH.
• Pharmacological Classification: This combination includes two drug classes:
  • Ambrisentan: Endothelin Receptor Antagonist (specifically, endothelin type-A receptor antagonist)
  • Tadalafil: Phosphodiesterase-5 (PDE-5) Inhibitor
• Mechanism of Action:
  • Ambrisentan blocks the effects of endothelin, a peptide that causes blood vessel constriction. By blocking endothelin receptors, ambrisentan helps relax and widen the pulmonary arteries, reducing blood pressure in the lungs.
  • Tadalafil inhibits PDE-5, an enzyme that breaks down cyclic guanosine monophosphate (cGMP). Increased cGMP levels lead to smooth muscle relaxation in the pulmonary arteries, further enhancing vasodilation and improving blood flow. The combined effect of these two mechanisms leads to better outcomes in PAH.

Alternate Names

• This combination does not have an International Nonproprietary Name (INN). It is generally referred to as the combination of ambrisentan and tadalafil.
• Brand Names: The combination is available under various brand names such as Pulmonext Kit and Endobloc T Kit. Letairis is the brand name for ambrisentan alone, and Adcirca or Cialis are brand names for tadalafil. Note: Letairis is subject to a Risk Evaluation and Mitigation Strategy (REMS) program in some regions due to the risk of serious birth defects.

How It Works

• Pharmacodynamics: Ambrisentan and tadalafil have synergistic effects on pulmonary hemodynamics. Ambrisentan counteracts the vasoconstricting effects of endothelin, while tadalafil enhances vasodilation through its effect on cGMP. Together, they reduce pulmonary vascular resistance and improve cardiac output, ultimately improving exercise capacity and delaying clinical worsening in PAH patients.
• Pharmacokinetics:
  • Ambrisentan: Well-absorbed orally. Primarily metabolized in the liver through glucuronidation and oxidation. Excreted mainly in bile and feces, with minimal renal excretion.
  • Tadalafil: Readily absorbed after oral administration. Metabolized primarily by CYP3A4 enzyme in the liver. Excreted in urine and feces.
• Mode of Action:
  • Ambrisentan: Competitively binds to endothelin type-A receptors on vascular smooth muscle cells, preventing endothelin-mediated vasoconstriction.
  • Tadalafil: Inhibits PDE-5, leading to increased cGMP levels, which activates protein kinase G, ultimately causing vascular smooth muscle relaxation.
• Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation:
  • Ambrisentan: Endothelin type-A receptor antagonist.
  • Tadalafil: PDE-5 inhibitor.
• Elimination Pathways:
  • Ambrisentan: Predominantly biliary/fecal excretion.
  • Tadalafil: Primarily hepatic metabolism (CYP3A4), followed by renal and fecal excretion.

Dosage

Standard Dosage

Adults:

• Initial dose: Ambrisentan 5 mg orally once daily with or without tadalafil 20 mg orally once daily.
• Titration: At 4-week intervals, either the ambrisentan or tadalafil dose can be increased, as needed and tolerated, to a maximum of ambrisentan 10 mg/day or tadalafil 40 mg/day.

Children:

• Safety and efficacy not established in pediatric patients.

Special Cases:

• Elderly Patients: No specific dose adjustments required.
• Patients with Renal Impairment: No dose adjustment required for mild to moderate impairment. Caution recommended in severe renal impairment.
• Patients with Hepatic Dysfunction: Not recommended in moderate to severe hepatic impairment. Dose adjustments may be needed in mild impairment. Discontinue if liver enzyme elevations occur during treatment.
• Patients with Comorbid Conditions: Exercise caution in patients with conditions such as heart failure, hypotension, anemia, or fluid retention.

Clinical Use Cases

The combination of ambrisentan and tadalafil is specifically indicated for pulmonary arterial hypertension and is not typically used in the clinical scenarios listed (intubation, surgical procedures, mechanical ventilation, ICU use, emergency situations). Other medications may be more appropriate for these situations.

Dosage Adjustments

• Coadministration with Cyclosporine: Limit ambrisentan dose to 5 mg once daily.

Side Effects

Common Side Effects

• Peripheral edema (swelling in hands, feet, and ankles), headache, nasal congestion, flushing, cough, anemia, dyspepsia (indigestion), upper respiratory tract infection.

Rare but Serious Side Effects

• Hepatotoxicity (liver damage), including rare cases of cirrhosis with prolonged use. Signs of liver problems may include loss of appetite, nausea, vomiting, fever, achiness, jaundice, dark urine, and itching.
• Acute pulmonary edema, especially during treatment initiation. This may indicate underlying pulmonary veno-occlusive disease.

Long-Term Effects

• Chronic liver damage with prolonged use.
• Decreased sperm count.

Adverse Drug Reactions (ADR)

• Angioedema (severe swelling), hypersensitivity reactions, significant liver enzyme elevations.

Contraindications

• Pregnancy: Ambrisentan can cause serious birth defects. Females of reproductive potential must have a negative pregnancy test before starting therapy and use two reliable forms of contraception during treatment and for one month after stopping.
• Idiopathic Pulmonary Fibrosis (IPF)
• Severe hepatic impairment.
• Hypersensitivity to ambrisentan or tadalafil.

Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole) may increase ambrisentan exposure.
• Cyclosporine: Limit ambrisentan dose to 5 mg/day.
• Other PAH medications: Use in combination with other endothelin receptor antagonists or PDE-5 inhibitors should be carefully considered.
• Alcohol: May increase the risk of hypotension with tadalafil.
• Grapefruit juice: May increase tadalafil blood levels.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: X (Contraindicated)
• Fetal Risks: Ambrisentan is teratogenic and can cause serious birth defects.
• Breastfeeding: It is unknown if ambrisentan is excreted in breast milk. Breastfeeding is not recommended.

Drug Profile Summary

• Mechanism of Action: Ambrisentan blocks endothelin receptors, causing vasodilation. Tadalafil inhibits PDE-5, increasing cGMP and further promoting vasodilation.
• Side Effects: Peripheral edema, headache, nasal congestion, flushing, cough, anemia, dyspepsia, liver damage (rare).
• Contraindications: Pregnancy, IPF, severe hepatic impairment.
• Drug Interactions: Strong CYP3A4 inhibitors, cyclosporine, alcohol, grapefruit juice.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Breastfeeding not recommended.
• Dosage: Adults: Ambrisentan 5 mg/day initially, titrated to 10 mg/day; Tadalafil 20 mg/day initially, titrated to 40 mg/day.
• Monitoring Parameters: Liver function tests, pregnancy tests (for females of reproductive potential), blood pressure, signs of fluid retention.

Popular Combinations

• Ambrisentan + Tadalafil: This combination is itself a popular and effective therapy for PAH.

Precautions

• General Precautions: Liver function tests before and during treatment. Monitor for signs of fluid retention, anemia, and other side effects. Females of reproductive potential must follow strict pregnancy prevention measures.
• Specific Populations (as outlined above).
• Lifestyle Considerations: Limit alcohol intake. Avoid grapefruit juice. Driving restrictions may be necessary if side effects like dizziness or lightheadedness occur.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ambrisentan + Tadalafil?

A: The initial dose is ambrisentan 5 mg once daily with or without tadalafil 20 mg once daily. The dose of either drug can be increased at 4-week intervals, as needed, to a maximum of ambrisentan 10 mg/day or tadalafil 40 mg/day.

Q2: How does this combination therapy compare to monotherapy with either ambrisentan or tadalafil?

A: Clinical trials have shown that the combination is more effective in delaying disease progression and reducing hospitalizations compared to either drug alone.

Q3: Are there any specific monitoring parameters for patients on Ambrisentan + Tadalafil?

A: Yes, monitor liver function tests regularly. Monitor patients for peripheral edema, signs of anemia, and hypotension. Monthly pregnancy tests are essential for women of childbearing age.

Q4: Can this combination be used in pregnant women?

A: No, ambrisentan is contraindicated in pregnancy due to the risk of serious birth defects.

Q5: What should be done if a patient on this therapy experiences significant liver enzyme elevations?

A: Discontinue the medication and investigate the cause of the liver dysfunction. If the elevations are accompanied by elevated bilirubin or signs of liver dysfunction, discontinuation is mandatory.

Q6: Are there any drug interactions I should be aware of with this combination?

A: Yes, concurrent use of strong CYP3A4 inhibitors (e.g., ketoconazole) can increase ambrisentan levels. Cyclosporine requires ambrisentan dose reduction. Alcohol may potentiate tadalafil’s hypotensive effects, and grapefruit juice can increase tadalafil levels. Be mindful of other PAH medications that might cause interactions.

Q7: Can Ambrisentan + Tadalafil be used in patients with renal impairment?

A: It can be used in patients with mild to moderate renal impairment without dose adjustment. Use with caution in severe renal impairment.

Q8: What is the role of the REMS program for Letairis (ambrisentan)?

A: The REMS program is designed to ensure that the benefits of ambrisentan outweigh the risks of birth defects. It mandates strict pregnancy testing and contraception requirements for women of childbearing potential.

Q9: What are the key patient counseling points for Ambrisentan + Tadalafil?

A: Counsel patients on the importance of adherence to the prescribed dosage, regular monitoring, potential side effects (especially liver-related), and the absolute need for reliable contraception in women of childbearing age. Advise patients to report any signs of liver problems, fluid retention, or other unusual symptoms to their physician immediately. Emphasize the importance of not sharing this medication with others.