Amodiaquine + Artesunate

Usage

• Amodiaquine + Artesunate is prescribed for the treatment of acute, uncomplicated Plasmodium falciparum malaria, including cerebral malaria. It is also indicated for uncomplicated malaria due to other Plasmodium species when chloroquine is ineffective. It can also be used for completion treatment following parenteral therapy for severe malaria. It is particularly valuable in regions where P. falciparum has developed resistance to chloroquine. It is not recommended for malaria prophylaxis.

• Pharmacological classification: Antimalarial (artemisinin-based combination therapy or ACT)

• Mechanism of action: This combination employs two distinct mechanisms to combat malaria. Artesunate, an artemisinin derivative, generates reactive oxygen species within the parasite, leading to damage of parasitic proteins and ultimately cell death. Amodiaquine, a 4-aminoquinoline, inhibits heme polymerization, a crucial process for parasite survival. This dual action enhances efficacy and reduces the risk of resistance development.

Alternate Names

• ASAQ

• Artesunate-amodiaquine

• Brand Names: ASAQ Winthrop, Camoquin, Artesdiaquine

How It Works

• Pharmacodynamics: Artesunate is rapidly metabolized to dihydroartemisinin, its active metabolite. Both artesunate and dihydroartemisinin exert their antimalarial effects by producing free radicals that damage parasitic proteins and other biomolecules. Amodiaquine interferes with heme detoxification within the parasite, leading to toxic heme accumulation.

• Pharmacokinetics: Artesunate is rapidly absorbed and converted to dihydroartemisinin. Both compounds have short half-lives. Amodiaquine is well absorbed orally. It is metabolized primarily by CYP2C8 to desethylamodiaquine, an active metabolite. Amodiaquine can accumulate in the liver. Elimination pathways are not fully characterized but involve both hepatic and renal routes.

• Mode of action: Artesunate acts through the generation of reactive oxygen species, leading to oxidative stress and damage to parasite cellular components. Amodiaquine inhibits heme polymerase, disrupting heme detoxification and causing toxic heme buildup within the parasite.

• Receptor binding, enzyme inhibition, or neurotransmitter modulation: The primary mechanism involves free radical generation (artesunate) and heme polymerase inhibition (amodiaquine). Limited information exists on receptor binding or neurotransmitter modulation.

• Elimination pathways: Both hepatic and renal excretion are involved. CYP2C8 plays a role in amodiaquine metabolism.

Dosage

Standard Dosage

Adults: The standard dosage is based on a total dose of 12 mg/kg artesunate and 25-35 mg/kg amodiaquine base over three days. This translates to a daily dose of 4 mg/kg artesunate and 10 mg/kg (7.5-15mg/kg range) amodiaquine base, administered once daily for three days.

Children: Pediatric dosing is weight-based, with the same daily and total dose as for adults (4 mg/kg artesunate and 10 mg/kg amodiaquine base, administered once daily for three days). For very young children unable to swallow tablets, the tablets can be crushed and mixed with a small amount of food or liquid for immediate consumption.

Special Cases:

• Elderly Patients: No specific dose adjustments are routinely recommended, but careful monitoring is advised.
• Patients with Renal Impairment: No data available on dosing adjustments. Use with caution.
• Patients with Hepatic Dysfunction: No data available on dosing adjustments. Use with caution and monitor liver function.
• Patients with Comorbid Conditions: Use with caution in patients with cardiac disease, a history of ventricular dysrhythmias, or those taking medications that prolong the QT interval.

Clinical Use Cases

The combination of artesunate and amodiaquine is not routinely indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or specific emergency situations outside of malaria treatment.

Dosage Adjustments

Dose modifications might be necessary for renal/hepatic impairment, though specific guidelines are lacking. Consult official treatment guidelines and exercise caution.

Side Effects

Common Side Effects

Anorexia, nausea, abdominal pain, vomiting, diarrhea, cough, pruritus, headache, dizziness, somnolence, asthenia, insomnia.

Rare but Serious Side Effects

Neutropenia, hepatotoxicity, agranulocytosis, serious allergic reactions (including anaphylaxis), QT prolongation, acute extrapyramidal symptoms, hemolytic anemia.

Long-Term Effects

Retinopathy (with frequent treatment).

Adverse Drug Reactions (ADR)

Agranulocytosis, severe hepatotoxicity, acute extrapyramidal reactions, severe allergic reactions.

Contraindications

• Hypersensitivity to artesunate or amodiaquine
• History of liver injury or hematological events with amodiaquine
• Retinopathy (in case of frequent treatment)
• Concomitant use of efavirenz

Drug Interactions

• Drugs that prolong the QT interval (e.g., amiodarone, other antimalarials, antipsychotics, fluconazole, fluoroquinolones)
• CYP2C8 inhibitors or inducers
• Nevirapine
• Medications for HIV and tuberculosis (potential for hepatotoxicity and neutropenia)

Pregnancy and Breastfeeding

• Pregnancy: Malaria poses significant risks during pregnancy. Use during the first trimester only if other antimalarials are unsuitable. Can be used with caution in the second and third trimesters if benefits outweigh risks.

• Breastfeeding: Small amounts of antimalarials are excreted in breast milk. Considered safe to use during breastfeeding, but close monitoring of the infant is recommended.

Drug Profile Summary

• Mechanism of Action: Artesunate generates reactive oxygen species, damaging parasite components. Amodiaquine inhibits heme polymerization.

• Side Effects: Common: Anorexia, nausea, vomiting, diarrhea, cough, pruritus, headache. Serious: Neutropenia, hepatotoxicity, agranulocytosis, allergic reactions, QT prolongation.

• Contraindications: Hypersensitivity, history of liver/hematological issues with amodiaquine, retinopathy (frequent use).

• Drug Interactions: Drugs prolonging QT interval, CYP2C8 modulators, nevirapine, HIV/TB medications.

• Pregnancy & Breastfeeding: Use with caution in pregnancy, especially the first trimester. Generally safe during breastfeeding.

• Dosage: Adults/Children: 4 mg/kg artesunate and 10 mg/kg amodiaquine base daily for 3 days. Weight-based dosing.

• Monitoring Parameters: Complete blood count, liver function tests, electrocardiogram (ECG), especially with prolonged use or in patients with cardiac risk factors.

Popular Combinations

Amodiaquine + artesunate is itself a popular combination. It is generally not combined with other antimalarials.

Precautions

• General Precautions: Assess for allergies, liver/kidney function, and concomitant medications.
• Specific Populations: Use with caution in pregnancy (especially first trimester), elderly, and patients with hepatic or renal impairment.
• Lifestyle Considerations: Advise patients against driving or operating machinery if experiencing dizziness, somnolence, or asthenia.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Amodiaquine + Artesunate?

A: The recommended dosage is 4 mg/kg artesunate and 10 mg/kg amodiaquine base once daily for 3 days, administered orally. Dosage is weight-based, and pediatric and adult regimens are the same.

Q2: What are the common side effects?

A: Common side effects include gastrointestinal disturbances (nausea, vomiting, diarrhea), cough, itching, headache, and sleep disturbances.

Q3: What are the contraindications?

A: Contraindications include hypersensitivity to the drug components, prior liver or blood disorders related to amodiaquine use, and retinopathy with frequent treatment.

Q4: Can Amodiaquine + Artesunate be used in pregnancy?

A: It should be used with caution during pregnancy, especially in the first trimester. It may be used if other options are unsuitable and the benefits outweigh the risks.

Q5: How is Amodiaquine + Artesunate metabolized?

A: Artesunate is rapidly metabolized to its active form, dihydroartemisinin. Amodiaquine is metabolized primarily by CYP2C8 to desethylamodiaquine.

Q6: What are the potential drug interactions?

A: It can interact with drugs that prolong the QT interval, CYP2C8 inhibitors/inducers, nevirapine, and certain HIV/TB medications.

Q7: Is Amodiaquine + Artesunate effective against chloroquine-resistant malaria?

A: Yes, it is often used in areas where chloroquine resistance is prevalent.

Q8: Can it be used for malaria prophylaxis?

A: No, it is not recommended for prophylaxis due to the risk of agranulocytosis and hepatotoxicity with prolonged use.

Q9: What monitoring parameters are important?

A: Monitoring complete blood counts, liver function tests, and ECG is advisable, particularly in patients with pre-existing conditions or receiving prolonged treatment.

Q10: What should be done if a patient vomits shortly after taking the medication?

A: If vomiting occurs within 30 minutes, the full dose should be re-administered. If vomiting occurs between 30 minutes and 1 hour, half the dose should be re-administered. If vomiting persists, consider treatment for severe malaria.