Piperaquine

Usage

• Medical Conditions: Piperaquine is an antimalarial drug primarily used in combination with dihydroartemisinin (DHA) for the treatment of uncomplicated Plasmodium falciparum malaria. It is also effective against other Plasmodium species. It is crucial to adhere to the latest WHO treatment guidelines and local resistance patterns when prescribing.
• Pharmacological Classification: Antimalarial, specifically a bisquinoline.
• Mechanism of Action: Piperaquine inhibits parasite growth by interfering with heme detoxification, a crucial process for the malaria parasite’s survival within red blood cells. It accumulates in the parasite’s food vacuole, preventing the formation of hemozoin from heme, leading to toxic heme buildup and parasite death.

Alternate Names

• Piperaquine tetraphosphate
• Brand Names: Eurartesim, Duo-Cotecxin, Artekin, P-ALAXIN Dispersible, Ridmal, CODISIN PLUS, EVERDESTINY

How It Works

• Pharmacodynamics: Piperaquine exhibits schizontocidal activity against Plasmodium species. It accumulates in the parasite’s food vacuole, disrupting heme detoxification.

• Pharmacokinetics:

  • Absorption: Piperaquine is absorbed orally. The presence of fatty food increases its absorption, but it should be taken with water on an empty stomach for consistent effects.
  • Metabolism: Primarily metabolized by CYP3A4.
  • Elimination: Piperaquine has a long elimination half-life (approximately 22 days), requiring consideration for subsequent antimalarial treatments.

• Mode of Action: Inhibits heme polymerization within the parasite’s food vacuole, leading to a toxic accumulation of free heme.

• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Inhibits CYP3A4 enzyme. It also blocks hERG potassium channels, which can lead to QT interval prolongation.

Dosage

Standard Dosage

Adults:

• The dosage depends on body weight and is administered once daily for 3 days. Standard tablets contain either 40mg DHA/320mg piperaquine or 20mg DHA/160mg piperaquine. Refer to the table below for detailed weight-based dosage.

Weight (kg)	20mg/160mg Tablet	40mg/320mg Tablet
5 to < 8	1 tablet	-
8 to < 11	1½ tablets	-
11 to < 17	-	1 tablet
17 to < 25	-	1½ tablets
25 to < 36	-	2 tablets
36 to < 60	-	3 tablets
60 to < 80	-	4 tablets
≥ 80	-	5 tablets

Children:

• Pediatric dosing is also weight-based and administered once daily for 3 days, using the same tablets and weight categories as adults. Safety and efficacy in infants under 6 months or weighing less than 5 kg haven’t been established.

Special Cases:

• Elderly Patients: No specific dosage recommendations due to limited data. Exercise caution due to potential age-related decrease in hepatic and renal function and potential heart disorders.
• Patients with Renal Impairment: No data available. Exercise caution.
• Patients with Hepatic Dysfunction: No data available. Exercise caution.
• Patients with Comorbid Conditions: Caution is advised when administering to patients with cardiac conditions, especially those predisposing to arrhythmias. Avoid in patients with congenital QT prolongation.

Clinical Use Cases

• Piperaquine is specifically indicated for the treatment of uncomplicated malaria. It is not indicated for the conditions mentioned (Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations).

Dosage Adjustments

• Adjustments are necessary for renal/hepatic impairment, low body weight, and concomitant medications metabolized by CYP3A4 (including efavirenz). Pregnant and breastfeeding women require special considerations (see below).

Side Effects

Common Side Effects

• Nausea, vomiting, diarrhea, anorexia, abdominal pain
• Dizziness, headache, fatigue
• Cough, fever
• Pruritus, skin rash

Rare but Serious Side Effects

• Cardiac arrhythmias, QT prolongation
• Severe allergic reactions
• Hepatotoxicity
• Changes in blood indices (decreased reticulocytes, increased liver enzymes)

Long-Term Effects

• Limited data available. Prolonged QT interval and cardiac effects are a primary concern. No more than two courses of treatment should be given in a 12-month period.

Contraindications

• Hypersensitivity to piperaquine or DHA
• Severe malaria
• Congenital QT prolongation or conditions known to prolong the QT interval (e.g., hypokalemia)
• History of symptomatic cardiac arrhythmias or clinically relevant bradycardia
• Concomitant use of other QT-prolonging drugs (e.g., some antihistamines, macrolides, antifungals)

Drug Interactions

• CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin): May increase piperaquine concentrations, increasing the risk of cardiotoxicity. ECG monitoring is recommended.
• CYP3A4 Inducers: (e.g., rifampicin, carbamazepine, phenytoin, St. John’s wort): Decrease piperaquine concentration, reducing its effectiveness. Co-administration is not recommended.
• QT Prolonging Drugs: Co-administration increases the risk of cardiac arrhythmias. Avoid.
• Grapefruit juice: Increases Piperaquine concentrations. Avoid co-administration.
• Food: Fatty foods increase Piperaquine’s absorption. Take piperaquine with water on an empty stomach.

Pregnancy and Breastfeeding

• Pregnancy: Limited data are available, especially for the first trimester. While animal studies suggest a risk of birth defects, studies in later trimesters have been reassuring. DP is generally considered safe in the second and third trimesters when other options are unsuitable.
• Breastfeeding: Piperaquine is excreted in breast milk, but infant exposure appears to be low and generally considered safe.

Drug Profile Summary

• Mechanism of Action: Inhibits heme polymerization in Plasmodium parasites.
• Side Effects: Nausea, vomiting, diarrhea, dizziness, headache, QT prolongation (rare).
• Contraindications: Hypersensitivity, severe malaria, QT prolongation, concomitant QT-prolonging drugs.
• Drug Interactions: CYP3A4 inhibitors/inducers, QT prolonging drugs, grapefruit juice.
• Pregnancy & Breastfeeding: Generally safe in 2nd and 3rd trimesters; breastfeeding is considered safe.
• Dosage: Weight-based, once daily for 3 days. See table above.
• Monitoring Parameters: ECG (for QT interval), liver function tests, complete blood count.

Popular Combinations

• Dihydroartemisinin: The combination of DHA and piperaquine is the most common and recommended. DHA provides rapid action against parasites, while piperaquine’s long half-life prevents recrudescence.

Precautions

• General Precautions: Assess cardiac history, including family history of sudden death. Monitor for QT interval prolongation during treatment. Check liver and kidney function.
• Specific Populations:
  • Pregnant Women: Use with caution in the first trimester. Generally safe for second and third trimesters when other options are unsuitable.
  • Breastfeeding Mothers: Safe for use.
  • Children & Elderly: Weight-based dosing for children. Use with caution in the elderly.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Piperaquine?

A: Piperaquine is always given in combination with dihydroartemisinin. The dosage is weight-based and is administered once daily for 3 days. Refer to the dosage table above for specifics.

Q2: Can Piperaquine be used in pregnant women?

A: Use with caution in the first trimester. It is generally considered safe in the second and third trimester when other suitable antimalarial options are not available.

Q3: What are the most common side effects of Piperaquine?

A: Common side effects include nausea, vomiting, diarrhea, dizziness, and headache.

Q4: Are there any serious side effects I should be aware of?

A: While rare, Piperaquine can cause QT interval prolongation, potentially leading to serious cardiac arrhythmias. Patients with pre-existing cardiac conditions should be closely monitored.

Q5: What are the contraindications for Piperaquine use?

A: Piperaquine is contraindicated in patients with hypersensitivity to the drug, severe malaria, congenital QT prolongation, a history of cardiac arrhythmias, or concomitant use of other QT prolonging drugs.

Q6: How does Piperaquine interact with other drugs?

A: Piperaquine is metabolized by CYP3A4. Co-administration with CYP3A4 inhibitors can increase piperaquine levels, while inducers can decrease its effectiveness. It should not be used with other QT-prolonging medications.

Q7: Can Piperaquine be used in patients with liver or kidney disease?

A: Use with caution in patients with hepatic or renal impairment due to limited data on its safety and efficacy in these populations.

Q8: How should Piperaquine be administered?

A: Administer orally with water on an empty stomach. Each dose should be taken at least 3 hours after the last food intake and no food should be consumed within 3 hours following each dose. Tablets can be crushed and mixed with water for patients who have difficulty swallowing them.

Q9: What should I do if a patient vomits after taking Piperaquine?

A: If vomiting occurs within 30 minutes, re-administer the whole dose. If vomiting occurs between 30 minutes and 1 hour, re-administer half the dose. If a second dose is vomited, use alternative antimalarial therapy. Do not attempt re-dosing more than once.