Plaquinol

Uses

Acute lupus erythematosus, Kawasaki disease and dermatomyositis sarcoidosis, Lyme disease, Malaria, Porphyria cutanea tarda, Q fever, Rheumatoid arthritis, Sjogren’s syndrome, Systemic lupus erythematosus (SLE)

Plaquinol is also used to associated treatment for these conditions: Discoid Lupus Erythematosus (DLE), Plasmodium Infections, Porphyria Cutanea Tarda, Q Fever, Rheumatoid Arthritis, Sjögren's Syndrome, Systemic Lupus Erythematosus (SLE), Uncomplicated Malaria caused by Plasmodium Vivax, Uncomplicated Malaria caused by Plasmodium malariae, Uncomplicated Malaria caused by Plasmodium ovale, Uncomplicated Malaria caused by Plasmodium falciparum

How Plaquinol works

The exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Plaquinol can also interfere with the action of parasitic heme polymerase, allowing for the accumulation of the toxic product beta-hematin.

Plaquinol accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Plaquinol also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors.

The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell.

Plaquinol inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry.

Dosage

Plaquinol dosage

Acute malaria:

• Adult: Initially, 800 mg followed by 400 mg 6-8 hr later, then a further 400 mg on each of the succeeding 2 days.
• Child: 13 mg/kg; followed by 6.5 mg/kg 6 hr later and repeat dose on the 2nd and 3rd days.

Prophylaxis of malaria:

• Adult: 400 mg every 7 days. Begin 2 wk before exposure, continue for 4-6 wk after leaving the endemic area.
• Child: 6.5 mg/kg once wkly. Max: 400 mg/dose.

Rheumatoid arthritis, Systemic lupus erythematosus:

• Adult: Initially, 400 mg daily in divided doses. Maintenance: 200-400 mg/day. Max: 6.5 mg/kg/day or 400 mg/day whichever is lower.
• Child: Up to 6.5 mg/kg/day or 400 mg/day whichever is lower. Lowest effective dose should be used.

Side Effects

Generally Plaquinol Sulphate is well tolerated. However, few side effects like nausea, vomiting, stomach upset, loss of appetite, diarrhea, tiredness, weakness or headache and visual problem may occur the first several days.

Toxicity

Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation. This may progress to sudden respiratory and cardiac arrest. Overdose should be treated with immediate gastric lavage and activated charcoal at a dose of at least 5 times the hydroxychloroquine dose within 30 minutes. Parenteral diazepam may be given to treat cardiotoxicity, transfusion may reduce serum concentrations of drug, patients should be monitored for at least 6 hours, fluids should be given, and ammonium chloride should be given to acidify urine and promote urinary excretion. Patients may also be given epinephrine.

Precaution

Impaired liver or renal function, severe GI disorders, porphyria, psoriasis, neurological disorders especially a history of epilepsy, myasthenia gravis, glucose-6-phosphate dehydrogenase deficiency, pregnancy, lactation. Monitor CBC in patients receiving prolonged therapy. Perform baseline and periodic 6-mth eye exams, test periodically for muscle weakness.

Interaction

Cimetidine may increase serum levels of hydroxychloroquine. Its absorption may be decreased by kaolin or Mg trisilicate. Avoid digoxin and alcohol. Increased risk of ventricular arrhythmias when used with halofantrine. Concurrent use with mefloquine may increase the risk of convulsions.

Food Interaction

• Take with food. Take with a meal or glass of milk.

[Moderate] GENERALLY AVOID: Theoretically, grapefruit and grapefruit juice may increase the plasma concentrations of hydroxychloroquine or chloroquine and the risk of toxicities such as QT interval prolongation and ventricular arrhythmias.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit.

Following coadministration with cimetidine, a weak to moderate CYP450 3A4 inhibitor, a 2-fold increase in chloroquine exposure occurred.

Since chloroquine and hydroxychloroquine have similar structures and metabolic elimination pathways, a similar interaction may be observed with hydroxychloroquine.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract during hydroxychloroquine or chloroquine therapy.

Plaquinol Drug Interaction

Moderate: duloxetine, duloxetine, pregabalin, pregabalinUnknown: aspirin, aspirin, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, levothyroxine, levothyroxine, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, ergocalciferol, ergocalciferol, cholecalciferol, cholecalciferol, cetirizine, cetirizine

Plaquinol Disease Interaction

Major: oculotoxicity, porphyriaModerate: arrhythmias, bone marrow suppression, ototoxicity, seizures, glucose-6-PD deficiency, hepatotoxicity, myasthenia gravis, psoriasis, diabetes, heart disease, renal impairment

Volume of Distribution

Plaquinol has a volume of distribution of 5522L from blood and 44,257L from plasma.

Elimination Route

Plaquinol is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a 200mg oral dose, hydroxychloroquine reached a C_max of 129.6ng/mL with a T_max of 3.26h in the blood and a C_max of 50.3ng/mL with a T_max of 3.74h in the plasma. Following 155mg and 310mg intravenous doses, C_max in the blood ranged from 1161-2436ng/mL with an average of 1918ng/mL.

Half Life

Oral hydroxychloroquine has an absorption half life of 3-4 hours. A 200mg oral dose of hydroxychloroquine has a half life of 537 hours or 22.4 days in blood, and 2963 hours or 123.5 days in plasma. A 155mg intravenous dose has a half life of 40 days.

Clearance

The clearance of hydroxychloroquine is 96mL/min.

Elimination Route

40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces.

Pregnancy & Breastfeeding use

Pregnancy category C. During pregnancy, this drug should be used only if clearly needed. Since small amounts of this medication are found in breast milk consult your doctor before medication.

Contraindication

Retinal or visual field changes, known hypersensitivity. Long-term use in children.

Acute Overdose

Symptoms of overdose consist of headache, drowsiness, visual disturbances, cardiovascular collapse, and convulsions, followed by sudden and early respiratory and cardiac arrest. Gastric lavage until the stomach is completely emptied.

Treatment should be prompt and symptomatic as symptoms appear quickly

Storage Condition

Store below 30° C.

Innovators Monograph

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