The last update and review: December 15, 2021.
A Short Summary.
Soon after the COVID-19 epidemic started, the FDA issued an authorization for the use of chloroquine and hydroxychloroquine (HCQ) for patients hospitalized with COVID-19. The dosage of hydroxychloroquine used in some of the trials investigating the effectiveness of HCQ as a treatment for COVID-19 was relatively high. Hydroxychloroquine is not perfectly safe. There is toxicity. The half-life is long. Be informed.
An update from June 15, 2022:
It is also important to (finally) learn to avoid infections. There is an article on this website that should stimulate your thinking and guide you in the right direction. The link to and a snapshot of the article are below:
snapshothttps://medical-en.nneandersphysiologicalliteracy.com/covid-19-learn-to-avoid-infections/
Hydroxychloroquine drug label (1): ” Patients should be informed of the early signs and symptoms of toxicity such as rash or visual changes.”
Drug label information for Hydroxychloroquine sulfate by Sandoz Inc for the US (referenced by the FDA) (1):
Pharmacokinetics
Following a single 200 mg oral dose of hydroxychloroquine sulfate to healthy males, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with a half-life of 537 hours (22.4 days). In the same study, the plasma peak concentration was 50.3 ng/mL reached in 3.74 hours with a half-life of 2963 hours (123.5 days). Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. The mean fraction of the dose absorbed was 0.74. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics.
Following chronic oral administration of hydroxychloroquine, significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) have been found in plasma and blood, with DHCQ being the major metabolite. The absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. The long half-life can be attributed to extensive tissue uptake rather than through decreased excretion. Peak plasma levels of hydroxychloroquine were seen in about 3 to 4 hours. Renal clearance in rheumatoid arthritis (RA) patients taking hydroxychloroquine for at least six months seemed to be similar to that of the single dose studies in volunteers, suggesting that no change occurs with chronic dosing. Range for renal clearance of unchanged drug was approximately 16 to 30% and did not correlate with creatinine clearance; therefore, a dosage adjustment is not required for patients with renal impairment. In RA patients, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Cellular levels of patients on daily hydroxychloroquine have been shown to be higher in mononuclear cells than polymorphonuclear leucocytes.
Hydroxychloroquine drug label (1): “Range for renal clearance of unchanged drug was approximately 16 to 30% and did not correlate with creatinine clearance; therefore, a dosage adjustment is not required for patients with renal impairment.”
Microbiology – Malaria
Mechanism of action
Hydroxychloroquine, like chloroquine, is a weak base and may exert its effect by concentrating in the acid vesicles of the parasite and by inhibiting polymerization of heme. It can also inhibit certain enzymes by its interaction with DNA.
Hydroxychloroquine drug label (1): “Hydroxychloroquine sulfate can lower the convulsive threshold.”
Hydroxychloroquine drug label (1): “hydroxychloroquine administered to nursing women is excreted in human milk and it is known that infants are extremely sensitive to the toxic effects.”
Hydroxychloroquine drug label (1):
Nursing Mothers
Caution should be exercised when administering hydroxychloroquine sulfate to nursing women. It has been demonstrated that hydroxychloroquine administered to nursing women is excreted in human milk and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.
Adverse reactions.
Hydroxychloroquine drug label (1):
The following adverse reactions have been identified during post-approval use of hydroxychloroquine sulfate or other 4-aminoqunoline compounds. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: Bone marrow failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Hemolysis reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
Cardiac disorders: Cardiomyopathy which may result in cardiac failure and in some cases a fatal outcome (see WARNINGS and OVERDOSAGE). Hydroxychloroquine sulfate prolongs the QT interval. Ventricular arrhythmias and torsade de pointes have been reported in patients taking hydroxychloroquine sulfate (see OVERDOSAGE and DRUG INTERACTIONS).
Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, nerve deafness, deafness.
Eye disorders: Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance), visual field defects (paracentral scotomas) and visual disturbances (visual acuity), maculopathies (macular degeneration), decreased dark adaptation, color vision abnormalities, corneal changes (edema and opacities) including corneal deposition of drug with or without accompanying symptoms (halo around lights, photophobia, blurred vision).
Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal pain.
General disorders and administration site conditions: Fatigue.
Hepatobiliary disorders: Liver function tests abnormal, hepatic failure acute.
Immune system disorders: Urticaria, angioedema, bronchospasm
Metabolism and nutrition disorders: Decreased appetite, hypoglycemia, porphyria, weight decreased.
Musculoskeletal and connective tissue disorders: Sensorimotor disorder, skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes and abnormal nerve conduction.
Nervous system disorders: Headache, dizziness, seizure, ataxia and extrapyramidal disorders such as dystonia, dyskinesia, and tremor have been reported with this class of drugs.
Psychiatric disorders: Affect/emotional lability, nervousness, irritability, nightmares, psychosis, suicidal behavior.
Skin and subcutaneous tissue disorders: Rash, pruritus, pigmentation disorders in skin and mucous membranes, hair color changes, alopecia. Dermatitis bullous eruptions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), photosensitivity, dermatitis exfoliative, acute generalized exanthematous pustulosis (AGEP). AGEP has to be distinguished from psoriasis, although hydroxychloroquine sulfate may precipitate attacks of psoriasis. It may be associated with pyrexia and hyperleukocytosis.
Dosage for malaria
One tablet of 200 mg of hydroxychloroquine sulfate is equivalent to 155 mg base. Take hydroxychloroquine sulfate with a meal or a glass of milk.
Malaria
Prophylaxis
Adults: 400 mg (310 mg base) once weekly on the same day of each week starting 2 weeks prior to exposure, and continued for 4 weeks after leaving the endemic area.
Weight-based dosing in adults and pediatric patients: 6.5 mg/kg (5 mg/kg base), not to exceed
400 mg (310 mg base), once weekly on the same day of the week starting 2 weeks prior to exposure, and continued for 4 weeks after leaving the endemic area.
Treatment of Uncomplicated Malaria
Adults: 800 mg (620 mg base) followed by 400 mg (310 mg base) at 6 hours, 24 hours and 48 hours after the initial dose (total 2000 mg hydroxychloroquine sulfate or 1550 mg base).
Weight based dosage in adults and pediatric patients: 13 mg/kg (10 mg/kg base), not to exceed
800 mg (620 mg base) followed by 6.5 mg/kg (5 mg/kg base), not to exceed 400 mg (310 mg base), at 6 hours, 24 hours and 48 hours after the initial dose. Hydroxychloroquine sulfate film-coated tablets cannot be divided, therefore they should not be used to treat patients who weigh less than 31 kg.
For radical cure of P. vivax and P. malariae infections, concomitant therapy with an 8-aminoquinoline compound is necessary.
Dosage for rheumatoid arthritis.
Lupus erythematosis.
The recommended adult dosage is 200 to 400 mg (155 to 310 mg base) daily, administered as a single daily dose or in two divided doses. Doses above 400 mg a day are not recommended.
The incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded.
Rheumatoid Arthritis
The action of hydroxychloroquine is cumulative and may require weeks to months to achieve the maximum therapeutic effect (see CLINICAL PHARMACOLOGY).
Initial adult dosage: 400 mg to 600 mg (310 to 465 mg base) daily, administered as a single daily dose or in two divided doses. In a small percentage of patients, side effects may require temporary reduction of the initial dosage.
Maintenance adult dosage: When a good response is obtained, the dosage may be reduced by 50 percent and continued at a maintenance level of 200 mg to 400 mg (155 to 310 mg base) daily, administered as a single daily dose or in two divided doses.
Do not exceed 600 mg or 6.5 mg/kg (5 mg/kg base) per day, whichever is lower, as the incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded.
Corticosteroids and salicylates may be used in conjunction with hydroxychloroquine sulfate, and they can generally be decreased gradually in dosage or eliminated after a maintenance dose of hydroxychloroquine sulfate has been achieved.
Hydroxychloroquine and chloroquine toxicity.
Below, there is a link to our article with our notes taken during a quick literature review on chloroquine and hydroxychloroquine toxicity:
Hydroxychloroquine and chloroquine (CQ) have been associated with irreversible visual loss due to retinal toxicity. Hydroxychloroquine retinal toxicity is far more common than previously considered; an overall prevalence of 7.5% was identified in patients taking HCQ for greater than 5 years, rising to almost 20% after 20 years of treatment.
Selected references:
1. Drug label information for Hydroxychloroquine sulfate by Sandoz Inc for the US (referenced by the FDA).
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d22f0a8-170b-4c3e-8c2e-a5cf64b9958b
Accessed on March 30, 2020.
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