Antimalarial and antirheumatic (4-aminoquinoline)
Hydroxychloroquine is a medicine used in lupus, rheumatoid arthritis and for the treatment and prevention of malaria. With prolonged use it can affect the retina, so periodic eye examinations are required.
Also known as: Plaquenil
Additive hypoglycaemic effect — higher risk of hypoglycaemia in diabetic patients.
Hydroxychloroquine can cause severe and potentially fatal hypoglycaemia, "in the presence or absence of antidiabetic agents" (the label explicitly states that it "may enhance the effects of insulin and antidiabetic drugs and, consequently, increase the hypoglycaemic risk — a decrease in the dosage of insulin and other antidiabetic drugs may be necessary", and recommends monitoring blood glucose in diabetic patients). The combination with metformin adds up the hypoglycaemic effects. Note: the hydroxychloroquine label indicates it does not inhibit OCT2 in vitro, so the mechanism is essentially pharmacodynamic. Monitor glycaemia at the start of the combination and whenever the hydroxychloroquine dose changes, warn the patient about hypoglycaemia signs (sweating, tremor, palpitations, confusion) and consider reducing the metformin or other antidiabetic dose.
Hydroxychloroquine + metformin: additive hypoglycaemia. Monitor glycaemia and consider reducing the antidiabetic dose.
Hydroxychloroquine improves insulin sensitivity, enhancing the Metformin effect.
Capillary glucose, HbA1c and hypoglycaemia symptoms.
Sweating, tremor, confusion, fainting.
Monitor glycaemia and adjust the antidiabetic dose if needed.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Metformin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13b1e35f-d047-8ddc-e063-6394a90a24dd
Additive QT prolongation with risk of ventricular arrhythmias.
Hydroxychloroquine blocks potassium channels (hERG) and prolongs the QT interval; with amiodarone the effect is additive and the risk of torsades de pointes increases, especially with hypokalaemia, bradycardia, renal impairment or heart disease. In patients on chronic amiodarone (e.g. AF) who need hydroxychloroquine (lupus, rheumatoid arthritis, malaria), prefer an alternative or monitor the ECG before and during treatment, correcting electrolytes.
Hydroxychloroquine + amiodarone: additive QT prolongation with risk of ventricular arrhythmias. Avoid or monitor the ECG.
Both prolong cardiac repolarisation.
ECG (QTc), potassium and magnesium.
Syncope, palpitations.
Avoid when possible; if needed, ECG and electrolytes.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Amiodarone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51a88e8e-da02-4b97-9e7e-442fbffd908d
Additive QT prolongation — risk of arrhythmias.
Both hydroxychloroquine and clarithromycin prolong the QT interval; the additive effect increases the torsades de pointes risk, especially in patients with a prolonged baseline QT, hypokalaemia, renal impairment or heart disease. In patients with lupus or rheumatoid arthritis on hydroxychloroquine who need an antibiotic, prefer a macrolide with less QT effect or another class; if the combination is unavoidable, monitor the ECG and electrolytes.
Hydroxychloroquine + clarithromycin: additive QT prolongation with risk of torsades de pointes. Avoid the combination or monitor the ECG.
Additive blockade of cardiac potassium channels.
ECG (QTc) and electrolytes.
Palpitations, syncope.
Caution; ECG if risk factors.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Clarithromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d836ae7e-fdbf-4dcb-a90d-ede1dcbc3e67
Hydroxychloroquine + aspirin: additive gastrointestinal risk.
Aspirin, especially at anti-inflammatory doses or with prolonged use, can irritate the gastric mucosa; hydroxychloroquine is also associated with gastrointestinal symptoms (nausea, diarrhoea, abdominal discomfort). The combination can add these effects and increase the risk of dyspepsia or, more rarely, mucosal injury. In patients with a history of ulcer, consider gastroprotection, use the lowest effective aspirin dose and monitor digestive symptoms; taking with food can reduce discomfort.
Hydroxychloroquine + aspirin: additive gastrointestinal risk. Use with caution and monitor digestive symptoms.
Both may irritate the gastric mucosa.
GI symptoms after the combination.
Dyspepsia, epigastric pain, melena.
Watch for dyspeptic symptoms; consider gastroprotection in at-risk patients.
DailyMed (FDA) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da435181-0c5a-4188-8d59-51234116b005 ; approved Aspirin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ba0a9f2-062a-401e-82eb-54383a822366 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Hydroxychloroquine may increase the effect of Warfarin — bleeding risk.
Hydroxychloroquine, like chloroquine, can inhibit warfarin metabolism and raise the INR, although the mechanism is not fully established. Reports are more frequent in patients with systemic lupus erythematosus or rheumatoid arthritis on chronic treatment, in whom the interaction can manifest weeks after initiation. The INR should be monitored at initiation and discontinuation of hydroxychloroquine and the warfarin dose adjusted; watch for bleeding signs.
Hydroxychloroquine can increase the effect of warfarin. Monitor the INR when starting and stopping, especially in prolonged treatment (lupus, rheumatoid arthritis).
Possible inhibition of Warfarin metabolism (CYP2C9).
INR and signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR on starting/stopping and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Hydroxychloroquine raises Digoxin levels — risk of digoxin toxicity.
Hydroxychloroquine, like chloroquine, can inhibit P-glycoprotein and reduce digoxin elimination, raising its concentrations and the risk of digitalis toxicity. The interaction is most relevant in patients with lupus or rheumatoid arthritis on prolonged treatment, in whom the effect can manifest over weeks. Monitor digoxin levels and the ECG when hydroxychloroquine is started or adjusted and watch for digitalis toxicity signs (nausea, bradycardia, arrhythmias, visual disturbances).
Hydroxychloroquine can inhibit P-gp and raise digoxin levels. Monitor digoxin levels in prolonged treatment.
P-glycoprotein inhibition, reducing renal Digoxin excretion.
Digoxin level, ECG and renal function.
Nausea, visual disturbances, bradycardia.
Monitor digoxin levels; adjust the dose if needed.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Digoxin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5886e233-b2da-4acb-be05-9bf40fb8e7f4
Two drugs of the same family (4-aminoquinolines) — no benefit from combining, with additive risk of ocular, QT and cardiac toxicity.
Chloroquine and hydroxychloroquine are antimalarials of the same class (4-aminoquinolines), both associated with QT prolongation, ventricular arrhythmias and, with prolonged use, cardiomyopathy (the hydroxychloroquine label describes fatal or potentially fatal cardiomyopathy and ventricular arrhythmias; the chloroquine label, QT prolongation, torsade de pointes and a higher risk with other QT-prolonging drugs). The combination adds no benefit and adds cardiac and retinopathy risk. Avoid; if for any reason they are co-administered (not recommended), monitor the ECG, electrolytes and signs of cardiotoxicity.
Chloroquine + hydroxychloroquine: additive QT and cumulative cardiotoxicity. Avoid the combination (same class).
Overlapping mechanisms: potassium channel blockade, tissue accumulation and additive retinal risk.
Not applicable if not combined; with prolonged use of either: ophthalmological screening.
Visual changes, palpitations, myopathy.
Do not combine; choose a single antimalarial drug.
DailyMed/FDA (NIH/NLM) — approved Chloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06c69e2b-211b-4746-9f3a-f86d36520570 ; approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341
Taking with food or milk reduces nausea.
Take with food or milk to improve tolerance.
EMC-UK (MHRA) — approved Hydroxychloroquine SmPC: https://www.medicines.org.uk/emc/product/11540/smpc
Reduced hepatic metabolism may increase exposure.
Use with caution and monitor liver function.
EMC-UK (MHRA) — approved Hydroxychloroquine SmPC: https://www.medicines.org.uk/emc/product/11540/smpc
Hydroxychloroquine may cause cumulative irreversible retinopathy.
Baseline and periodic ophthalmological review (especially > 5 years or risk factors).
EMC-UK (MHRA) — approved Hydroxychloroquine SmPC: https://www.medicines.org.uk/emc/product/11540/smpc
Routinely used in lupus during pregnancy (reduces flares); benefit usually outweighs risk.
Keep under specialist supervision; do not stop in lupus without medical advice.
Low milk levels; considered compatible with breastfeeding.
Plan pregnancy with the team; contraception not contraindicated.
EMC-UK (MHRA) — approved Hydroxychloroquine SmPC: https://www.medicines.org.uk/emc/product/11540/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
4-aminoquinoline antimalarial and antirheumatic agent. Mean absolute oral bioavailability of 79% while fasting; Tmax of about 3.3 hours (whole blood) after 200 mg. Extensive tissue distribution (large volume of distribution); about 50% bound to plasma proteins. Steady-state whole blood concentrations are dose-proportional (200 to 400 mg/day).
Antimalarial: it concentrates in the acid vesicles of the parasite and inhibits heme polymerisation; it can inhibit certain enzymes by interaction with DNA. The anti-inflammatory and immunomodulatory effects in rheumatoid arthritis, systemic lupus erythematosus and chronic discoid lupus are not fully known.
Mean absolute oral bioavailability of 79% while fasting; whole blood peak about 3.3 hours after 200 mg. The absorbed fraction is highly variable in rheumatoid arthritis (30 to 100%), with mean levels significantly higher in patients with less disease activity.
Metabolised mainly by CYP2C8, CYP3A4 and CYP2D6 (and FMO-1 and MAO-A). Metabolites: desethylhydroxychloroquine (main), desethylchloroquine and bidesethylhydroxychloroquine. Renal clearance of unchanged drug of about 16 to 30% of the dose; unchanged with chronic administration.
Half-life of about 40 days in whole blood after a single dose; with chronic use, the terminal half-life ranges from 40 to 50 days and steady state is reached by 6 weeks with 400 mg/day (the absorption half-life is 3 to 4 hours).
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
