Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics, PO Box 62027, Sylvia Park Auckland 1644, Freecall: 0800 283 684, Email: medinfo.australia@sanofi.com
Plaquenil is contraindicated in:
Plaquenil is not effective against chloroquine-resistant strains of P.falciparum.
Patients should be warned to keep Plaquenil out of the reach of children, as small children are particularly sensitive to the 4-aminoquinolines.
Plaquenil should be used with caution or not at all in patients with severe gastrointestinal, neurological or blood disorders. If such severe disorders occur during therapy, the drug should be stopped. Periodic blood counts are advised.
When used in patients with porphyria or psoriasis, these conditions may be exacerbated. Plaquenil should not be used in these conditions unless in the judgement of the physician, the benefit to the patient outweighs the possible risk.
Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated with Plaquenil. Clinical monitoring for signs and symptoms of cardiomyopathy is advised and Plaquenil should be discontinued if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block/atrioventricular heart block) as well as biventricular hypertrophy are diagnosed.
Hydroxychloroquine has been shown to cause severe hypoglycaemia including loss of consciousness that could be life threatening in patients treated with and without anti-diabetic medications. Patients treated with hydroxychloroquine should be warned about the risk of hypoglycaemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycaemia during treatment with hydroxychloroquine should have their blood glucose level checked and treatment reviewed as necessary.
Irreversible retinal damage has been observed in some patients who had received long-term or high-dosage 4-aminoquinolone therapy for discoid and systemic lupus erythematosus, or rheumatoid arthritis. Retinopathy has been reported to be dose related. Exceeding the recommended daily dose sharply increases the risk of retinal toxicity.
If there is any indication of abnormality in the visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and streaks) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be discontinued immediately and the patient closely observed for possible progression. Retinal changes (and visual disturbances) may progress after cessation of therapy. (See section 4.8 Adverse effects (Undesirable effects))
Concomitant use of hydroxychloroquine with drugs known to induce retinal toxicity, such as tamoxifen, is not recommended.
Before starting treatment with hydroxychloroquine, all patients should have a careful complete examination of both eyes which includes slit lamp microscopy for corneal changes, fundoscopy, visual acuity, central visual field and colour vision. A complete eye examination before treatment will determine the presence of any visual abnormalities, either coincidental or due to the disease and establish a baseline for further assessment of the patient’s vision. Ophthalmological testing should be conducted at 6 monthly intervals in patients receiving hydroxychloroquine at a dose of not more than 6 mg per kg body weight per day.
Ophthalmological testing should be conducted at 3-4 monthly intervals in the following circumstances:
Corneal changes often subside on reducing the dose or on interrupting therapy for a short period of time, but any suggestion of retinal change or restriction in the visual field is an indication for complete withdrawal of the drug.
The use of sunglasses in patients exposed to strong sunlight is recommended, as this may be an amplifying factor in retinopathy.
Pleomorphic skin eruptions (morbilliform, lichenoid, purpuric), itching, dryness and increased pigmentation sometimes appear after a few months of therapy. The rash is usually mild and transient. If a rash appears, Plaquenil should be withdrawn and only started again at a lower dose.
Patients with psoriasis appear to be more susceptible to severe skin reactions than other patients.
Cases of severe cutaneous adverse drug reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported during treatment with hydroxychloroquine. Patients with serious dermatological reactions may require hospitalisation, as these conditions may be life-threatening and may be fatal. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. If signs and symptoms suggestive of severe skin reactions appear, hydroxychloroquine should be withdrawn at once and alternative therapy should be considered.
Patients on long-term therapy should have periodic full blood counts. If evidence of abnormalities such as agranulocytosis, aplastic anaemia, thrombocytopenia or leukopenia becomes apparent, and cannot be attributed to the disease being treated, Plaquenil should be discontinued.
All patients on long-term therapy with this preparation should be questioned and examined periodically, including the testing of knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs discontinue the drug.
Hydroxychloroquine has the potential to prolong the QTc interval in patients with specific risk factors. Hydroxychloroquine should be used with caution in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT internal such as:
The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded (see Section 4.5 and Section 4.8).
Carefully consider the benefits and risks before prescribing azithromycin or other macrolide antibiotics for any patients taking Plaquenil, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see Section 4.5 Interactions with other medicines and other forms of interactions).
Gastrointestinal disturbances such as nausea, anorexia, abdominal cramps or rarely vomiting, occur in some patients. The symptoms usually stop on reducing the dose or temporarily stopping the drug.
Muscle weakness, vertigo, tinnitus, nerve deafness, headache and nervousness, have been reported less frequently.
In the treatment of rheumatoid arthritis, if objective improvement (such as reduced joint swelling, increased mobility) does not occur within six months, the drug should be discontinued. Safe use of the drug in the treatment of juvenile rheumatoid arthritis has not been established.
Suicidal behaviour and psychiatric disorders have been reported in some patients treated with hydroxychloroquine.
Psychiatric side effects typically occur within the first month after the start of treatment with hydroxychloroquine sulfate and have been reported also in patients with no prior history of psychiatric disorders. Patients should be advised to seek medical advice promptly if they experience psychiatric symptoms during treatment.
Extrapyramidal disorders may occur with hydroxychloroquine.
Also observe caution in patients with gastrointestinal, neurological, or blood disorders, in those with a sensitivity to quinine, and in glucose-6-phosphate dehydrogenase deficiency.
Patients with porphyria cutanea tarda (PCT) are more susceptible to hepatotoxicity (see Section 4.8 Adverse effects (Undesirable effects))
Experimental data showed a potential risk of inducing gene mutations. Animal carcinogenicity data is only available for one species for the parent drug chloroquine and this study was negative. In humans, there are insufficient data to rule out an increased risk of cancer in patients receiving long term treatment.
Observe caution in patients with hepatic disease, as well as in those taking medicines known to affect the organ. A reduction in dosage may be necessary.
Observe caution in patients with renal disease, as well as in those taking medicines known to affect the organ. A reduction in dosage may be necessary.
See Section 4.4 Special warnings and precautions for use – Ophthalmological.
No data available.
Drugs known to prolong QT interval / with potential to induce cardiac arrhythmia: Hydroxychloroquine should be used with caution in patients receiving drugs known to prolong the QT interval, e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some anti-infectives due to increased risk of ventricular arrhythmia (see Section 4.4 and Section 4.9). Halofantrine should not be administered with hydroxychloroquine.
Observational data have shown that co-administration of hydroxychloroquine with azithromycin in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine. Similar careful consideration of the balance of benefits and risks should also be undertaken before prescribing other macrolide antibiotics for any patients taking hydroxychloroquine because of the potential for a similar risk when hydroxychloroquine is co-administered with these medicines.
As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.
Hydroxychloroquine can lower the convulsive threshold. Co-administration of hydroxychloroquine with other anitmalarials known to lower the convulsion threshold (e.g. mefloquine) may increase the risk of convulsions.
The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine.
There is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when hydroxychloroquine is co-administered with agalsidase.
Concurrent use with drugs with oculotoxic or haemotoxic potential should be avoided if possible.
It has been suggested that 4-aminoquinolines are pharmacologically incompatible with monoamine oxidase inhibitors.
Hydroxychloroquine sulphate may also be subject to several of the known interactions of chloroquine even though specific reports have not appeared. These include: potentiation of its direct blocking action at the neuromuscular junction by aminoglycoside antibiotics; inhibition of its metabolism by cimetidine which may increase plasma concentration of the antimalarial; antagonism of effect of neostigmine and pyridostigmine; reduction of the antibody response to primary immunisation with intradermal human diploid-cell rabies vaccine.
Concomitant administration with magnesium-containing antacids or kaolin may result in reduced absorption of chloroquine. Per extrapolation, hydroxychloroquine should therefore be administered at least two hours apart from antacids or kaolin.
Concomitant use of cimetidine, a moderate CYP2C8 and CYP3A4 inhibitor, resulted in a 2-fold increase of chloroquine exposure. Per extrapolation, due to the similarities in structure and metabolic elimination pathways between hydroxychloroquine and chloroquine, a similar interaction could be observed for hydroxychloroquine. Caution is advised (e.g. monitoring for adverse reactions) when CYP2C8 and CYP3A4 strong or moderate inhibitors (such as gemfibrozil, clopidogrel, ritonavir, itraconazole, clarithromycin, grapefruit juice) are concomitantly administered.
Lack of efficacy of hydroxychloroquine was reported when rifampicin, a CYP2C8 and CYP3A4 strong inducer, was concomitantly administered. Caution is advised (e.g. monitoring for efficacy) when CYP2C8 and CYP3A4 strong inducers (such as rifampicin, St John’s Wort, carbamazepine, phenobarbital) are concomitantly administered.
Hydroxychloroquine inhibits CYP3A4 in vitro and PBPK predictions show that hydroxychloroquine is a moderate CYP3A4 inhibitor in vivo. Hydroxychloroquine would increase the exposures of drugs highly metabolized by CYP3A4 such as midazolam and simvastatin by 2.1- and 4.2-fold, respectively. An increased plasma level of ciclosporin (a CYP3A4 and p-gp substrate) was reported when ciclosporin and hydroxychloroquine were coadministered. Caution is advised (e.g. monitoring for adverse reactions) when CYP3A4 substrates (such as ciclosporin, statins) are concomitantly administered.
Hydroxychloroquine inhibits CYP2D6 in vitro. In patients receiving hydroxychloroquine and a single dose of metoprolol, a CYP2D6 probe, the Cmax and AUC of metoprolol were increased by 1.7-fold, which suggests that hydroxychloroquine is a mild inhibitor of CYP2D6. However, given that metoprolol is a moderate sensitive substrate, the maximum increase in exposure could result in levels considered consistent with a moderate or strong inhibitor when co-administered with a sensitive substrate. Caution is advised (e.g. monitoring of adverse reactions or for plasma concentrations as appropriate) when CYP2D6 substrates with narrow therapeutic index (such as flecainide, propafenone) are concomitantly administered.
The inhibitory potential of hydroxychloroquine on P-gp substrates has not been evaluated. In vitro observations show that all other aminoquinolines tested inhibit P-gp. Therefore, there is a potential for increased concentrations of P-gp substrates when hydroxychloroquine is concomitantly administered. Increased plasma cyclosporin levels have been reported when cyclosporin and hydroxychloroquine are co-administered.
Increased digoxin serum levels were reported when digoxin and hydroxychloroquine were coadministered. Caution is advised (e.g. monitoring for adverse reactions or for plasma concentrations as appropriate) when P-gp substrates with narrow therapeutic index (such as digoxin, ciclosporin, dabigatran) are concomitantly administered.
In a single-dose interaction study, chloroquine has been reported to reduce the bioavailability of praziquantel. It is not known if there is a similar effect when hydroxychloroquine and praziquantel are co-administered. Per extrapolation, due to the similarities in structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect may be expected for hydroxychloroquine.
There are no animal data on hydroxychloroquine action on fertility.
A study in male rats after 30 days of oral treatment at 5 mg/day of chloroquine showed a decrease in testosterone levels, weight of testes, epididymis, seminal vesicles and prostate. The fertility rate was also decreased in another rat study after 14 days of intraperitoneal treatment at 10 mg/kg/day.
Category D
Only limited preclinical data are available for hydroxychloroquine, therefore chloroquine data are considered due to the similarity of structure and pharmacological properties between the 2 products. In animal studies on chloroquine, embryo-fetal development toxicity was shown at very high, supratherapeutic doses (ranging from 250 to 1500 mg/kg bodyweight).
Hydroxychloroquine crosses the placenta. It should be noted 4-aminoquinolines in therapeutic doses have been associated with central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal haemorrhages and abnormal retinal pigmentation. Literature review of observational data and meta-analyses, on the use of hydroxychloroquine in women with autoimmune disease during pregnancy excluded a large risk of congenital malformations (RR>3). However, the statistical power to detect modest risks was limited and various limitations of observational data do not allow robust exclusion of causality.
Due to lack of studies, no conclusions can be made from the epidemiologic literature about paternal exposure to Hydroxychloroquine affecting fertility or birth outcomes.
Hydroxychloroquine should be avoided in pregnancy except when, in the judgement of the physician, the individual potential benefits outweigh the potential hazards. The use of this drug in the treatment of malaria or suppression of malaria in high risk situations may be justified if the treating physician considers the risk to the foetus is outweighed by the benefits to the mother and foetus.
Hydroxychloroquine is excreted in breast milk and it is known that infants are extremely sensitive to the toxic effects of 4-amonioquinones. In one study, the daily HCQ exposures to infant from breast milk were estimated to be less than 2% of the maternal dose (after bodyweight correction).
Breastfeeding is possible in case of curative treatment of malaria. Although hydroxychloroquine is excreted in breast milk, the amount is insufficient to confer any protection against malaria to the infant. Separate chemoprophylaxis for the infant is required.
There are very limited data on the safety in the breastfed infant during hydroxychloroquine longterm treatment; the prescriber should assess the potential risks and benefits of use during breastfeeding, according to indication and duration of treatment.
Patients should be warned about driving and operating machinery since hydroxychloroquine can impair visual accommodation and cause blurring of vision. If the condition is not self-limiting, the dosage may need to be temporarily reduced.
Very common ≥1/10 (≥10%), common ≥1/100 and <1/10 (≥1% and <10%), uncommon ≥1/1000 and <1/100 (≥0.1% and <1.0%), rare ≥1/10,000 and <1/1000 (≥0.01% and <0.1%), very rare <1/10,000 (<0.01%), not known frequency cannot be estimated from available data.
Not known: bone marrow depression, anaemia, aplastic anaemia, leucopenia, thrombocytopenia, agranulocytosis
Not known: urticaria, angioedema, bronchospasm
Common: anorexia
Not known: hypoglycaemia
Hydroxychloroquine may exacerbate porphyria.
Common: affect lability
Uncommon: nervousness
Very rare: nightmares
Not known: psychosis, suicidal behaviour, depression, hallucinations, anxiety, agitation, confusion, delusions, mania and sleep disorders
Common: headache
Uncommon: dizziness, nerve deafness
Very rare: nystagmus, ataxia
Not known: convulsions, extrapyramidal disorders such as dystonia, dyskinesia, tremor
Common: blurring of vision
Uncommon: corneal changes, retinal changes, retinopathy with changes in pigmentation and visual field defects. In its early form, it appears reversible on discontinuation of Plaquenil. If allowed to develop, there may be a risk of progression even after treatment withdrawal.
Corneal changes including oedema and opacities have occurred from three weeks (infrequently) to some years after the beginning of therapy. They are either symptomless or may cause disturbances such as halos, blurring of vision, or photophobia. They may be transient or are reversible on stopping treatment. Should these types of corneal changes occur with Plaquenil, it should be either stopped or temporarily withdrawn.
Reversible extra-ocular muscle palsies and temporary blurring of vision due to interference with accommodation have also been noted.
Retinal changes such as abnormal macular pigmentation and depigmentation (sometimes described as a “bull's eye”), pallor of the optic disc, optic atrophy and narrowing of the retinal arterioles have been reported.
Not known: Cases of maculopathies and macular degeneration have been reported and may be irreversible.
Patients with retinal changes may be asymptomatic initially, or may even have scotomatous vision with paracentral, pericentral ring types, temporal scotomas and abnormal colour visions.
Originally, the condition was thought to be progressive and irreversible but more recent evidence suggests that routine ophthalmological examinations may detect retinal changes, especially pigmentation, at an early and reversible stage when there is no apparent visual disturbance.
Much evidence suggests that there is a threshold of dosage above which retinopathy appears. These results seem to correlate more with daily dosage than with a cumulative dose, although the risk increases with increased duration of treatment.
See section 4.4 Special warnings and precautions for use – Ophthalmological for information on eye examinations.
Any adverse changes in the ocular findings or the appearance of scotoma, night blindness or other retinal changes require immediate discontinuation of Plaquenil; these patients should not subsequently receive any pharmacologically similar drugs.
Uncommon: vertigo, tinnitus
Not known: hearing loss
Rare: cardiomyopathy which may result in cardiac failure, and in some cases a fatal outcome (see section 4.4 Special warnings and precautions for use).
Not known: chronic toxicity should be considered when conduction disorders (bundle branch block /atrioventricular heart block) as well as biventricular hypertrophy are diagnosed.
Not known: QT interval prolongation in patients with specific risk factors, which may lead to arrhythmia (torsade de pointes, ventricular tachycardia) (See Section 4.4 Special warnings and precautions for use and 4.5 Interactions with other medicines and other forms of interactions and 4.9 Overdose).
Very common: abdominal pain, nausea
Common: diarrhoea, vomiting
Very Rare: Drug-induced liver injury (DILI) including hepatocellular injury, acute hepatitis and fulminant hepatic failure
Common: skin rashes, alopecia, pruritus
Uncommon: pigmentary changes, bleaching of hair
Rare: exacerbation or precipitation of porphyria and attacks of psoriasis
Very rare: erythema multiforme, photosensitivity, exfoliative dermatitis, Sweet’s syndrome and severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), toxic epidermal necrolysis (TEN), acute generalised exanthematous pustolosis (AGEP) (see Section 4.4 warnings and precautions for use).
Uncommon: sensori motor disorders
Not known: absent or hypoactive deep tendon reflexes, muscle weakness or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups (muscle weakness may be reversible after drug discontinuation, but recovery may take many months). Depression of tendon reflexes and abnormal nerve conduction studies
Very rare: extraocular muscle palsies
Very rare: weight loss, lassitude
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions at https://nzphvc.otago.ac.nz/reporting/
No incompatibilities are known.
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