Hydroxychloroquine

Author(s): Dr Anes Yang, Clinical Researcher, Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia; Dr Monisha Gupta, Senior Staff Specialist, Department of Dermatology, Liverpool Hospital, Senior Lecturer, University of New South Wales, Sydney, New South Wales, Australia. DermNet NZ Medical Editor: Dr Delwyn Dyall-Smith, Dermatologist, Wagga Wagga, NSW, Australia. DermNet New Zealand Editor in Chief: Adjunct Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. September 2018.


What is hydroxychloroquine?

Hydroxychloroquine [Plaquenil] is a 4-amino-quinoline antimalarial medication that is widely used to treat systemic lupus erythematosus (SLE), rheumatoid arthritis, and related inflammatory and dermatological conditions. It is a hydroxylated version of chloroquine, with a similar mechanism of action. However, following an identical dose of hydroxychloroquine and chloroquine, tissue levels of chloroquine are 2.5 times those of hydroxychloroquine. Hydroxychloroquine is preferred due to its safer profile.

If there is a contraindication to hydroxychloroquine, an alternative antimalarial medication used in dermatology is quinacrine. Due to differences in chemical structure, there is no cross-reactivity between the 4-amino-quinolines (chloroquine, hydroxychloroquine) and quinacrine. An adverse reaction to one does not preclude the use of the other.

Skin conditions that may be treated with hydroxychloroqine

Who uses hydroxychloroquine?

Indications as a first-line medication in dermatology:

Indications as a second- or third-line treatment option in dermatology:

Other dermatological conditions where hydroxychloroquine may be considered:

What are the contraindications with hydroxychloroquine?

The contraindications to hydroxychloroquine include:

  • Known hypersensitivity to 4-aminoquinoline
  • Children below 6 years of age, due to increased risk of overdose
  • Patients taking tamoxifen, as this increases the risk of retinopathy
  • Patients with severe renal impairment, who require dose reduction
  • Patients with pre-existing retinopathy of the eye — this is a relative contraindication in that it makes monitoring more difficult.

Tell me more about hydroxychloroquine

Hydroxychloroquine has a lower risk of ocular toxicity, both corneal and retinal, compared with chloroquine.

Smoking possibly reduces the efficacy of hydroxychloroquine, although studies have not usually confirmed this clinical impression.

Hydroxychloroquine is considered safer than chloroquine during pregnancy and lactation.

Hydroxychloroquine is rapidly absorbed from the gastrointestinal tract and steady-state concentrations are reached after 4 to 6 weeks.

45% binds to plasma proteins that are deposited in tissues such as the liver, spleen, kidney and lung. There is a particularly high affinity for melanin containing cells such as in the skin and retina. Deposits in these cells can lead to cutaneous pigmentation and possibly retinal toxicity.

Hydroxychloroquine breaks down into two pharmacologically active metabolites — desethylhydroxychloroquine and desethylchloroquine.

After a single dose, hydroxychloroquine is excreted mainly in the faeces, and only 20% is excreted unchanged in the urine. Dose adjustment is therefore only required in patients with severe renal impairment.

How does hydroxychloroquine work?

Hydroxychloroquine is:

  • Anti-inflammatory
  • Antiproliferative
  • Immunomodulatory
  • Antithrombotic
  • Photoprotective.

Anti-inflammatory effects are thought to result through a variety of pathways reducing the cascade of cytokine production and including actions related to an increase in lysosome pH. This causes:

  • Decreased protease activity
  • Decreased class II major histocompatibility complex (MHC) assembly
  • Decreased toll-like receptor TLR-9, -7, -8 and -3 activation
  • Promotion of CD8 T-cell stimulation.

These lysosomotropic effects occur in macrophages, dendritic cells and lymphocytes. HCQ has a dichotomous effect on T cells. It inhibits CD4 T-cell stimulation, but also promotes CD8 T-cell stimulation. The combined effect is a beneficial action in autoimmunity without a penalty of increased opportunistic infections.

Anti-proliferative and immunomodulatory effects are mediated by decreasing lymphocyte proliferation, interference with natural killer cell activity, and possibly alteration of auto-antibody production.

Photoprotective effects are not completely understood. Current theories include:

  • Accumulation of hydroxychloroquine in the skin provides a physical photoprotective barrier by absorbing certain wavelengths of light
  • The inflammatory response of keratinocytes that is normally triggered by sunlight exposure is dampened by the antimalarial medications anti-inflammatory effect.

Antimalarial medications prevent platelet aggregation and act as prostaglandin antagonists due to inhibition of phospholipase A2. Therefore, it may be used as life-long therapy for patients with systemic lupus who are at an increased risk of cardiovascular disease.

Other effects of hydroxychloroquine include:

  • A 15–20% decrease in serum cholesterol, triglyceride and LDL levels
  • Lowering glucose by decreasing insulin degradation
  • Antiviral properties
  • Antineoplastic action
  • Increasing the bone mineral density measured in the spine and in the hips.

Dosing of hydroxychloroquine

Hydroxychloroquine [PlaquenilTM] is dispensed as 200 mg tablets which is equivalent to 155 mg of the base.

Hydroxychloroquine should be taken with a meal or a glass of milk to minimise the gastrointestinal side effects.

Alternate day dosing can be used. For example, 400 mg alternating with 200 mg daily can be used to reach an effective daily dosing of 300 mg/day.

If a therapeutic response is not achieved with hydroxychloroquine alone, adding quinacrine may improve the therapeutic effect.

Dosing recommendations in lupus erythematosus

For the treatment of cutaneous lupus erythematosus, the usual dose range is 200–400 mg daily until therapeutic response is achieved.

Although maximum doses were previously calculated on ideal body weight and advised not to exceed 6.5 mg/kg/d, dosing is now recommended not to exceed 5.0 mg/kg/d actual body weight. However, this may require adjustment in obese patients as the maximum daily dose should not exceed 400 mg/d.

To minimise the cumulative dose, which is also believed to be of some importance in the development of retinal toxicity, the dose should be reduced as tolerated, for example over the winter months.

Dosing recommendations in porphyria cutanea tarda

In the treatment of porphyria cutanea tarda, 100 mg hydroxychloroquine should be prescribed twice weekly for one month, then 200 mg/day until plasma porphyrin levels are normal for at least a month. Initial higher doses may lead to hepatotoxicity as a result of rapid mobilisation of hepatic porphyrin stores.

There are no dosage adjustments provided in the manufacturer’s labelling for renal or hepatic impairment. However, dose reduction may be needed in patients with severe renal impairment.

What are the side effects and risks of hydroxychloroquine?

Ocular side effects

Hydroxychloroquine can cause irreversible retinal toxicity resulting in bilateral bull’s eye maculopathy but is regarded as less toxic to the retina than chloroquine and does not cause the corneal deposits seen with chloroquine therapy.

Irreversible retinal toxicity from hydroxychloroquine has been recognised for many years with the bull’s eye maculopathy seen as the end-stage of this process. The high affinity for melanin containing cells such as those found in the retinal pigment epithelium (RPE) is hypothesised to be the cause.

Recent research has suggested that damage patterns vary with ethnicity, and those of Asian heritage present with a more peripherally distributed area of damage compared to the classic bull’s eye pattern seen in Caucasian patients.

The risk of retinal toxicity is dependent on several factors:

  • Daily dose of hydroxychloroquine > 5.0 mg/kg actual body weight
  • Severe renal impairment
  • Concomitant use of tamoxifen
  • Duration of use > 5 years.

In 2016, with new scientific data, the American Academy of Ophthalmology revised the screening recommendations for patients to be commenced on longterm hydroxychloroquine therapy. Fundal examination alone is insufficient for screening, and further tests are required including at least automated visual fields and spectral domain optical coherence tomography (SD OCT).

Every patient should undergo a baseline ophthalmic examination within the first year of commencing hydroxychloroquine if long-term use is anticipated. In the absence of risk factors listed above, annual screening should then be performed after five years.

Sunglasses can be recommended to avoid additional retinal injury due to sun exposure.

Patients with hydroxychloroquine-induced retinal toxicity will not have any visual symptoms in the early stages, and will only develop clinical symptoms with severe endstage damage. Therefore, it is important that the screening recommendations outlined above are followed, and hydroxychloroquine should be ceased if there are signs of definite retinopathy. The retinopathy does not reverse, but progression is rare following cessation of hydroxychloroquine.

Visual symptoms may present as paracentral scotomas (islands of vision loss) when reading.

Should blurring or vision changes occur, hydroxychloroquine should be ceased and a careful eye examination conducted.

Gastrointestinal effects

Nausea, vomiting and diarrhoea are common side effects but are usually transient or resolve on reduction of the dose. They can be minimised by taking the hydroxychloroquine with food.

Cutaneous effects

Blue-grey pigmentation of the skin is seen in up to 25% of patients taking hydroxychloroquine, especially where there has been bruising. Transverse pigmented nail bands and mucosal pigmentation have also been reported.

Rashes may occur in up to 10% of patients, most commonly morbilliform or psoriasiform. If a rash appears, hydroxychloroquine should be withdrawn and may be restarted at a lower dose.

Less common skin side effects may include:

Haematological effects

Haematological side effects are rare. Haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anaemia, and leukopenia has been reported. The largest study to date evaluating G6PD deficiency with concurrent use of hydroxychloroquine reported no episodes of haemolysis in over 700 months of exposure among the 11 G6PD-deficient patients. Routine screening for G6PD deficiency is no longer recommended for hydroxychloroquine.

Drug interactions with hydroxychloroquine

Increased plasma levels of:

Decreased bioavailability of penicillin.

Increased levels of hydroxychloroquine:

  • Cimetidine
  • Ritonavir.

Decreased levels of hydroxychloroquine:

  • Cholestyramine
  • Antacids.

Increased risk of myopathy:

Decreased effect of:

  • Neostigmine
  • Physostigmine.

Pregnancy and hydroxychloroquine

Hydroxychloroquine does cross the placenta, and is considered Category D in pregnancy.

However, in multiple studies hydroxychloroquine use has not been associated with congenital defects, stillbirth, prematurity, low birth weight, fetal death, or retinopathy following maternal intake at recommended doses.

Hydroxychloroquine has been reported to reduce the risk of cardiac manifestations of neonatal lupus in pregnant women with antiSSA/Ro positive systemic lupus erythematosus (SLE).

International experts currently recommend that hydroxychloroquine can continue during pregnancy and breastfeeding.

Hydroxychloroquine is regarded as safer than chloroquine if required in women planning a pregnancy or breastfeeding.

What monitoring is required?

The amount of monitoring varies from centre to centre. More frequent surveillance is needed if laboratory values are abnormal or with high-risk patients.

  • Full blood count, renal function and liver function should be performed at baseline, then checked periodically.
  • Pregnancy test is undertaken at baseline in women of childbearing age and the use of a reliable method of contraception during treatment should be recommended.
  • Every patient should undergo a baseline ophthalmic examination within the first year of commencing therapy. In the absence of additional risk factors, annual screening should be performed after five years.

Hydroxychloroquine levels can be measured in the blood. This can potentially be used for monitoring compliance to treatment and where response has been inadequate. No standardised effective reference level has been validated. Systemic lupus cohorts with significant improvement/remission have had hydroxychloroquine blood levels of > 750 ng/ml. A blood level of > 500 ng/ml is considered as compliant.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References

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