Read this first:
The White Coat Summit at Capital Hill. Lots of white coats. Lots of agenda
(With thanks to the brilliant Claire Chapman who sourced the following.)
Want some hydroxychloroquine?
CONTRAINDICATIONS
Hydroxychloroquine is contraindicated in:
patients with pre-existing maculopathy of the eye;
patients with known hypersensitivity to 4-aminoquinoline compounds;
long-term therapy in children;
children under 6 years of age.
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum.
Patients should be warned to keep hydroxychloroquine out of the reach of children, as small children are particularly sensitive to 4-aminoquinolines.
Hydroxychloroquine 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, hydroxychloroquine should be stopped. Periodic blood counts are advised.
When used in patients with porphyria or psoriasis, these conditions may be exacerbated. Hydroxychloroquine should not be used in these conditions unless in the judgement of the physician, the benefit to the patient outweighs the possible risk.
Chronic cardiac toxicity
Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated with hydroxychloroquine. Clinical monitoring for signs and symptoms of cardiomyopathy is advised and hydroxychloroquine should be discontinued if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) as well as biventricular hypertrophy are diagnosed.
Hypoglycaemia
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.
QT interval prolongation
Hydroxychloroquine prolongs the QTc interval and should not be used 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 4.5 Interactions with other medicines and other forms of interactions and Section 4.9 Overdose).
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 interval such as:
cardiac disease, e.g., heart failure, myocardial infarction
proarrhythmic conditions, e.g., bradycardia (< 50 bpm)
a history of ventricular dysrhythmias
uncorrected hypokalaemia and/or hypomagnesaemia
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 Interactions with other medicines and other forms of interactions and Section 4.8 Adverse effects (Undesirable effects)).
Ophthalmological
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, hydroxychloroquine 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/kg body weight per day.
Ophthalmological testing should be conducted at 3–4 monthly intervals in the following circumstances:
dose exceeds 6 mg/kg ideal (lean) body weight per day. Using absolute body weight, as a guide to dosage, could result in an overdosage in the obese;
significant renal impairment;
significant hepatic impairment;
elderly;
complaints of visual disturbances;
duration of treatment exceeds 8 years.
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.
Skin Reactions
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, hydroxychloroquine 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.
Other monitoring on long term treatments
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, hydroxychloroquine should be discontinued.
All patients on long-term therapy with hydroxychloroquine 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.
Miscellaneous
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, hydroxychloroquine should be discontinued. Safe use of hydroxychloroquine in the treatment of juvenile rheumatoid arthritis has not been established.
Suicidal behaviour has been reported in very rare cases in patients treated with hydroxychloroquine.
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.
Use in hepatic impairment
Observe caution in patients with hepatic disease, in whom a reduction in dosage may be necessary, as well as in those taking medicines known to affect the organ.
Use in renal impairment
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.
Use in the elderly
See Section 4.4 Special warnings and precautions for use – Ophthalmological.
Paediatric use
No data available.
Effects on laboratory tests
No data available.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS
It has been suggested that 4-aminoquinolines are pharmacologically incompatible with monoamine oxidase inhibitors.
Concomitant hydroxychloroquine and digoxin therapy may result in increased serum digoxin concentrations. Consequently, serum digoxin concentrations should be closely monitored in patients receiving concomitant therapy.
As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.
Drugs known to prolong QT interval / with potential to induce cardiac arrhythmia: Hydroxychloroquine should not be used 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 Special precautions and warnings for use and Section 4.9 Overdose). Halofantrine should not be administered with hydroxychloroquine.
Increased plasma cyclosporin levels have been reported when cyclosporin and hydroxychloroquine are co-administered.
Hydroxychloroquine can lower the convulsive threshold. Co-administration of hydroxychloroquine with other antimalarial 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.
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 is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when hydroxychloroquine is co-administered with agalsidase.
4.6 FERTILITY, PREGNANCY AND LACTATION
Effects on fertility
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.
In another rat study with chloroquine the male fertility rate was decreased after 14 days of intraperitoneal treatment at 10 mg/kg/day.
There are no data in humans.
Use in pregnancy
Category D
Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. It should be noted that 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. Hydroxychloroquine should be avoided in pregnancy except when, in the judgement of the physician, the potential benefits outweigh the potential hazards.
The use of hydroxychloroquine 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.
Use in lactation
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).
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 long-term hydroxychloroquine treatment; the prescriber should assess the potential risks and benefits of use during breastfeeding, according to indication and duration of treatment.
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
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.
4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)
Note:
very common: ≥ 1/10 (≥ 10%)
common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%)
uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%)
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 the available data
Eye Disorders
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 hydroxychloroquine. If allowed to develop, there may be a risk of progression even after treatment withdrawal.
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.
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 hydroxychloroquine, it should be either stopped or temporarily withdrawn.
Not known:
cases of maculopathies and macular degeneration have been reported and may be irreversible.
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.
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.
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, repeated at six month intervals during therapy (see Section 4.4 Special warnings and precautions for use – Opthalmological).
Any adverse changes in the ocular findings or the appearance of scotoma, night blindness or other retinal changes require immediate discontinuation of hydroxychloroquine; these patients should not subsequently receive any pharmacologically similar drugs.
Ear and Labyrinth Disorders
Uncommon: vertigo, tinnitus
Not known: hearing loss
Immune System Disorders
Not known: urticaria, angioedema, bronchospasm
Blood and Lymphatic System Disorders
Rare: bone marrow depression, anaemia, aplastic anaemia, leukopenia, thrombocytopenia.
Very rare: agranulocytosis.
Psychiatric Disorders
Common: affect lability
Very rare: psychosis, suicidal behaviour, nightmares
Nervous System Disorders
Common: headache
Uncommon: nerve deafness, nervousness, dizziness.
Rare: convulsions, neuromyopathy.
Very rare: nystagmus, ataxia
Not known: extrapyramidal disorders such as dystonia, dyskinesia, tremor.
Musculoskeletal and Connective Tissue Disorders
Uncommon: sensory 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.
Gastrointestinal Disorders
Very common: abdominal pain, nausea
Common: diarrhoea, vomiting
Metabolism and Nutrition Disorders
Common: anorexia
Not known: hypoglycaemia
Hydroxychloroquine may exacerbate porphyria.
Hepatobiliary Disorders
Uncommon: abnormal liver function tests.
Very rare: fulminant hepatitis.
Cardiac Disorders
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)
Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular 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).
Skin and Subcutaneous Tissue Disorders
Common: skin rashes, alopecia, pruritus.
Uncommon: pigmentary changes, bleaching of hair
Very rare: bullous eruptions such as acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis and erythema multiforme, Stevens-Johnson syndrome, Drug rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), toxic epidermal necrolysis, photosensitivity.
Miscellaneous
Rare: exacerbation or precipitation of porphyria and attacks of psoriasis.
Very rare: weight loss, lassitude.
patients with known hypersensitivity to 4-aminoquinoline compounds;
long-term therapy in children;
children under 6 years of age.
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum.
Patients should be warned to keep hydroxychloroquine out of the reach of children, as small children are particularly sensitive to 4-aminoquinolines.
Hydroxychloroquine 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, hydroxychloroquine should be stopped. Periodic blood counts are advised.
When used in patients with porphyria or psoriasis, these conditions may be exacerbated. Hydroxychloroquine should not be used in these conditions unless in the judgement of the physician, the benefit to the patient outweighs the possible risk.
Chronic cardiac toxicity
Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated with hydroxychloroquine. Clinical monitoring for signs and symptoms of cardiomyopathy is advised and hydroxychloroquine should be discontinued if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) as well as biventricular hypertrophy are diagnosed.
Hypoglycaemia
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.
QT interval prolongation
Hydroxychloroquine prolongs the QTc interval and should not be used 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 4.5 Interactions with other medicines and other forms of interactions and Section 4.9 Overdose).
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 interval such as:
cardiac disease, e.g., heart failure, myocardial infarction
proarrhythmic conditions, e.g., bradycardia (< 50 bpm)
a history of ventricular dysrhythmias
uncorrected hypokalaemia and/or hypomagnesaemia
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 Interactions with other medicines and other forms of interactions and Section 4.8 Adverse effects (Undesirable effects)).
Ophthalmological
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, hydroxychloroquine 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/kg body weight per day.
Ophthalmological testing should be conducted at 3–4 monthly intervals in the following circumstances:
dose exceeds 6 mg/kg ideal (lean) body weight per day. Using absolute body weight, as a guide to dosage, could result in an overdosage in the obese;
significant renal impairment;
significant hepatic impairment;
elderly;
complaints of visual disturbances;
duration of treatment exceeds 8 years.
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.
Skin Reactions
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, hydroxychloroquine 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.
Other monitoring on long term treatments
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, hydroxychloroquine should be discontinued.
All patients on long-term therapy with hydroxychloroquine 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.
Miscellaneous
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, hydroxychloroquine should be discontinued. Safe use of hydroxychloroquine in the treatment of juvenile rheumatoid arthritis has not been established.
Suicidal behaviour has been reported in very rare cases in patients treated with hydroxychloroquine.
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.
Use in hepatic impairment
Observe caution in patients with hepatic disease, in whom a reduction in dosage may be necessary, as well as in those taking medicines known to affect the organ.
Use in renal impairment
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.
Use in the elderly
See Section 4.4 Special warnings and precautions for use – Ophthalmological.
Paediatric use
No data available.
Effects on laboratory tests
No data available.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS
It has been suggested that 4-aminoquinolines are pharmacologically incompatible with monoamine oxidase inhibitors.
Concomitant hydroxychloroquine and digoxin therapy may result in increased serum digoxin concentrations. Consequently, serum digoxin concentrations should be closely monitored in patients receiving concomitant therapy.
As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.
Drugs known to prolong QT interval / with potential to induce cardiac arrhythmia: Hydroxychloroquine should not be used 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 Special precautions and warnings for use and Section 4.9 Overdose). Halofantrine should not be administered with hydroxychloroquine.
Increased plasma cyclosporin levels have been reported when cyclosporin and hydroxychloroquine are co-administered.
Hydroxychloroquine can lower the convulsive threshold. Co-administration of hydroxychloroquine with other antimalarial 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.
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 is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when hydroxychloroquine is co-administered with agalsidase.
4.6 FERTILITY, PREGNANCY AND LACTATION
Effects on fertility
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.
In another rat study with chloroquine the male fertility rate was decreased after 14 days of intraperitoneal treatment at 10 mg/kg/day.
There are no data in humans.
Use in pregnancy
Category D
Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. It should be noted that 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. Hydroxychloroquine should be avoided in pregnancy except when, in the judgement of the physician, the potential benefits outweigh the potential hazards.
The use of hydroxychloroquine 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.
Use in lactation
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).
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 long-term hydroxychloroquine treatment; the prescriber should assess the potential risks and benefits of use during breastfeeding, according to indication and duration of treatment.
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
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.
4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)
Note:
very common: ≥ 1/10 (≥ 10%)
common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%)
uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%)
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 the available data
Eye Disorders
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 hydroxychloroquine. If allowed to develop, there may be a risk of progression even after treatment withdrawal.
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.
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 hydroxychloroquine, it should be either stopped or temporarily withdrawn.
Not known:
cases of maculopathies and macular degeneration have been reported and may be irreversible.
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.
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.
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, repeated at six month intervals during therapy (see Section 4.4 Special warnings and precautions for use – Opthalmological).
Any adverse changes in the ocular findings or the appearance of scotoma, night blindness or other retinal changes require immediate discontinuation of hydroxychloroquine; these patients should not subsequently receive any pharmacologically similar drugs.
Ear and Labyrinth Disorders
Uncommon: vertigo, tinnitus
Not known: hearing loss
Immune System Disorders
Not known: urticaria, angioedema, bronchospasm
Blood and Lymphatic System Disorders
Rare: bone marrow depression, anaemia, aplastic anaemia, leukopenia, thrombocytopenia.
Very rare: agranulocytosis.
Psychiatric Disorders
Common: affect lability
Very rare: psychosis, suicidal behaviour, nightmares
Nervous System Disorders
Common: headache
Uncommon: nerve deafness, nervousness, dizziness.
Rare: convulsions, neuromyopathy.
Very rare: nystagmus, ataxia
Not known: extrapyramidal disorders such as dystonia, dyskinesia, tremor.
Musculoskeletal and Connective Tissue Disorders
Uncommon: sensory 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.
Gastrointestinal Disorders
Very common: abdominal pain, nausea
Common: diarrhoea, vomiting
Metabolism and Nutrition Disorders
Common: anorexia
Not known: hypoglycaemia
Hydroxychloroquine may exacerbate porphyria.
Hepatobiliary Disorders
Uncommon: abnormal liver function tests.
Very rare: fulminant hepatitis.
Cardiac Disorders
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)
Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular 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).
Skin and Subcutaneous Tissue Disorders
Common: skin rashes, alopecia, pruritus.
Uncommon: pigmentary changes, bleaching of hair
Very rare: bullous eruptions such as acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis and erythema multiforme, Stevens-Johnson syndrome, Drug rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), toxic epidermal necrolysis, photosensitivity.
Miscellaneous
Rare: exacerbation or precipitation of porphyria and attacks of psoriasis.
Very rare: weight loss, lassitude.
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