Adverse Drug Reaction Overview
The adverse events listed below reflect the experience
from the clinical studies conducted with EPURIS® (isotretinoin) and the
post-marketing experience. The relationship of some of these events to EPURIS®
therapy is unknown.
Many of the side effects and adverse events seen or
expected in patients receiving isotretinoin are similar to those described in
patients taking high doses of vitamin A.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific
conditions the adverse reaction rates observed in the clinical trials may not
reflect the rates observed in practice and should not be compared to the rates
in the clinical trials of another drug. Adverse drug reaction information from
clinical trials is useful for identifying drug-related adverse events and for
Table 1 presents common adverse events (≥ 1%)
reported in a double-blind, randomized, Phase III, parallel group study of
EPURIS® compared to a Reference Product dosed under fed conditions, in 925
patients with severe recalcitrant nodular acne.
In the above-described study (ISOCT.08.01) almost all
patients experienced at least one adverse event (AE) in both groups at similar
rates (92% with EPURIS® and 90% with the Reference Product (a marketed
formulation of isotretinoin)). Most of these AEs were treatment related (87%
with EPURIS® and 84% with the reference drug). Adverse events related to the
musculoskeletal system and connective tissues were reported in approximately
37% of the patients, and musculoskeletal symptoms in approximately 24% of the patients.
Elevations in levels of serum creatine kinase were reported as high alert
laboratory values (≥ 350 u/L) in approximately 29% of patients, and
incidence of the AE “blood creatine kinase increase” in 6% of patients.
Systematic assessment of visual acuity (Snellen chart)
was performed in most patients and revealed that 20% of patients in the EPURIS®
group and 15% of patients in the Reference group experienced VA worsening that
was reversible for most. However, 3.7% (17/464) of patients in the EPURIS®
group and 3% (14/460) of patients in the Reference group did not fully recover baseline
visual acuity values.
No deaths were reported during the study, and the rate of
serious adverse events (SAE) was relatively low in both groups (1.1% to 1.5%).
Three serious AEs were considered to be possibly related to EPURIS® and
recovered completely: severe abdominal pain, severe upper abdominal pain and
Adverse events leading to discontinuation were reported
in 4.1% of patients with EPURIS®, and 3.3% of patients with the Reference
Product. These AEs were classified as psychiatric events and gastrointestinal
events in the EPURIS® group, and as psychiatric events and musculoskeletal/connective
tissue events in the Reference Product group.
Table 1: Adverse Events Reported in ≥ 1% of
Patients in the EPURIS® group versus the Reference Product Group in the
Double-Blind, Phase III Study
(N = 464)
(N = 460)
(N = 464)
(N = 460)
|Patients with any adverse events
||X-ray limb abnormal
||Asparate aminotransferase increased
|Blood creatine kinase increased
|Upper respiratory tract infection
|Visual acuity reduced
|Blood triglycerides increased
|Bone density decreased
|Pain in extremity
|Alanine aminotransferase increased
Some AEs tended to be reported
with a differential in frequency according to gender in both treatment groups:
For example, triglycerides increased, arthralgia, pain, and blurred vision tended
to be more often reported in females, while chapped lips, cheilitis, epistaxis,
creatine kinase increased, and bone density decreased tended to be more
reported in males.
Reduced visual acuity, blurred
vision, increased triglycerides, headache and fatigue tended to be more often
reported in adults as compared to adolescents (12 to 17 years).
Decreased bone density was reported
in adolescents of both treatment groups (4% to 8%) but not in adults.
Adverse reactions were
generally reversible when therapy was discontinued; however, some have
persisted after cessation of therapy.
Less Common (<1%) Clinical
Trial Adverse Reactions
Adverse events in subjects
receiving EPURIS® in any clinical trial are listed below.
Body as a Whole: Herpes simplex, irritability, oedema peripheral, thirst,
chest pain, cyst, impaired healing, influenza like illness, lymphadenopathy,
xerosis, discomfort, oedema, gravitational oedema, mucous membrane disorder and
Cardiovascular: Palpitations, tachycardia and coronary artery disease.
Endocrine and Metabolism: Increased appetite and thyroid disorder.
Gastrointestinal: Bleeding and inflammation of the gums, dry mouth,
abdominal discomfort, dyspepsia, haemorrhoids, rectal haemorrhage, abdominal
pain lower, lip swelling, mouth ulceration, oral pain, tooth impacted,
abdominal distension, abdominal tenderness, anal fissure, frequent bowel
movement, gastrooesophageal reflux disease, gingival recession, haematochezia, hypoaesthesia
oral, lip haemorrhage, lip ulceration, oesophageal pain, painful defaecation,
rectal fissure, tooth disorder and toothache.
Hearing Disorders: Tinnitus, ear pain, hypoacusis, ear discomfort, external
ear inflammation, cerumen impaction, hyperacusis and vertigo.
Dermatologic: Bruising, pruritus,
alopecia, eczema nummular, scar, eczema asteatotic, acne, rash popular, skin
exfoliation, acne cystic, blister, hair texture abnormal, intertrigo, pain of
skin, photosensitivity reaction, pyogenic granuloma, skin discolouration, acrodermatitis,
alopecia effluvium, androgenic alopecia, dermatitis atopic, dermatitis
exfoliative, exfoliative rash, livedo reticularis, onycholysis, pityriasis
rosea, psoriasis, rash follicular, paronychia, seborrhoea, skin depigmentation,
skin fissures, skin irritation, skin infections, skin lesion, skin ulcer,
swelling face and telangiectasia.
Musculoskeletal: Tendonitis, muscle spasms, arthropathy, joint stiffness,
joint swelling, joint pain, muscle tightness, musculoskeletal chest pain,
arthritis, bone pain, fibromyalgia, groin pain, intervertebral disc space
narrowing, joint crepitation, limb discomfort, muscle atrophy, myositis, spinal
osteoarthritis, synovial cyst and tendon pain.
Neurologic: Dizziness, drowsiness, malaise, memory impairment,
nervousness, paresthesia, presyncope, sinus headache, syncope, weakness.
Ophthalmologic: Ocular hyperaemia, lacrimation increased, photophobia, xerophthalmia,
blepharitis, eye pain, visual impairment, blepharospasm, conjunctival
haemorrhage, conjunctival hyperaemia, conjunctivitis allergic, diplopia, eczema
eyelids, eye haemorrhage, eye swelling, eyelid oedema, foreign body sensation
in eyes, keratitis, myopia, orbital edema, photopsia, pinguecula and punctuate
Psychiatric Disorders: Depression, attention deficit/hyperactivity disorder, mood
swings, sleep disorder, panic attack, restlessness, stress, adjustment
disorder, affect lability, anger, bradyphrenia, delusion, depressed mood,
disorientation, dysthymic disorder, emotional distress, hallucination auditory,
libido decreased, middle insomnia, obsessive thoughts, paranoia and substance
Respiratory: Rhinorrhoea, sinus congestion, asthma, respiratory tract
congestion, dry throat, nasal mucosal disorder, rales, rhinitis seasonal, sleep
apnoea syndrome, throat irritation, voice hoarseness and wheezing.
Reproductive System: Metrorrhagia, menstruation irregular, vulvovaginal
bleeding, vulvovaginal discomfort, amenorrhoea, breast cyst, dysmenorrhoea,
epididymitis, erectile dysfunction, menorrhagia, ovarian cyst, ovarian cyst
ruptured, pruritus genital, testicular cyst, vaginal discharge and vulva cyst.
Urinary System: Proteinuria, haematuria, dysuria, nephrolithiasis and
Abnormal Laboratory Findings
Blood potassium increased,
blood alkaline phosphatase increased, blood bilirubin increased, blood urea
increased, elevated platelet counts, eosinophil count increased, false positive
tuberculosis test, gamma-glutamyltransferase abnormal, blood cholesterol
increased, glucose urine present, haematocrit decreased, protein urine,
thrombocytopenia, white blood cell count decreased.
Post-Marketing Adverse Drug
The following additional
adverse reactions have been identified during post-approval use of EPURIS®.
Body as a whole: Weight loss, anemia, allergic responses and
Cardiovascular: Transient pain in the chest and vascular thrombotic
Endocrine and Metabolism: New cases of diabetes (see WARNING AND PRECAUTIONS:
Endocrine and Metabolism).
Gastrointestinal: Inflammatory bowel disease, colitis,
esophagitis/esophageal ulceration and other nonspecific gastrointestinal
symptoms (see WARNINGS AND PRECAUTIONS: Gastrointestinal).
Hearing Disorders: Impaired hearing at certain frequencies.
Hepatic/Biliary/Pancreatic: Pancreatitis (see WARNINGS AND PRECAUTIONS: Hepatic/Biliary/Pancreatic).
Laboratory Abnormalities: Elevated fasting blood sugar and red blood cells in the
Dermatologic: Acne flare, hair loss,
hypopigmentation, sweating and urticaria.
Musculoskeletal: Other types of bone abnormalities and rhabdomyolysis.
Neurologic: Seizures and benign intracranial hypertension (see WARNINGS
AND PRECAUTIONS: Serious WARNINGS AND PRECAUTIONS, Neurologic).
Ophthalmologic: Visual disturbances.
Psychiatric Disorders: Emotional instability, suicidal ideation, suicide
attempts, suicide, aggression and violent behaviors.
Urinary system: Nonspecific urogenital findings.
The following additional
adverse reactions have been identified during the use of other isotretinoin
Body as a Whole: Allergic vasculitis, systemic hypersensitivity.
Dose-Relationship: Cheilitis and hypertriglyceridemia were usually dose
Gastrointestinal: Ileitis and other nonspecific gastrointestinal symptoms.
Hepatic/Biliary/Pancreatic: Patients treated with isotretinoin, especially those with
high triglyceride levels are at risk of developing pancreatitis. Rare cases of
fatal pancreatitis and several cases of clinical hepatitis have been reported
(see WARNINGS AND PRECAUTIONS: Hepatic/Biliary/Pancreatic).
Laboratory Abnormalities: Decreases in red blood cell parameters, decrease in serum
high density lipoprotein (HDL), hyperuricemia, elevated sedimentation rates,
white blood cells in the urine and blood protein present.
A rise in serum levels of liver
enzymes may occur, especially with higher dosages. Although the changes have
usually been within the normal range, and may return to baseline levels despite
continued treatment, significant increases have occurred in a few cases,
necessitating dosage reduction or discontinuation of isotretinoin (see WARNINGS
AND PRECAUTIONS: Hepatic/Biliary/Pancreatic).
Dermatologic: Acne fulminans,
desquamation, eruptive xanthomas, facial erythema, nail dystrophy, flushing,
fragility of skin, hirsutism, hyperpigmentation, peeling of palms and soles,
photoallergic, vasculitis (including Wegener’s granulomatosis), abnormal wound
healing (delayed healing or exuberant granulation tissue with crusting),
erythema nodosum and exanthema. Erythema multiforme (EM), Stevens-Johnson
syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported to be
associated with isotretinoin (see WARNING AND PRECAUTIONS: Serious
Musculoskeletal: Calcification of tendons and ligaments, premature
epiphyseal closure, skeletal hyperostosis (see WARNINGS AND PRECAUTIONS:
Musculoskeletal, Hyperostosis) and other types of bone
abnormalities. There have been post-marketing serious reports of rhabdomyolysis,
often leading to hospitalization, particularly in those undergoing strenuous physical
Ophthalmologic: Cataracts, colour vision disorder, optic neuritis,
papilledema as a sign of benign intracranial hypertension and colour vision
disturbances. Corneal opacities were reported in nodular and/or inflammatory
acne patients (see WARNINGS AND PRECAUTIONS: Ophthalmologic).
Decreases in night vision were reported and, in rare instances, persisted after
cessation of therapy (see WARNINGS AND PRECAUTIONS: Ophthalmologic).
Respiratory: Voice alteration and bronchospasm, sometimes in patients
with pre-history of asthma.
Urinary system: Glomerulonephritis.