PRODUCT MONOGRAPH CLARUS Isotretinoin 10 mg and 40 mg

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PRODUCT MONOGRAPH
Pr
CLARUS®
Isotretinoin
10 mg and 40 mg capsules
USP
Nodular/Inflammatory and Conglobate Acne Therapy
MYLAN PHARMACEUTICALS ULC
85 Advance Rd.
Etobicoke, Ontario, Canada
M8Z 2S6
Control No: 169603
Date of Revision:
November 18, 2013
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION............................................................... 3
SUMMARY PRODUCT INFORMATION ............................................................................... 3
INDICATIONS AND CLINICAL USE ..................................................................................... 3
CONTRAINDICATIONS .......................................................................................................... 4
WARNINGS AND PRECAUTIONS ......................................................................................... 5
ADVERSE REACTIONS......................................................................................................... 16
DRUG INTERACTIONS ......................................................................................................... 19
OVERDOSAGE ....................................................................................................................... 21
ACTION AND CLINICAL PHARMACOLOGY ................................................................... 22
STORAGE AND STABILITY ................................................................................................. 24
SPECIAL HANDLING INSTRUCTIONS .............................................................................. 24
DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................... 24
PART II: SCIENTIFIC INFORMATION .................................................................................... 25
PHARMACEUTICAL INFORMATION ................................................................................. 25
DETAILED PHARMACOLOGY ............................................................................................ 27
TOXICOLOGY ........................................................................................................................ 28
REFERENCES ......................................................................................................................... 32
PART III: CONSUMER INFORMATION .................................................................................. 34
2
CLARUS®
Isotretinoin Capsules, USP
10 mg and 40 mg
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Oral
Dosage Form /
Strength
Capsules/10 mg
Oral
Capsules/40 mg
All Nonmedicinal Ingredients
Ammonium hydroxide, beeswax yellow,
gelatin, glycerin, hydrogenated vegetable oil,
polyethylene glycol, polyvinyl acetate
phthalate, propylene glycol, red iron oxide,
soybean oil, synthetic black iron oxide,
lecithin, medium chain triglyceride,
isopropyl alcohol, SDA 35A alcohol.
Ammonium hydroxide, beeswax yellow,
gelatin, glycerin, hydrogenated vegetable oil,
polyethylene glycol, polyvinyl acetate
phthalate, propylene glycol, red iron oxide,
soybean oil, synthetic black iron oxide,
titanium dioxide, yellow iron oxide, lecithin,
medium chain triglyceride, isopropyl alcohol,
SDA 35A alcohol.
INDICATIONS AND CLINICAL USE
CLARUS® (isotretinoin) is indicated for the treatment of:
•
•
•
Severe Nodular and/or Inflammatory Acne
Acne Conglobata
Recalcitrant Acne
Because of significant side effects associated with its use, CLARUS® should be reserved for
patients where the conditions listed above are unresponsive to conventional first line
therapies.
CLARUS® should only be prescribed by physicians knowledgeable in the use of retinoids
systemically, who understand the risk of teratogenicity in females of child bearing age and who
are experienced in counselling young adults for whom isotretinoin is generally indicated (see
3
CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Serious Warnings and
Precautions and Special Populations, Pregnant Women).
A careful assessment of the patient’s mental state should be made, including whether or not they
have a history of previous psychiatric illness (see WARNINGS AND PRECAUTIONS, Serious
Warnings and Precautions, Psychiatric).
It is strongly recommended that each CLARUS® prescription be limited to a one-month supply
in order to encourage patients to return for follow-up to monitor side-effects.
Prescriptions of CLARUS® for women of child-bearing potential should be limited to 30
days of treatment and continuation of treatment requires a new prescription.
Pediatrics
The use of CLARUS® in pediatric patients less than 12 years of age is not recommended. The
use of CLARUS® for the treatment of severe recalcitrant nodular acne in pediatric patients ages
12 to 17 years should be given careful consideration, especially for those patients where a known
metabolic or structural bone disease exists (see WARNINGS AND PRECAUTIONS: Special
Populations, Pediatrics).
Geriatrics
Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and
over to determine whether they respond differently from younger subjects. Although reported
clinical experience has not identified differences in responses between elderly and younger
patients, effects of aging might be expected to increase some risks associated with isotretinoin
therapy
CONTRAINDICATIONS

CLARUS® is contraindicated in pregnancy.
Females must not become pregnant while taking CLARUS® or for at least one month after its
discontinuation. Isotretinoin causes severe birth defects in a very high percentage of infants born
to women who became pregnant during treatment with isotretinoin in any amount, even for a
short period of time. Birth defects which have been documented following isotretinoin
exposure include: CNS (hydrocephalus, hydranecephaly, microcephaly, posterior fossa
abnormalities, cranial nerve dysfunction, cerebellar malformation); craniofacial (anotia,
microtia, low set ears, small or absent external auditory canals, microphthalmia, facial
dysmorphia, cleft palate); cardiac (septal defects, aortic arch abnormalities, tetralogy of
Fallot); thymus gland abnormalities; and parathyroid hormone deficiency. Cases of IQ
scores less than 85 with or without other abnormalities have been reported.
4
o Potentially any exposed fetus can be affected. There are no accurate means of
determining whether an exposed fetus has been affected (see WARNINGS AND
PRECAUTIONS: Special populations, Pregnant women).
o If pregnancy does occur during treatment with CLARUS® or for one month after its
discontinuation, CLARUS® treatment must be immediately stopped and the physician
and patient should discuss the desirability of continuing the pregnancy.

CLARUS® should only be prescribed by physicians knowledgeable in the use of retinoids
systemically (see INDICATIONS AND CLINICAL USE).
CLARUS® is also contraindicated in the following conditions:
 breastfeeding women,
 hepatic and renal insufficiency,
 hypervitaminosis A,
 patients with excessively elevated blood lipid values,
 patients taking tetracyclines (see WARNINGS AND PRECAUTIONS, Serious Warnings
and Precautions, Neurologic and DRUG INTERACTION: Drug-Drug Interactions).
 patients who are sensitive to isotretinoin, or to any of the excipients. CLARUS® capsules
contain Ammonium hydroxide, beeswax yellow, gelatin, glycerin, hydrogenated vegetable
oil, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, red iron oxide, yellow
iron oxide, soybean oil, synthetic black iron oxide, titanium dioxide, lecithin, medium chain
triglyceride, isopropyl alcohol and SDA 35A alcohol. (see DOSAGE FORMS,
COMPOSITION AND PACKAGING: Composition). CLARUS® does not contain peanut
oil.
WARNINGS AND PRECAUTIONS
The Information/Consent/Agreement should be signed by all patients prior to starting therapy
with isotretinoin. This consent form is designated to ensure that patients have been
counselled on and understand the psychiatric and teratogenic risks associated with
isotretinoin, prior to starting treatment. The consent form can be obtained by downloading it
from the CLARUS® Clear Program Website, www.clarusclearprogram.ca, or by contacting
Customer Service centre at [email protected]
Serious Warnings and Precautions
All patients must sign the informed consent form prior to initiating therapy.

Pregnancy Prevention: Isotretinoin is a known teratogen contraindicated in pregnancy (see
boxed CONTRAINDICATIONS). Physicians should only prescribe CLARUS® to females of
5
childbearing potential if ALL the conditions described below under “Conditions of use” are
met.
In addition, when prescribing this drug to female patients of childbearing potential,
physicians must use Mylan Pharmaceuticals ULC Clinical Education and Awareness
Resource (CLEARTM), which includes the following:
 comprehensive information about the potential risks of this drug
 a checklist for criteria which must be met prior to prescribing this drug to female
patients of childbearing potential
 detailed information on birth control options
 a patient informed consent for review and signature
 monthly pregnancy reminders for physicians to use at each patient visit during the
treatment period

Psychiatric: Some patients treated with isotretinoin have become depressed and some
attempted or committed suicide. Although a causal relationship has not been established, all
patients should be screened and monitored for signs of depression during therapy (see
WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). Before starting
therapy with CLARUS® physicians should determine whether the patient may be depressed
or has a history of depression including a family history of major depression before starting
therapy with CLARUS®. If symptoms of depression develop or worsen during treatment with
CLARUS®, the drug should be discontinued promptly and the patient referred for appropriate
psychiatric treatment as necessary. However, discontinuation of CLARUS® may not alleviate
symptoms and therefore further psychiatric or psychological evaluation may be necessary.
A Psychiatric Screening Checklist is available to assist physicians in screening patients for
depression/suicidality prior to treatment and in monitoring for the development of psychiatric
symptoms during treatment.
The following materials are available to physicians and pharmacists. Please contact
your CLARUS® Representative or the Customer Service centre provided below.







Pregnancy Prevention Checklist
Information/Consent/Agreement
Patient Monitoring Chart
Blood Monitoring Guide
CLEARTM Flowchart
Patient Reminder Slips
Psychiatric Screening Checklist
Mylan Pharmaceuticals Customer Service:
85 Advance Road, Etobicoke, ON M8Z 2S6
Toll Free: 1-888-270-2298
Toll Free Fax: 1-888-745-7373
[email protected]
6

Neurologic: Isotretinoin use has been associated with a number of cases of pseudotumor
cerebri (benign intracranial hypertension), some of which involved concomitant use of
tetracyclines (see CONTRAINDICATIONS and DRUG INTERACTIONS: Drug-Drug
Interactions). Early symptoms of pseudotumor cerebri include headache, nausea and
vomiting, and visual disturbances. Patients with these symptoms should be screened for
papilledema and, if present, the drug should be discontinued immediately and the patient
referred to a neurologist for diagnosis and care. Concomitant treatment with tetracyclines
should be avoided (see CONTRAINDICATIONS and DRUG INTERACTIONS: Drug-Drug
Interactions).
Serious Skin Reactions
There have been very rare post-marketing reports of severe skin reactions (e.g., erythema
multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN))
associated with isotretinoin use. These events may be serious and result in hospitalization, life
threatening events, disfiguration, disability and/or death. CLARUS® treatment should be
discontinued if the patient develops any of the following reactions: rash, especially if associated
with fever and/or malaise, conjunctivitis (red or inflamed eyes); blisters on legs, arms or face
and/or sores in mouth, throat, nose or eyes; peeling skin or other serious skin reactions.
Conditions of Use:
1. The patient has severe disfiguring nodular and/or inflammatory acne, acne conglobata or
recalcitrant acne that has not responded to standard therapy, including systemic antibiotics.
2. The patient is reliable in understanding and carrying out instructions.
3. All patients must sign the informed consent form prior to initiating therapy. This form
is provided to the physician via the www.clarusclearprogram.ca website or by
contacting
Mylan Pharmaceuticals Customer Service line at 1-888-270-2298.
CLARUS® is contraindicated in females of childbearing potential unless ALL of the following
conditions apply:
4. The patient is able and willing to comply with the mandatory effective contraceptive
measures.
5. The patient has received, and acknowledged understanding of, a careful oral and printed
explanation of the hazards of fetal exposure to isotretinoin and the risk of possible
contraception failure. This explanation may include showing a line drawing to the patient of
an infant with the characteristic external deformities resulting from isotretinoin exposure
during pregnancy.
7
6. The patient has been informed and understands the need to rapidly consult her physician if
there is a risk of pregnancy.
7. The patient understands the need for rigorous follow-up on a monthly basis.
8. The patient uses effective contraception without any interruption for one month before
beginning CLARUS® therapy, during CLARUS® therapy and for one month following
discontinuation of CLARUS® therapy. It is recommended that two reliable forms of
contraception be used simultaneously (see WARNINGS AND PRECAUTIONS: Special
Populations, Pregnant Women).
9. The patient has had two negative pregnancy tests before starting CLARUS® therapy with the
first pregnancy test conducted at initial assessment when the patient is qualified for
CLARUS® therapy by the physician. The patient has had a second serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL with a negative result, performed in a licensed
laboratory, within 11 days prior to initiating therapy. The patient has had two or three days of
the next normal menstrual period before CLARUS® therapy is initiated.
10. In the event of relapse treatment, the patient must also use the same uninterrupted and
effective contraceptive measures one month prior to, during and for one month after
CLARUS®.
(Re items 4 to 10 see WARNINGS AND PRECAUTIONS: Special Populations, Pregnant
Women).
Even female patients who normally do not employ contraception due to a history of infertility, or
claim absence of sexual activity should be advised to employ contraception while taking
CLARUS® following the above guidelines. Even female patients who have amenorrhea must
follow all the advice on effective contraception unless the patient has undergone
hysterectomy, bilateral oophorectomy, or has been medically confirmed to be
postmenopausal.
Information concerning the CLEARTM program (see boxed Serious Warnings and Precautions)
has also been provided directly to patients via the CLARUS® compliance packaging. This
“Patient Information” asks female patients of childbearing potential, who have not been
counseled using Mylan Pharmaceuticals ULC’s CLEARTM program, to contact their physician
for further information. All patient materials and physician materials can be downloaded
from the www.clarusclearprogram.ca website or by contacting Mylan Pharmaceuticals
Customer Service line at 1-888-270-2298.
Patients should also be informed that confidential contraception counseling (provided by a health
care professional) is available from Mylan Pharmaceuticals ULC.
8
Special Populations
Pregnant Women: There is an extremely high risk (25% or greater) that major human fetal
abnormalities will occur if pregnancy occurs during treatment with isotretinoin or up to one
month following its discontinuation. Potentially any exposed fetus can be affected. These
abnormalities, associated with isotretinoin administration during pregnancy, have been reported
and include:
CNS (hydrocephalus, hydranecephaly, microcephaly, posterior fossa abnormalities, cranial nerve
dysfunction, cerebellar malformation); craniofacial (anotia, microtia, low set ears, small or
absent external auditory canals, microphthalmia, facial dysmorphia, cleft palate); cardiac (septal
defects, aortic arch abnormalities, tetralogy of Fallot); thymus gland abnormalities; and
parathyroid hormone deficiency. Cases of IQ scores less than 85 with or without other
abnormalities have been reported.
Pregnancy Tests: Female patients of childbearing potential must not be given CLARUS® until
pregnancy is excluded. The patient must have two negative pregnancy tests before starting
CLARUS® therapy with the first pregnancy test conducted at initial assessment when the patient
is qualified for CLARUS® therapy by the physician. A second pregnancy test must be performed
within 11 days prior to starting CLARUS® treatment. CLARUS® treatment should start on the
second or third day of the next normal menstrual period following this negative pregnancy test.
It is mandatory that all female patients of childbearing potential treated with CLARUS® have
regular monthly pregnancy tests during treatment and one month after the discontinuation of
treatment. The dates and results of pregnancy tests should be documented. The blood
monitoring chart can be used to document these results as well as to serve as a
reminder of all the tests that should be carried out and their frequency. This physician
material can be downloaded from the www.clarusclearprogram.ca website or by contacting
Mylan Pharmaceuticals Customer Service line at 1-888-270-2298.
These pregnancy tests will:
a) Serve primarily to reinforce to the patient the necessity of avoiding pregnancy.
b) In the event of accidental pregnancy, provide the physician and patient an immediate
opportunity to discuss the serious risk to the fetus from this exposure to CLARUS® and
the desirability of continuing the pregnancy in view of the potential teratogenic effect of
CLARUS® (see CONTRAINDICATIONS and TOXICOLOGY: Reproduction and
Teratology Studies).
Contraception: Effective contraception must be used for at least one month before starting
CLARUS® treatment, during treatment and for at least one month following the discontinuation
of CLARUS® treatment. Any birth control method can fail. Therefore it is recommended
9
that two reliable forms of contraception be used simultaneously (see DRUG
INTERACTIONS: Drug-Drug Interactions). At least 1 of these forms of contraception must be
a primary form, unless the patient has undergone a hysterectomy, bilateral oophorectomy, or
has been medically confirmed to be postmenopausal. Effective forms of contraception
include: primary forms which are tubal ligation, partner’s vasectomy, intrauterine devices, birth
control pills, and topical/injectable/insertable hormonal birth control products and secondary,
or barrier forms of contraception which include diaphragms, latex condoms, and cervical caps.
A diaphragm and cervical cap must each be used with a spermicide.
Pregnancy occurring during treatment with isotretinoin and for one month after its
discontinuation carries the risk of fetal malformation and the increased risk of spontaneous
abortion (see CONTRAINDICATIONS and TOXICOLOGY: Reproduction and Teratology
Studies). CLARUS®, treatment must be stopped and the patient should be fully counselled on the
serious risk to the fetus should they become pregnant while undergoing treatment. If pregnancy
does occur during this time the physician and patient should discuss the desirability of continuing
the pregnancy.
Nursing Women: It is not known whether isotretinoin is excreted in human milk. As isotretinoin
is highly lipophilic, the passage of the drug in human milk is very likely. Because of the potential
for adverse effects, women should not breast-feed if they are receiving CLARUS® (see
CONTRAINDICATIONS).
Pediatrics: The long term safety of isotretinoin, in prepubertal children ( 12 years of age), has
not been established.
In studies with isotretinoin adverse reactions reported in pediatric patients ages 12 to 17 years
were similar to those described in adults except for the increased incidence of back pain and
arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see
ADVERSE REACTIONS).
Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of
pediatric patients treated with isotretinoin developed back pain. Back pain was severe in 13.5%
(14/104) of the cases and occurred at a higher frequency in female patients than male patients.
Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in
7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in
patients who present with these symptoms during or after a course of CLARUS®. Consideration
should be given to discontinuation of CLARUS® if any significant abnormality is found.
Geriatrics ( 65 years of age): Clinical studies of isotretinoin did not include sufficient numbers
of subjects aged 65 years and over to determine whether they respond differently from younger
subjects.
10
Special Patient Groups: In high risk patients (with diabetes, obesity, alcoholism or lipid
metabolism disorder) undergoing treatment with CLARUS®, more frequent checks of serum
values for lipids (see WARNINGS AND PRECAUTIONS: Endocrine and Metabolism and
Hepatic/Biliary/Pancreatic) and/or blood glucose may be necessary.
Male Patients: The available data suggest that the level of maternal exposure from the semen of
the patients receiving isotretinoin is not of a sufficient magnitude to be associated with the
teratogenic effects of isotretinoin. The threshold dose of isotretinoin exposure causing birth
defects is not known. Postmarketing reports through 20 years include 4 with isolated defects
compatible with features of retinoid exposed fetus; however 2 of these reports were incomplete,
and 2 had other possible explanations for the defects observed.
Male patients should be reminded that they must not share their medication with anyone,
particularly not females.
Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of
sperm.
Both male and female patients should be given a copy of the Consumer Information (Part
III).
Blood Donation
It is recommended that blood donation for transfusion purposes be deferred during therapy with
CLARUS® and for one month after discontinuation of treatment. Theoretically, blood from such
donors could present a small risk to the fetus if transfused to a pregnant mother during the first
trimester of pregnancy.
Cardiovascular
Approximately 25% of patients receiving isotretinoin experienced an elevation in plasma
triglycerides. Approximately 15% developed a decrease in high density lipoproteins and about
7% showed an increase in cholesterol levels. These effects on triglycerides, HDL and cholesterol
were reversible upon reduction of the dose or cessation of isotretinoin therapy (see ADVERSE
REACTIONS: Laboratory Abnormalities).
Patients with increased tendency to develop hypertriglyceridemia include those with diabetes
mellitus, obesity, increased alcohol intake and familial history.
The cardiovascular consequences of hypertriglyceridemia are not well understood, but may
increase the patient’s risk status. Therefore, every attempt should be made to control significant
triglyceride elevation (see WARNINGS AND PRECAUTIONS: Monitoring and Laboratory
Tests). Some patients have been able to reverse triglyceride elevation by reduction in weight,
restriction of dietary fat and alcohol, and reduction in dose while continuing isotretinoin. An
obese male patient with Darier’s disease developed elevated triglycerides and subsequent
eruptive xanthomas.
11
Ear/Nose/Throat
Impaired hearing at certain frequencies has been reported in some patients treated with
isotretinoin. Patients who experience tinnitus or hearing impairment should discontinue
CLARUS® treatment and be referred for specialized care for further evaluation.
Endocrine and Metabolism
Patients with diabetes or a family history of diabetes may experience problems with the control
of their blood sugar during CLARUS® therapy. Therefore, known or suspected diabetics should
have periodic blood sugar determinations. Although no causal relationship has been established,
elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed
during isotretinoin therapy (see ADVERSE REACTIONS: Clinical Trial and Post-Market
Adverse Reactions, Laboratory Abnormalities).
Gastrointestinal
Isotretinoin has been temporally associated with inflammatory bowel disease (including regional
ileitis, colitis and hemorrhage) in patients without a prior history of intestinal disorders. Patients
experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue CLARUS®
immediately.
Hepatic/Biliary/Pancreatic
Liver function tests should be monitored before treatment and at regular intervals during
treatment (one month after the start of treatment and at least three month intervals thereafter)
unless more frequent monitoring is clinically indicated. Several cases of clinical hepatitis have
been noted which are considered to be possibly or probably related to isotretinoin therapy.
Additionally, mild to moderate elevations of liver enzymes have been observed in approximately
15% of individuals treated during clinical trials, some of which normalized with dosage
reduction or continued administration of the drug. If normalization does not readily occur, or if
hepatitis is suspected during treatment with CLARUS®, the drug should be discontinued and the
etiology further investigated (see WARNINGS AND PRECAUTIONS: Monitoring and
Laboratory Tests).
There have been some reports of acute pancreatitis, which is known to be potentially fatal. This
is sometimes associated with elevation of serum triglycerides in excess of 800 mg/dL or 9
mmol/L (see ADVERSE REACTIONS: Clinical Trial and Post-Market Adverse Drug Reactions,
Laboratory Abnormalities). Therefore, every attempt should be made to control significant
triglyceride elevation (see WARNINGS AND PRECAUTIONS: Cardiovascular). CLARUS®
should be discontinued if uncontrolled hypertriglyceridemia or symptoms of pancreatitis occur.
Immune
Anaphylactic reactions have been reported. These reactions were more serious after prior
exposure to topical retinoids. Allergic cutaneous reactions and serious cases of allergic vasculitis,
often with purpura (bruises and red patches) of the extremities and extracutaneous involvement
have been reported. Severe allergic reactions necessitate interruption of therapy and careful
monitoring.
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Musculoskeletal
Effects of multiple courses of isotretinoin on the developing musculoskeletal system are
unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with
isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system
(see also WARNINGS AND PRECAUTIONS: Special Populations, Pediatrics).
In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for severe
recalcitrant nodular acne in pediatric patients 12 to 17 years, bone density measurements at
several skeletal sites were not significantly decreased (lumbar spine change
-4% and total hip change-5%) or were increased in the majority of patients. One patient had a
decrease in lumbar spine bone mineral density 4% based on unadjusted data. Sixteen (7.9%)
patients had decreases in lumbar spine bone mineral density 4%, and all the other patients
(92%) did not have significant decreases or had increases (adjusted for body mass index). Nine
patients (4.5%) had a decrease in total hip bone mineral density 5% based on unadjusted data.
Twenty-one (10.6%) patients had decreases in total hip bone mineral density
5%, and all the other patients (89%) did not have significant decreases or had increases
(adjusted for body mass index). Follow-up studies performed in 8 of the patients with decreased
bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5
patients at the lumber spine, while the other 3 patients had lumbar spine bone density
measurements below baseline values. Total hip bone mineral densities remained below baseline
(range-1.6% to -7.6%) in 5 of 8 patients (62.5%).
In this clinical trial transient elevations in CPK were observed in 12% of patients, including
those undergoing strenuous physical activity in association with reported musculoskeletal
adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients,
approximately half of the CPK elevations returned to normal within 2 weeks and half returned to
normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second
course of isotretinoin 4 months after the first course, two patients showed a decrease in mean
lumbar spine bone mineral density up to 3.25%.
Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone
fractures have been seen in the isotretinoin population. While causality to isotretinoin has not
been established, an effect cannot be ruled out. Longer term effects have not been studied. It is
important that isotretinoin be given at the recommended doses for no longer than the
recommended duration.
Although an effect of isotretinoin on bone loss is not established, physicians should use caution
when prescribing isotretinoin to patients with a genetic predisposition for age-related
osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of
bone metabolism. This would include patients diagnosed with anorexia nervosa and those who
are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects
vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be
at increased risk when participating in sports with repetitive impact where the risks of
13
spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late
adolescence are known. There are spontaneous reports of fractures and/or delayed healing in
patients while on treatment with isotretinoin or following cessation of treatment with isotretinoin
while involved in these activities. While causality to isotretinoin has not been established, an
effect cannot be ruled out.
Hyperostosis: Due to possible occurrence of bone changes, a careful evaluation of the
risk/benefit ratio should be carried out in every patient and CLARUS® administration should be
restricted to severe cases of acne. Bone changes including, premature epiphyseal closure,
hyperostosis and calcification of tendons and ligaments have occurred after several years of
administration at high doses for treating disorders of keratinization. The dose levels, duration of
treatment and total cumulative dose in these patients generally far exceeded those recommended
for the treatment of acne.
In clinical trials of disorders of keratinization, with a mean dose of 2.24 mg/kg/day, a high
prevalence of skeletal hyperostosis was noted. Two children showed x-ray findings suggestive of
premature closure of the epiphysis. Additionally, skeletal hyperostosis was noted in six of eight
patients in a prospective study of disorders of keratinization.
Minimal skeletal hyperostosis and calcification of tendons have also been observed by x-rays in
prospective studies of cystic acne patients treated with a single course of therapy at
recommended doses. There are spontaneous reports of premature epiphyseal closure in acne
patients receiving recommended doses of isotretinoin. The effect of multiple courses of
isotretinoin on epiphyseal closure is unknown.
In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day
of isotretinoin given in two divided doses. Hyperostosis may require a longer time frame to
appear. The clinical course and significance remain unknown.
Myalgia and arthralgia (mild to moderate) may occur and may be associated with reduced
tolerance to vigorous exercise (see ADVERSE REACTIONS: Clinical Trial and Post-Market
Adverse Drug Reactions, Musculoskeletal). Instances of raised serum creatine phosphokinase
(CPK) values have been reported in patients receiving isotretinoin, particularly those undertaking
vigorous physical activity. Discontinuation of CLARUS® may be required.
Ophthalmologic
Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently
when higher drug dosages were used in patients with disorders of keratinization. Dry eyes,
corneal opacities, decreased night vision, keratitis, blepharitis and conjunctivitis usually resolve
after discontinuation of therapy. Due to the possible occurrence of keratitis, patients with dry
eyes should be monitored. All CLARUS® patients experiencing visual difficulties should
discontinue the drug and have an ophthalmological examination. (see ADVERSE REACTIONS:
Clinical Trial and Post-Market Adverse Drug Reactions, Ophthalmologic). Dry eyes, can be
helped by the application of a lubricating eye ointment or by the application of tear replacement
14
therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear
glasses during treatment.
A number of cases of decreased night vision have occurred during isotretinoin therapy and in
rare instances have persisted after therapy (see ADVERSE REACTIONS: Clinical Trial and
Post-Market Adverse Drug Reactions, Ophthalmologic). Because the onset in some patients was
sudden, patients should be advised of this potential problem and warned to be cautious when
driving or operating any vehicle at night. CLARUS® patients experiencing visual impairment
should discontinue treatment and have an ophthalmological examination. Visual problems
should be carefully monitored.
Skin
Acute exacerbation of acne is occasionally seen during the initial period but this subsides with
continued treatment, usually 7-10 days, and usually does not require dose adjustment.
Exposure to intense sunlight or to UV rays should be avoided. When necessary a sun-protection
product with a high protection factor of a least SPF 15 should be used.
It is recommended that aggressive chemical dermabrasion and cutaneous laser treatment be
avoided in patients on CLARUS® and for a period of 5-6 months after the end of treatment
because of the risk of hypertrophic scarring in atypical areas, and more rarely hyper- or hypopigmentation in treated areas.
It is recommended that wax epilation be avoided in patients on CLARUS® therapy and for a
period of 5-6 months after treatment because of the risk of epidermal stripping, scarring or
dermatitis.
Concurrent administration of CLARUS® with keratolytic or exfoliative anti-acne agents should
be avoided as local irritation may increase.
Patients should be advised to use a skin-moisturizing ointment or cream and a lip balm from the
start of treatment as isotretinoin is likely to cause dryness of the skin and lips.
There have been post-marketing reports of severe skin reactions. (see WARNINGS AND
PRECAUTIONS: Serious Skin Reactions)
Monitoring and Laboratory Tests
Pregnancy tests: The patient should have two negative pregnancy tests (-hCG in urine or
serum) before starting CLARUS® therapy with the first pregnancy test conducted at initial
assessment when the patient is qualified for CLARUS® therapy by the physician. The patient
then should have a second pregnancy test with a sensitivity of at least 25 mIU/mL with a
negative result, performed in a licensed laboratory, within 11 days prior to initiating therapy. The
patient has had two or three days of the next normal menstrual period before CLARUS® therapy
is initiated. Pregnancy test must be repeated monthly for pregnancy detection during
15
CLARUS® treatment and at one month after discontinuation of treatment. The dates and results
of the pregnancy tests should be documented.
Signs of Depression: sad mood, hopelessness, feeling of guilt, worthlessness or helplessness,
loss of pleasure or interest in activities, fatigue, difficulty concentrating, changes in sleep pattern,
change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on
dangerous impulses, and persistent physical symptoms unresponsive to treatment. If symptoms
of depression develop or worsen during treatment with CLARUS®, the drug should be
discontinued promptly and the patient referred for appropriate psychiatric treatment.
The following tests are required before starting CLARUS®, at first month, then as
clinically indicated:
 Serum blood lipid determinations (under fasting conditions) should be performed before
CLARUS® is given and then at intervals (one month after the start of therapy) until the lipid
response to CLARUS® is established (which usually occurs within four weeks), and also at
the end of treatment.
 Complete blood count and differential: for early detection of leukopenia, neutropenia,
thrombocytopenia and anemia.
 Liver function tests: Increases in about 15% of ALT, AST, ALP baseline levels have been
reported. Liver function tests should be monitored before treatment and at regular intervals
during treatment (one month after the start of treatment and at least three month intervals
thereafter) unless more frequent monitoring is clinically indicated.
 Blood glucose levels: all patients and in particular patients with known or suspected diabetes
should have periodic blood sugar determinations.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
The adverse reactions listed below reflect the experience from clinical studies of isotretinoin, and
the post-marketing experience. The relationship of some of these events to isotretinoin therapy is
unknown.
Many of the side effects and adverse reactions seen or expected in patients receiving isotretinoin
are similar to those described in patients taking high doses of vitamin A.
Clinical Trial and Post-Market Adverse Drug Reactions:
Dose-Relationship and Duration:
Cheilitis and hypertriglyceridemia are usually dose related.
Adverse reactions were generally reversible when therapy was discontinued; however, some
have persisted after cessation of therapy.
16
The most common side-effects are mucocutaneous or dermatologic. The common side effects
include: cheilitis (96%), facial erythema/dermatitis (55%), dry nose (51%), desquamation (50%),
pruritus (30%), dry skin (22%), conjunctivitis (19%), alopecia (13%), irritation of the eyes
(11%), rash (10%). Dryness of the nasal mucosa and pharynx may be associated with mild
epistaxis and hoarseness, respectively. Mild-to-moderate conjunctivitis may be alleviated by use
of an ophthalmic ointment. In rare cases, hair loss persisted after treatment was completed.
Approximately 13% of patients experience joint pain during treatment.
Peeling of palms and soles, skin infections, increased susceptibility to sunburn, non-specific
urogenital symptoms, non-specific gastrointestinal symptoms, headache, fatigue occurred in
approximately 5% of patients.
Body as a whole: weight loss, anemia, lymphadenopathy, vasculitis including Wegener’s
granulomatosis, allergic vasculitis, allergic responses, and systemic hypersensitivity.
Cardiovascular: edema, transient pain in the chest, palpitations, tachycardia, vascular
thrombotic disease, stroke
Endocrine and Metabolism: new cases of diabetes (see WARNING AND PRECAUTIONS:
Endocrine and Metabolism)
Gastrointestinal: nausea, severe diarrhea, mild gastrointestinal bleeding, rectal bleeding,
abdominal pain, inflammatory bowel disease (including regional ileitis, colitis and hemorrhage)
(see WARNINGS AND PRECAUTIONS: Gastrointestinal)
Hearing Disorders: tinnitus, impaired hearing at certain frequencies.
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).
Mucocutaneous and Dermatologic: flushing, changes in skin pigment, urticaria, bruising,
disseminated herpes simplex, hair problems (other than thinning), hirsutism, erythema nodosum,
paronychia, nail dystrophy, pyogenic granuloma, bleeding and inflammation of the gums, acne
fulminans, exanthema, sweating, increased formation of granulation tissue,
photoallergic/photosensitizing reactions, skin fragility. Acne flare occurs at the start of treatment
and persists for several weeks.
During the post-marketing period, 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 Skin Reactions).
17
Musculoskeletal: arthritis, muscle pain (myalgia; elevations of serum CPK values), arthralgia,
calcification of ligaments, tendon and tendinitis, reduced bone density, back pain, premature
fusion of epiphyses, hyperostosis (see WARNINGS AND PRECAUTIONS: Musculoskeletal,
Hyperostosis).
There have been postmarketing serious reports of rhabdomyolysis, often leading to
hospitalization and some with fatal outcome, particularly in those undergoing strenuous physical
activity.
Neurologic: seizures, dizziness, nervousness, drowsiness, malaise, weakness, insomnia,
lethargy, paresthesia, benign intracranial hypertension (see WARNINGS AND PRECAUTIONS:
Serious Warnings and Precautions, Neurologic)
Ophthalmologic: optic neuritis, photophobia, eye lid inflammation, lenticular cataracts,
keratitis, blurred vision, blepharitis, conjunctivitis, decreased night vision, papilledema as sign of
benign intracranial hypertension and colour vision disturbances. Dry eyes and/or decreased
tolerance to contact lenses have also been reported during therapy. In some instances these
conditions have persisted after cessation of therapy.
Of 72 patients who had normal pre-treatment ophthalmological examinations, five developed
corneal opacities while taking isotretinoin (all five patients had a disorder of keratinization).
Corneal opacities have also been reported in nodular and/or inflammatory acne patients treated
with isotretinoin (see WARNINGS AND PRECAUTIONS: Ophthalmologic). Decrease in night
vision has been reported and in rare instances has persisted (see WARNINGS AND
PRECAUTIONS: Ophthalmologic). Cataracts and visual disturbances have also been reported.
Psychiatric Disorders: Depression, psychotic symptoms and, rarely, suicide attempts, suicide,
and aggressive and/or violent behaviours (see WARNINGS AND PRECAUTIONS:
Psychiatric). Depression has been reported during and after therapy. In some of these patients,
depression has subsided with discontinuation of therapy and recurred when isotretinoin therapy
was reintroduced. Emotional instability has been reported with isotretinoin.
Respiratory: respiratory infections
Bronchospasm has been rarely reported; sometimes in patients with pre-history of asthma.
Reproductive system: abnormal menses.
Urinary system: glomerulonephritis
Laboratory Abnormalities:
Isotretinoin therapy induces changes in serum lipids in a significant number of treated subjects.
These changes consisted of: elevation of serum triglycerides (25% of patients), mild to moderate
decrease in serum high density lipoprotein (HDL) (16% of patients), and minimal elevations of
serum cholesterol (7% of patients). Abnormalities of serum triglycerides, HDL and cholesterol
were reversible upon cessation of isotretinoin therapy.
18
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). An elevated erythrocyte sedimentation rate may also occur (40% of
patients).
Other less commonly reported laboratory abnormalities were: Elevated fasting blood sugar,
elevated CPK, and hyperuricemia. Decreases in red blood cell parameters, decreases in white
blood cell counts, elevated sedimentation rates, elevated platelet counts, thrombocytopenia and
anemia. White blood cells in the urine, proteinuria, and red blood cells in the urine.
DRUG INTERACTIONS
Drug-Drug Interactions
Tetracyclines: Rare cases of benign intracranial hypertension ‘pseudotumor cerebri’ have been
reported after use of isotretinoin and/or tetracyclines. Therefore, concomitant treatment with
tetracyclines must be avoided (see WARNINGS AND PRECAUTIONS: Serious Warnings and
Precautions, Neurologic).
Vitamin A: Because of the relationship of isotretinoin to vitamin A, patients should be advised
against taking vitamin supplements containing vitamin A, to avoid additive toxic effects.
Phenytoin: Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a study
in seven healthy volunteers. These results are consistent with the in vitro finding that neither
isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450
enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been
conducted to assess if there is an interactive effect on bone loss between phenytoin and
isotretinoin. Therefore, caution should be exercised when using these drugs together.
Norethindrone/ethinyl estradiol: In a study of 31 premenopausal women with severe
recalcitrant nodular acne receiving OrthoNovum® 7/7/7 1Tablets as an oral contraceptive agent,
isotretinoin at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes
in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of
progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). A drug
interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled
out for isotretinoin.
Microdosed progesterone preparations (minipills) are not a suitable method of contraception
during CLARUS® therapy.
Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal
clinical studies have been conducted to assess if there is an interactive effect on bone loss
19
between systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when
using these drugs together.
______________________________
1
Ortho-Novuum® 7/7/7 is a registered Trade-Mark of Johnson & Johnson
Drug-Food Interactions
Due to its lipophilic properties, absorption of isotretinoin is increased when taken with food.
Therefore, the recommended dose is to be taken with food (see DOSAGE AND
ADMINISTRATION: Recommended Dose and Dosage Adjustment).
Drug-Herb Interactions
St. John’s Wort: Isotretinoin use is associated with depression in some patients (see
WARNINGS AND PRECAUTIONS: Serious Warnings and Precautions, Psychiatric and
ADVERSE REACTIONS: Psychiatric Disorders). Patients should be prospectively cautioned
not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction
has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on
oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by
users of combined hormonal contraceptives who also used some form of St. John’s Wort.
DOSAGE AND ADMINISTRATION
Dosing Considerations
The therapeutic response to isotretinoin is dose-related and varies between patients. This
necessitates individual adjustment of dosage according to the response of the condition and the
patient’s tolerance of the drug. In most cases, complete or near-complete suppression of acne is
achieved with a single 12 to 16 week course of therapy. If a second course of therapy is needed,
it can be initiated eight or more weeks after completion of the first course, since experience has
shown that patients may continue to improve while off the drug.
Recommended Dose and Dosage Adjustment
Initial Therapy:
The initial dose of CLARUS® should be individualized according to the patient’s weight and
severity of the disease.
In general, patients initially should receive CLARUS® 0.5 mg/kg body weight daily for a period
of two to four weeks, when their responsiveness to the drug will usually be apparent. It should be
noted that transient exacerbation of acne is occasionally seen during this initial period.
20
The daily dosage should be taken with food in the nearest number of whole capsules, either as a
single dose or in two divided doses during the day, whichever is more convenient.
Maintenance Therapy:
Maintenance dose should be adjusted between 0.1 and 1 mg/kg body weight daily and, in
exceptional instances, up to 2 mg/kg body weight daily, depending upon individual patient
response and tolerance to the drug.
A complete course of therapy consists of 12-16 weeks of CLARUS® administration.
Patients may show additional improvement for up to several months after a course of isotretinoin
has been completed. With effective treatment, appearance of new lesions will not normally be
evident for a period of at least three to six months.
OVERDOSAGE
For the management of suspected drug overdose, please contact your regional Poison
Control Centre Immediately.
In the event of acute CLARUS® overdose evacuation of the stomach should be considered during
the first few hours after this overdose. Signs and symptoms of acute overdose have been
associated with headache, vomiting, facial flushing, cheilitis, abdominal pain, dizziness and
ataxia. To date, all symptoms have quickly resolved without apparent residual effects and usually
without treatment. Elevated intracranial pressure has been reported with patients receiving
therapeutic doses of isotretinoin. Patients with a CLARUS® overdose should be monitored
closely for signs of increased intracranial pressure. Signs of hypervitaminosis A could appear in
cases of overdose.
Limited data exists on the pharmacokinetic characteristics of isotretinoin in an overdose
situation. Following the oral administration of single 80, 160, 240 and 340 mg doses to 12
healthy male subjects Cmax was 366, 820, 1,056 and 981 ng/mL, and t1/2 was 13.6, 14.1, 14.4 and
16.5 hours for isotretinoin, respectively. Twenty-three compromised cancer patients received
weekly oral doses of 200 (3 patients); 400 (7 patients); 660 (2 patients); 1,000 (3 patients); 1,400
(6 patients) and 1,800 (1 patient) mg/m2. Normal body surface area for healthy subjects is 1.73
m2. After the first dose, Cmax was 1.5, 3.8, 3.5, 2.5, 2.7 and 4.6 g/mL, and t1/2 was 45, 9.1, 14.5,
57, 13.1 and 6.1 hours for isotretinoin, respectively. The absorption of isotretinoin appears to be
a saturable process.
Since it is difficult to extrapolate from the results of these studies to the overdose situation, the
following precautions should be taken with all female patients of childbearing potential who
have taken an overdose of CLARUS®.
1. At the time of the overdose, a pregnancy test must be performed and a blood sample
collected for the determination of isotretinoin and metabolite concentrations.
21
2. One complete menstrual cycle after the overdose, a second pregnancy test must be
performed and a second blood sample collected for the determination of isotretinoin and
metabolite concentrations.
3. Effective contraception must be used for at least one complete menstrual cycle after the
overdose and continued longer, if necessary until physiological plasma concentrations
of isotretinoin and its major metabolites are reached.
Patients who present with a positive pregnancy test at the time of the overdose, one complete
menstrual cycle after the overdose, or while isotretinoin or metabolite blood concentrations are
measurable, should be fully counselled on the serious risk to the fetus from this exposure to
isotretinoin and the physician and patient should discuss the desirability of continuing the
pregnancy. (See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Special
Populations, Pregnant Women and TOXICOLOGY: Reproduction and Teratology Studies).
Canadian Regional Poison Information Centres have been advised on the proper collection and
handling of isotretinoin blood samples and also on the laboratory(s) equipped to assay these
samples.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of isotretinoin is unknown. Vitamin A is important for functional
integrity of the skin and is known to affect the keratinization process. In acne patients,
improvement occurs in association with a reduction in sebum secretion. The decrease in sebum
secretion is temporary and is related to either the dose or duration of isotretinoin administration
and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland
differentiation.
Pharmacokinetics
Absorption: Following oral administration of 80 mg, peak plasma concentrations ranged from
167 to 459 ng/mL (mean 256 ng/mL) with a mean time to peak of 3.2 hours in volunteers, while
in acne patients peak plasma concentrations ranged from 98 to 535 ng/mL (mean 262 ng/mL)
with a mean time to peak of 2.9 hours.
When isotretinoin is taken with food, the bioavailability is doubled relative to fasting conditions
(see DOSAGE AND ADMINISTRATION).
Distribution: Isotretinoin is 99.9% protein bound in human plasma, almost exclusively to
albumin.
Metabolism: The major metabolite identified in blood and urine was 4-oxo-isotretinoin.
Tretinoin and 4-oxo-tretinoin were also observed. The apparent half-life for elimination of the 4oxo-isotretinoin ranged from 11 to 50 hours, with a mean of 28 hours. Following 80 mg of
22
isotretinoin administered orally, maximum plasma concentrations of the 4-oxo-isotretinoin was
87 to 399 ng/mL and maxima were observed between 6 and 20 hours. The blood concentration
of the major metabolite generally exceeded that of isotretinoin after 6 hours. The data suggest
that both isotretinoin and the major metabolite are excreted in the bile and reabsorbed.
The mean minimum steady-state blood concentrations of isotretinoin were 160 ng/mL in 10
patients receiving 40 mg twice daily doses. After single and multiple doses, the mean ratio of
areas under the curves of 4-oxo-isotretinoin to isotretinoin was between 3 and 3.5.
Excretion: The mean terminal elimination half-life of isotretinoin in patients with acne has a
mean value of 19 hours. Following oral administration of 14C-isotretinoin, 14C activity in blood
declined with a mean half-life of 90 hours. Approximately equal amounts of radioactivity were
recovered in the urine and feces, with 65-83% of the dose recovered.
Special Populations and Conditions
Pediatrics: The pharmacokinetics of isotretinoin were evaluated after single and multiple doses
in 38 pediatric patients (12 to 15 years) and 19 adult patients ( 18 years) who received
isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxoisotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The
dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses
are summarized in Table 1 for pediatric patients. There were no statistically significant
differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.
Table 1
Pharmacokinetic Parameters of Isotretinoin Following Single and
Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age
Mean (± SD), N=38*
Parameter
Cmax (ng/mL)
AUC(0-12) (ng·hr/mL)
AUC(0-24) (ng·hr/mL)
Tmax (hr)†
CSSmin (ng/mL)
T1/2 (hr)
CL/F (L/hr)
Isotretinoin
(Single Dose)
573.25 (278.79)
3033.37 (1394.17)
6003.81 (2885.67)
6.00 (1.00-24.60)
—
—
—
Isotretinoin
(Steady-State)
731.98 (361.86)
5082.00 (2184.23)
—
4.00 (0-12.00)
352.32 (184.44)
15.69 (5.12)
17.96 (6.27)
*The single and multiple dose data in this table were obtained following a non-standardized meal (non-high-fat
meal).
†Median (range)
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin
and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The
accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
23
STORAGE AND STABILITY
CLARUS® (isotretinoin) 10 mg and 40 mg capsules: Store at controlled room temperature (15°C
to 30°C). Store in the original package. Protect from exposure to heat and light.
Keep in a safe place out of the reach of children.
SPECIAL HANDLING INSTRUCTIONS
The release of pharmaceuticals in the environment should be minimized. Medicines should not
be disposed of via wastewater and disposal through household waste should be avoided.
Use established “collection systems” if available in your location.
Return any unused CLARUS® (isotretinoin) capsules to the pharmacist.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Composition:
10 mg capsules:
An oval capsule with a yellow to orange paste fill and a reddish brown
opaque gelatin shell, printed with black ink “I” logo on one side.
Non-medicinal ingredients (alphabetical order): Ammonium
hydroxide, beeswax yellow, gelatin, glycerin, hydrogenated vegetable
oil, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol,
red iron oxide, soybean oil, synthetic black iron oxide, lecithin,
medium chain triglyceride, isopropyl alcohol, SDA 35A alcohol.
40 mg capsules:
An oval capsule with a yellow to orange paste fill and an orange
brown opaque gelatin shell, printed with black ink “I 40” logo on one
side.
Non-medicinal ingredients (alphabetical order): Ammonium
hydroxide, beeswax yellow, gelatin, glycerin, hydrogenated vegetable
oil, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol,
red iron oxide, soybean oil, synthetic black iron oxide, titanium
dioxide, yellow iron oxide, lecithin, medium chain triglyceride,
isopropyl alcohol, SDA 35A alcohol.
Availability:
CLARUS® 10 mg and 40 mg capsules are available in blister packages of 30 capsules.
24
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name:
Isotretinoin
Chemical Name:
3-7-dimethyl-9-(2,6,6-trimethyl-1-cyclo-hexen-1-yl)-2,4,6,8nonatetraenoic acid
Molecular Formula:
C20H28O2
Molecular Weight:
300.44 g/mol
Structural Formula:
Physiochemical
properties:
Orange crystalline powder, insoluble in water; soluble in chloroform
(10g / 100 mL). Melting point approximately 175°C; pKa
approximately 4.
CLINICAL TRIALS
Comparative Bioavailability
A blinded, randomized, single-dose, 2-way crossover, relative bioavailability study was
conducted in healthy volunteers to compare CLARUS® 40 mg soft gelatin capsules and
AccutaneTM Roche® 40 mg soft gelatin capsules under fed conditions. The pharmacokinetic data
is summarized below.
25
Summary Table of the Comparative Bioavailability Data for Single Dose Fed Study
Parameter
AUCT (ng.h/ml)
AUCINF
(ng.h/ml)
CMAX
(ng/ml)
TMAX *
(h)
T1/2 *
(h)
Test*
10228.66
Isotretinoin
(2 x 40 mg)
From measured data
Geometric Mean
Arithmetic Mean (CV%)
Reference†
% Ratio of
Geometric Means
11257.18
90.9%
95% Confidence
Interval
87.3%-94.6%
10397.5 (18.0%)
10591.93
11455.8(18.5%)
11647.46
90.9%
87.4%-94.6%
10772.1 (18.2%)
1134.17
11856.6 (18.7%)
1260.06
90.0%
81.7%-99.2%
1221.5 (36.5%)
4.406 (36.8%)
1374.81 (38.6%)
5.129 (60.1%)
15.75 (16.9%)
15.55 (18.7%)
*CLARUS® soft gelatine capsules manufactured by Mylan Pharmaceuticals ULC, Etobicoke, Canada
† AccutaneTM Roche® soft gelatin capsules manufactured by Hoffmann-LaRoche Limited/Limitée (Canada) were
purchased in Canada.
* Expressed as arithmetic mean (CV%) only.
A blinded, randomized, single-dose, 2-way crossover, relative bioavailability study was
conducted in healthy volunteers to compare CLARUS 40 mg soft gelatin capsules and
AccutaneTM Roche® 40 mg soft gelatin capsules under fasting conditions. The pharmacokinetic
data is summarized below.
26
Summary Table of the Comparative Bioavailability Data for Single Dose Fasted Study
Parameter
AUCT (ng.h/ml)
AUCINF
(ng.h/ml)
CMAX
(ng/ml)
TMAX *
(h)
T1/2 *
(h)
Test*
4247.97
Isotretinoin
(2 x 40 mg)
From measured data
Geometric Mean
Arithmetic Mean (CV%)
Reference†
% Ratio of
Geometric Means
4412.22
96.3%
95% Confidence
Interval
86.3%-107.5%
4481.4 (33.7%)
4567.88
4636.2 (3 1.2%)
4819.48
94.8%
85.5%-105.1%
4812.5 (33.2%)
390.98
5037.7 (30.2%)
386.46
101.2%
90.6%-113.0%
407.35 (27.4%)
3.892 (103.0%)
407.63 (32.4%)
3.208 (51.8%)
20.06 (21.3%)
20.76 (40.9%)
*CLARUS® soft gelatine capsules manufactured by Mylan Pharmaceuticals ULC, Etobicoke, Canada
† AccutaneTM Roche® soft gelatin capsules manufactured by Hoffmann-LaRoche
Limited/Limitée (Canada) were purchased in Canada.
* Expressed as arithmetic mean (CV%) only.
DETAILED PHARMACOLOGY
Isotretinoin exerts a specific action on the sebaceous glands of the hamster flank organs.
Subcutaneous administration of isotretinoin to female hamsters treated simultaneously with
testosterone enanthate prevents the androgen-induced growth of flank organ sebaceous glands
without affecting other androgen dependent cells (i.e. does not inhibit development of pigment or
larger hair follicles).
Doses up to 300 mg/kg orally of isotretinoin have no effect upon circulation and respiratory
parameters in the anesthetized cat. A dose of 1 g/kg results in respiratory stimulation and a slight
decrease in blood pressure, pulse rate, blood flow to the extremities as well as oxygen saturation.
27
TOXICOLOGY
Acute Toxicity Studies:
Animal
mouse
mouse
rat
rat
rabbit
Route
oral
intraperitoneal
oral
intraperitoneal
oral
LD50
3,389 mg/kg
904 mg/kg
> 4,000 mg/kg
901 mg/kg
approx. 1,960 mg/kg
Observation Period
-10, 20 days
14 days
10, 20 days
14 days
(Signs and symptoms: sedation and respiratory depression)
Pyramiding doses of 4.8, 13.1, 41.2 and 79.8 mg/kg of isotretinoin were administered to dogs.
All dogs survived. Diarrhea occurred in dogs treated with doses of 13.1 mg/kg or higher.
Long-Term Toxicity Studies:
55-week Oral Toxicity - Dog
In a 55-week toxicity study conducted in beagle dogs (9/sex/group), isotretinoin was
administered as a dietary admix at doses of 3, 20 or 120 mg/kg/day. Severe toxicity developed in
the high-dose group and administration was stopped at the end of week 4. Isotretinoin was
restarted in this group at the end of 12 weeks, but at a reduced dosage of 60 mg/kg/day. After 7
weeks, administration again had to be stopped for 6 weeks. Administration continued
uninterrupted until week 30. Thereafter, the high-dose group was maintained on a cycle of 2
weeks no treatment followed by 6 weeks of treatment with 60 mg/kg/day.
In the high-dose group (60/120 mg/kg/day), the following toxic manifestations were observed:
weight loss, skin lesions, visible blood in feces, ophthalmological changes (epiphora, superficial
punctate corneal opacities in the subepithelial stroma, vascularization of the subepithelial corneal
stroma and congestion or hyperemia of the palpebral and/or bulbar conjunctiva), decreases in
hematocrit and hemoglobin, decreased mean serum glucose levels, slight alterations in mean
serum transaminase activity, elevations in mean serum alkaline phosphatase activity, and
qualitative albuminuria.
Most clinical signs of toxicity disappeared or diminished when isotretinoin was withdrawn and
reappeared when treatment was reactivated. Pathological changes in the high-dose group
included: increased incidence of focal gross lesions in the gastrointestinal tract, testicular atrophy
with evidence of spermatogenic arrest, increased mean liver weight, microscopic evidence for
edema and/or erythrophago-cytosis of the lymph nodes, encephalomalacia limited to single
microscopic foci in the brain of two dogs, and degeneration of elastic fibre in four dogs.
Many of the clinical and pathological signs, except for weight loss and corneal opacities, seen in
the high dosage group were also evident in the dogs treated with 20 mg/kg/day. However, a
tendency towards a decreased frequency and a longer time to first appearance than in the highdose group was noted.
28
The low dosage (3 mg/kg/day) was well tolerated, but microscopic changes in the lymph nodes
were observed in the same number of dogs as was recorded for the mid-dose group.
Two-year Oral Toxicity - Rat
Isotretinoin was administered to rats (80/sex/group) as a dietary admix for two years. All groups
received 1 mg/kg/day for 13 weeks in order to avoid excessive bone fractures during the major
period of growth. Thereafter, doses of 2, 8 and 32 mg/kg/day were administered. In the highdose group, administration of drug was discontinued during weeks 29-41 and 67-73 due to long
bone fracture.
All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after
withdrawal of isotretinoin. Even experimental animals in a poor general state had largely
recovered within 1-2 weeks.
32 mg/kg/day
Upon completion of the study, the following clinical and laboratory findings were observed in
the high dose group: increased mortality, decreased body weight gain and food consumption;
altered gait (related to possible long bone fracture); decreased hemoglobin and hematocrit;
elevated serum alkaline phosphatase, serum triglycerides, serum phosphate, and serum urea
nitrogen; exacerbated age- and sialodacryoadenitis (SDA) virus-related eye changes; skin
lesions; some increased organ weights. The following histopathological findings were noted:
reduplication of small bile ducts; focal fibrosis and focal chronic inflammation of the heart; focal
dilation of renal tubules and focal chronic inflammation of the kidney; adrenal medullary lesions
(hyperplasia and pheochromocytomas); arteritis; calcification of arteries; focal calcification in
tissues; focal osteolysis of bone.
8 mg/kg/day
When isotretinoin was administered to rats at 8 mg/kg/day as a dietary admix for two years, the
clinical and laboratory findings were: increased mortality; decreased body weight gain;
decreased hemoglobin and hematocrit; elevated serum alkaline phosphatase and serum
triglycerides; exacerbated age- and SDA virus-related eye changes; skin lesions; some increased
organ weights. The histopathological findings were: reduplication of small bile ducts; focal
fibrosis and focal chronic inflammation in the heart; renal tubular dilation and focal chronic
inflammation in the kidney; adrenal medullary lesions (hyperplasia and pheochromocytomas);
arteritis; calcification of arteries; focal calcification in tissues; focal osteolysis of bone.
2 mg/kg/day
When isotretinoin was administered to rats at 2 mg/kg/day as a dietary admix for two years, the
clinical and laboratory findings were: elevated serum alkaline phosphatase values, some
increased organ weights. The histopathological findings were: reduplication of small bile ducts;
increased focal chronic inflammation of the kidneys; arteritis; calcification of arteries; focal
calcification in tissues.
Although an increased incidence of pheochromocytomas and adrenal medullary hyperplasia were
observed at the high and mid doses, no increase was observed at the low dose. It is very likely
29
that this increase in number of adrenal medullary proliferative lesions was mediated by an effect
upon hormonal status in rats that were already hormonally abnormal because of their genetic
origin and overfeeding, as well as other aspects of the environment of laboratory rats. Doserelated decreases in the incidence of liver adenomas and angiomas in male rats and leukemia in
female rats were also noted.
Reproduction and Teratology Studies:
Like other Vitamin A derivatives, isotretinoin has been shown in animal experiments to be
teratogenic and embryotoxic; however, there is a large species variation in the teratogenic effect.
Rats have been reported to be less sensitive to the teratogenic effects of isotretinoin; whereas,
humans have been reported to be the most sensitive. Differences in sensitivity are a result of
interspecies differences in the pharmacokinetics and placental transfer of isotretinoin.
The following table provides the low dose (mg/kg) reported to elicit teratogenesis in animal
models.
Species
Mouse/rat
Rabbit
Monkey
Human
Low dose to elicit teratogenic effect
75-150 mg/kg
10 mg/kg
2.5-5 mg/kg
0.4-1 mg/kg
Fertility and General Reproductive Performance
Rat
Isotretinoin at doses of 2, 8 or 32 mg/kg/day was administered orally to male rats for 63 days
prior to mating and through the mating period and to females for 14 days prior to mating and
through day 13 of gestation or day 21 of gestation or day 21 of lactation. No adverse effects on
fertility and general reproductive performance were observed except for a slight reduction in the
weight of weanlings in the high-dose group.
Teratology - Rat
A teratology study was conducted in rats with 5, 15 or 50 mg/kg/day of isotretinoin administered
orally on gestation days 7 through 15. Doses of up to 50 mg/kg/day of isotretinoin were found to
be non-teratogenic. In an earlier study a dose of 150 mg/kg/day was observed to be teratogenic.
Teratology - Rabbit
New Zealand white rabbits were administered isotretinoin at doses of 1, 3 or 10 mg/kg/day on
days 7 through 18 of gestation. No teratogenic or embryotoxic effects were observed at 1 and 3
mg/kg/day. At 10 mg/kg/day, 9/13 does aborted and teratogenicity and embryotoxicity were
observed in the remaining four litters.
Perinatal and Postnatal Evaluation - Rat
Rats were administered isotretinoin at doses of 5, 15 or 32 mg/kg/day orally from gestation day
14 through day 21 of lactation. Increased pup mortality, considered secondary to reduced
maternal food intake, was noted in all treated groups and particularly in the high-dose group.
30
Body weight development of pups was impaired significantly in the high-dose group. Similarly,
this effect was considered due to a reduced food intake by the dams.
Mutagenicity Testing
Isotretinoin was non-mutagenic in the Ames Test at concentrations up to 2 mg per plate in the
absence or presence of metabolic activation. Isotretinoin has not been shown to be mutagenic or
carcinogenic in in vitro or in vivo animal tests, respectively.
31
REFERENCES
1. Blackman HJ, Peck GL, Olsen TG, Bergsma DR. Blepharoconjunctivitis: a side effect of oral
13-cis retinoic acid therapy for dermatologic diseases. Ophthalmology 1979;86:753-8.
2. Colburn WA, Gibson DM. Isotretinoin kinetics after 80 to 320 mg oral doses. Clin
Pharmacol Ther 1985;37:411-4.
3. Clamon G, et al. Phase I study and pharmacokinetics of weekly high-dose 13-cis-retinoic
acid. Cancer Res 1985;45:1874-8.
4. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic
acid). Arch Dermatol 1980; 116:951-2.
5. Dicken CH. Retinoids: A review. J Am Acad Dermatol 1984; 11:541-52.
6. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with
13-cis-retinoic acid. Evaluation of sebum production and the clinical response in a multipledose trial. J Am Acad Dermatol 1980;3:602-11.
7. Jones H, Blanc D, Cunliffe WJ. 13-cis retinoic acid and acne. Lancet 1980;2:1048-9.
8. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral
isotretinoin in disorders of keratinization. Arch Dermatol 1980;116:1369-72.
9. Peck GL, Olsen TG, Yoder FW, Strauss JS, Downing DT, Pandya M, Butkus D, and ArnaudBattandier J. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N
Engl J Med 1979;300:329-33.
10. Plewig G, Nagner A, Nikoloski J, Landtholen M. Effects of two retinoids in animal
experiments and after clinical application in acne patients: 13-cis-retinoic acid Ro 4-3780 and
aromatic retinoid Ro 10-9359. In: Orfanos CE et al, eds. Retinoids:
advances in basic research and therapy. Berlin:Springer-Verlag, 1980:219-35.
11. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne
classification. J Am Acad Dermatol 1991;24:495-500.
12. Shalita AR, Cunningham WJ, Leyden JL, Pochi PE, Strauss JS. Isotretinoin treatment of acne
and related disorders: An update. J Am Acad Dermatol 1983;4:629-38.
13. Strauss JS, Stranieri AM, Farrell LM, Downing DT. The effect of marked inhibition of
sebum production with 13-cis-retinoic acid on skin surface lipid composition. J Invest
Dermatol 1980;74:66-7.
32
14. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Isotretinoin: a review of its
pharmacological properties and therapeutic efficacy in acne and other skin disorders. Drugs
1984;28:6-37.
15. AccutaneTM Roche® Product Monograph, Control No. 164918 (Revision Date: August 16,
2013).
33
IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION
Pr
CLARUS®
(Isotretinoin Capsules, USP)

This leaflet is part III of a three-part “Product
Monograph” published when CLARUS® was
approved for sale in Canada and is designed
specifically for Consumers. This leaflet is a summary
and will not tell you everything about CLARUS ®.
Contact your doctor or pharmacist if you have any
questions about the drug.

Read this Consumer Information every time you get a
prescription or a refill for CLARUS®. There may be new
information. This information does not take the place of
talking with your doctor.


Do not breast feed while taking CLARUS® and for 1
month after stopping CLARUS®. Isotretinoin may
pass through your milk and harm the baby.
Do not take tetracyclines with CLARUS®. For
some antibiotics, you may have to stop taking
CLARUS® until the antibiotic treatment is finished.
Use of tetracyclines with isotretinoin together can
increase the chances of getting increased pressure in
the brain. Certain antibiotics interfere with the
effectiveness of birth control pills.
Do not take Vitamin A supplements. Vitamin A in
high doses has many of the same side effects as
isotretinoin. Taking both together may increase your
chance of getting side effects.
Do not take CLARUS® if you have liver or kidney
disease.
Do not take CLARUS® if you have high blood fat
(lipid) levels.
Do not take CLARUS® if you are sensitive to
retinoids, or hydrogenated soybean oil, parabens,
partially hydrogenated soybean oil, soybean oil, or
any other non-medicinal ingredient listed under:
“What the non-medicinal ingredients are:”
ABOUT THIS MEDICATION
What the medication is used for:
CLARUS® is a medicine used to treat severe acne
(nodular and or inflammatory acne) that cannot be cleared
up by other acne treatments, including antibiotics.

What it does:
 The mechanism of action of isotretinoin is not
known. It is believed to act on the sebaceous glands
(oil/wax producing glands) to reduce sebum
excretion. This may indirectly reduce bacterial
activity associated with acne and improve the
condition.
 CLARUS® contains the active ingredient isotretinoin.
This is a vitamin A derivative, belonging to the
retinoid class of medicines. Retinoids are normally
used to treat skin problems.
 During the first few weeks of treatment, your acne
may seem to get worse. Redness and itching of the
affected skin are common initial effects. These
should disappear as you continue to take isotretinoin.
Most often, the first signs of healing occur after two
to three weeks of treatment. It may take one to two
months before beneficial effects are seen. Most
patients with severe acne notice a marked
improvement after one or two courses of treatment
with isotretinoin.
What the medicinal ingredient is:
isotretinoin.
What the non-medicinal ingredients are:
CLARUS® 10 mg capsules:
Ammonium hydroxide, beeswax yellow, gelatin,
glycerine, hydrogenated vegetable oil, polyethylene
glycol, polyvinyl acetate phthalate, propylene glycol,
red iron oxide, soybean oil, synthetic black iron
oxide, lecithin, medium chain triglyceride, isopropyl
alcohol and SDA 35A alcohol.
CLARUS® 40 mg capsules:
Ammonium hydroxide, beeswax yellow, gelatin,
glycerine, hydrogenated vegetable oil, polyethylene
glycol, polyvinyl acetate phthalate, propylene glycol,
red iron oxide, soybean oil, synthetic black iron
oxide, titanium dioxide, yellow iron oxide, lecithin,
medium chain triglyceride, isopropyl alcohol and
SDA 35A alcohol.
What dosage forms it comes in:
CLARUS® capsules 10 mg and 40 mg are available in
blister packages of 30 capsules.
When it should not be used:
 Do not use if pregnant
 Do not get pregnant while taking CLARUS® and
stop taking immediately if you do get pregnant
(See SERIOUS WARNINGS AND
PRECAUTIONS)
WARNINGS AND PRECAUTIONS
CLARUS® can cause serious side effects. Before starting
CLARUS®, discuss with your doctor how bad your acne
is, the possible benefits of CLARUS®, and its possible
34
IMPORTANT: PLEASE READ

side effects, to decide if CLARUS® is right for you. Your
doctor will ask you to read and sign a form indicating you
understand some of the serious risks of CLARUS®.
Possible serious side effects of taking CLARUS®
include birth defects and mental health problems.
Serious Warnings and Precautions

All patients must sign the informed consent form
prior to initiating therapy.

All Females: Birth defects:
Isotretinoin can cause birth defects (deformed babies).
It can also cause miscarriage, premature birth, or death of
the baby. Therefore, adequate birth control measures are
essential when taking CLARUS®. See “What are the
important warnings for females taking CLARUS®?”
All Patients:
Mental health problems and suicide:
Some patients, while taking isotretinoin or soon after
stopping isotretinoin, have become depressed or developed
other serious mental health problems. Signs of these
problems include feelings of sadness, irritability, unusual
tiredness, trouble concentrating, and loss of appetite. Some
patients taking isotretinoin have had thoughts about putting
an end to their own lives (suicidal thoughts), tried to end
their own lives, and some people have ended their own
lives. There were reports that some of these people did not
appear depressed. There have been reports of patients on
isotretinoin becoming aggressive or violent.
No one knows if isotretinoin caused these behaviors or if
they would have happened even if the person did not take
isotretinoin.
For other possible serious side effects of CLARUS®, see:
“Serious Side Effects and What to do About Them”
table.




There have been reports of serious skin reactions
occurring with the use of isotretinoin, such as erythema
multiforme (EM), Stevens-Johnson Syndrome (SJS) and
toxic epidermal necrolysis (TEN) which can result in
hospitalization, disability and/or death.

Stop using CLARUS® and call your doctor immediately if
you develop a serious skin reaction with symptoms such
as blisters, peeling skin, severe red/purple rash, multiple
lesions and sores, particularly in your mouth, nose, eyes
and genitals, as well as facial and tongue swelling.
What are the important warnings for females taking
CLARUS®?
 Do not take CLARUS® if you are pregnant
 If you become pregnant, stop taking CLARUS®
and contact your doctor immediately

Isotretinoin can cause deformed babies. There is
an extremely high risk that your baby will be
deformed if you are pregnant while taking
isotretinoin. This risk exists even if CLARUS ® is
taken for a short time. If you are a female of
childbearing potential, your physician should have
discussed this risk with you, and explained how to
avoid becoming pregnant while taking CLARUS®.
You must avoid becoming pregnant while you are
taking CLARUS® and for at least one month after
you stop taking CLARUS®.
You must discuss effective birth control with your
doctor before beginning CLARUS® treatment,
and you must use effective birth control:
 For at least one month before you start
CLARUS®
 While you are taking CLARUS®; and
 For at least one month after you stop taking
CLARUS®;
Bearing in mind that any method of birth control
can fail.
It is recommended that you either abstain from
sexual intercourse or use two reliable methods of
birth control at the same time, even if you have a
history of infertility or are not sexually active.
Do not take CLARUS® until you are sure that you
are not pregnant.
You must have two negative pregnancy tests, one
of them must be done in a lab, before you start
CLARUS®, and be assessed on a monthly basis
while on the drug and one month after the
termination of CLARUS®. If your menstrual
period is abnormal in length and intensity, first
contact your doctor. (see the CLARUS®
CLEARTM program)
You must wait until the second or third day of
your next normal menstrual period before you
start CLARUS®.
Stop taking CLARUS® and contact your doctor
immediately if you do become pregnant while
taking CLARUS® or during the first month after
treatment has stopped, if you miss your period, or
if you have sexual intercourse without using
effective birth control. You should discuss with
your doctor the serious risk of your baby having
severe birth deformities because you are taking or
have taken CLARUS®. You should also discuss
the desirability of continuing with your
pregnancy.
Do not breast feed while taking CLARUS®.
You should have been counseled using the manufacturer’s
CLEARTM program which includes:
35

Comprehensive information about the risks of this
 Tell your doctor if you or someone in your family has
drug
ever had any mental illness, including depression,
READbehaviour, or psychosis. Psychosis means a
 A line drawing of a deformed baby IMPORTANT: PLEASEsuicidal
loss of contact with reality, such as hearing voices or
 A checklist of criteria you had to meet before
seeing things that are not there. Also, you should tell
receiving this drug
your doctor if you are taking medicines for any of
 Detailed information on birth control options
these problems.
 A chart: “CLARUS® CLEARTM program”
 Tell your doctor if you or any member of your family
 An informed consent for you to review and sign. A
have liver disease, kidney disease, heart disease or
high cholesterol or, diabetes or asthma.
copy of this form should be given to you by your
 Tell your doctor if you plan vigorous physical
doctor.
activity during treatment with CLARUS®.
 Tell your doctor if you have any food or drug
Please note that the manufacturer of CLARUS ® provides
allergies.
confidential contraception counseling (from a health care
 Tell your doctor if you are taking any vitamin
professional). For more information, please contact Mylan
preparations or health food supplements that contain
Pharmaceuticals ULC.
Vitamin A.
 Tell your doctor the brand of contraceptives you are
TM
If you were not counseled using the CLEAR Program,
taking. There are certain types of contraceptives that
please contact your doctor for more information.
should not be taken while on CLARUS®.
 Tell your doctor if you are taking an antibiotic
ISOTRETINOIN CLEAR PLAN
(particularly tetracyclines).
What should you avoid while taking CLARUS ®?
 Do not give blood while you take CLARUS® and for
1 month after stopping CLARUS®. If someone who
is pregnant gets your donated blood, her baby may be
exposed to isotretinoin and may be born with birth
defects.
 Do not have cosmetic procedures to smooth your
skin, such as waxing, dermabrasion, or laser
procedures, while you are using CLARUS® and
for at least 6 months after you stop. Isotretinoin
can increase your chance of scarring or inflammation
of the skin from these procedures. Check with your
doctor for advice about when you can have cosmetic
procedures.
 Avoid the use of artificial ultraviolet lights such as
the ones used in tanning machines and protect
yourself from excessive sunlight. Isotretinoin may
make your skin more sensitive to ultraviolet light.
When necessary, sunscreen with a high protection
factor of at least SPF 15 should be used
 Avoid the use of exfoliative anti-acne agents
 Do not share CLARUS® with other people. It can
cause birth defects and other serious health problems.
 Do not take Vitamin A
 Do not take antibiotics unless you have discussed
with your doctor. See “When it should not be
used”
For more information regarding the CLEARTM plan and CLARUS®,
please call the toll free number: 1-877-776-7711.
All patients should read the rest of this Consumer
Information.
Do not take CLARUS® unless you completely
understand its possible risks and are willing to follow
all of the instructions in this Consumer Information.

What should you tell your doctor before starting
CLARUS®?
36
INTERACTIONS WITH THIS MEDICATION
Do not use low dose birth control pills. They may
not work while you take CLARUS®.

of the following signs and symptoms, listed in the
The following medications may interact with
table below:
isotretinoin or isotretinoin may interfere with the
IMPORTANT: PLEASE READ
actions of: low-dose contraceptives, antibiotics,
corticosteroids, phenytoin, and natural health
SERIOUS SIDE EFFECTS AND WHAT TO DO
products such as herbs (i.e., St. John’s Wort)
ABOUT THEM
Effect
Symptom
PROPER USE OF THIS MEDICATION
If you are of child bearing age, your doctor will limit
Talk with
your doctor
or pharmacist
Only
if
severe
your
CLARUS® prescription to 30 days, so that continued
treatment will require a new prescription.
Signs of
mental
health
problems
such as
Usual dose:
 Read your prescription label carefully and be sure to
take the exact amount of medicine prescribed by your
doctor. Your doctor may change your prescribed dose
from time to time, therefore, it is important that you
check the label each time you fill your CLARUS®
prescription. If you have any questions, call your
doctor.
 Take CLARUS® with food or just after a meal.
 Be sure to return to your doctor as scheduled. It is
important for your doctor to see you regularly, every
month, when you are taking CLARUS®. Blood tests
and other tests allow your doctor to check your
response to CLARUS®. Discuss your progress and
any concerns with your doctor.
depression or
psychosis (a
severe mental
disturbance)
 changes in
your mood
such as
becoming
depressed,
feeling sad,
or having
crying spell
 losing
interest in
your usual
activities
 changes in
your normal
Overdose:
sleep
In case of drug overdose, contact a health care practitioner,
hospital emergency department or regional Poison Control
Centre immediately, even if there are no symptoms.
patterns
 becoming
more
Missed Dose:
If you forget to take a dose of CLARUS® it may be taken
later the same day, but, do not take more CLARUS® in
one day than your doctor has prescribed. Do not double
dose.
irritable or
SIDE EFFECTS AND WHAT TO DO ABOUT
THEM
Serious side effects you must immediately tell your
doctor about:
example,
aggressive
than usual
(for
temper
outbursts,
thoughts of
CLARUS® may cause serious side effects. Stop
violence)
taking CLARUS and call you your doctor right away
 losing your
if you or a family member notices that you have any
appetite,
®
becoming
unusually
37
In
all
cases
Stop
taking
drug and
seek
immediate
medical
assistance
√
SERIOUS SIDE EFFECTS AND WHAT TO DO
ABOUT THEM
SERIOUS SIDE EFFECTS AND WHAT TO DO
ABOUT THEM
Effect
Effect
Symptom
Talk with
your doctor
or pharmacist
Only
if
severe
In
all
cases
Stop
taking
drug and
seek
immediate
medical
assistance
tired

aches or
or joints, back
concentratin
pain, or
g
difficulty in
 withdrawing
√
moving, muscle
from family
 having
In
all
cases
Stop
taking
drug and
seek
immediate
medical
assistance
pains in bones
trouble
and friends
Talk with
your doctor
or pharmacist
Only
if
severe
Signs of Bone
and Muscle
Changes
 having
Symptom
pain, especially
IMPORTANT: PLEASE READ after vigorous
exercise
thoughts

muscle
about taking
weakness
your own life
with or without
(suicidal
pain can be a
thoughts)
sign of serious
muscle
Your doctor
damage
may
recommend a
Tell a
consultation
healthcare
with a
provider you
specialist if you
are taking
become
CLARUS® if
depressed or
you break a
experience
bone.
these changes
Signs of
hypersensitivty
(allergic)
reactions
in mood.
Signs of
inflammation
of
the liver,
pancreas or
intestine
(bowel)

severe
√
 hives,
swollen
face or mouth,
stomach pain,
trouble
diarrhea, rectal
breathing,
bleeding;
fever, rash, red
yellowing of the
patches,
skin or eyes
bruises
and/or dark
urine.
In some
38
√
SERIOUS SIDE EFFECTS AND WHAT TO DO
ABOUT THEM
SERIOUS SIDE EFFECTS AND WHAT TO DO
ABOUT THEM
Effect
Effect
Symptom
Talk with
your doctor
or pharmacist
Only
if
severe
In
all
cases
Stop
taking
drug and
seek
immediate
medical
assistance
Symptom
Talk with
your doctor
or pharmacist
Only
if
severe
patients a rash
night,
can be serious
decreased
these include;
night vision
In
all
cases
Stop
taking
drug and
seek
immediate
medical
assistance
may occur
 conjunctivitis
suddenly in
(red or
some patients
inflamed eyes,
(take caution
like “pink
when driving at
eye”), a rash
night),
with fever,
persistent
blisters on legs,
feelings of dry
arms or face
eyes
and/or sores in
Signs of heart
problems
your mouth,
vascular
eyes, or if your
thrombotic
skin begins to
disease,

bad
stroke,
√
leg swelling,
headaches,
seizures
blurred vision,
(convulsions),
dizziness,
slurred speech,
nausea,
problems
vomiting,
moving or any
seizures
other serious
(convulsions)
unusual
and stroke.
Signs of
hearing
and vision
differences

changes in
problems.
√
Signs of
problems with
blood sugar
levels
your hearing or
ringing in your
ears

√
palpitations,
throat, nose,
peel.
Signs of
increased
pressure in the
brain
 chest pain,

fainting,
become very
thirsty,
urinating a lot,
changes in
feeling weak.
your vision
especially at
39
√
It is recommended that CLARUS® not be disposed of in
household waste or waste water. Please return any unused
CLARUS® to the pharmacist or use an established
“collection system” if available in your location.
CLARUS® may affect blood fat, cholesterol, or sugar
levels. Therefore it is important for you to see your
doctor at regularly scheduled visits.
What are the other possible side effects of isotretinoin?
It is important to watch for the symptoms listed in the
table above as these may be signs of serious side
effects.
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions associated
with the use of health products to the Canada Vigilance
Program by one of the following 3 ways:
-----------------------------------------------------------------------
Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form and:
- Fax toll-free to 1-866-678-6789, or
- Mail to:
Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, Ontario
K1A 0K9
The side effects listed below are generally temporary and
disappear when isotretinoin treatment is stopped;
however, you must tell your doctor if any of your side
effects do not clear up in a few weeks after you stop
taking isotretinoin. You must also check with your
doctor, if these effects become bothersome, to see if
any change in your medication is needed.
 Some of the most common side effects are: dryness
of the skin, lips, mouth, and lining of the nose. It is
recommended that you use a skin-moisturizing
ointment or cream and a lip balm from the start of
treatment of CLARUS®.
 Some other side effects that may occur include: facial
or body rash, flaking of the skin, itching, peeling of
the palms and soles, increased sensitivity to the sun,
sunburn, inflammation of the lips, mild nose bleed,
bleeding and inflammation of the gums, easily
injured skin and increased fatigue. You may
experience some redness, dryness, or irritation of the
eyes.
 If you wear contact lenses, you may find them
uncomfortable during treatment because isotretinoin
may cause dry eyes. This may continue after
treatment has stopped. Dry eyes can be helped by
applying a lubricating eye ointment or tear
replacement therapy.
 In some patients variable amounts of hair loss have
occurred. In rare cases, this hair loss persisted after
treatment was completed.
These are not all of the possible side effects associated
with isotretinoin. Your doctor or pharmacist can give you
more detailed information that is written for health care
TANT: PLEASE
READ
professionals.
Postage paid labels, Canada Vigilance Reporting Form and
the adverse reaction reporting guidelines are available on
the MedEffectTM”Canada Web site at
www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to the
management of side effects, contact your health professional.
The Canada Vigilance Program does not provide medical
advice.
MORE INFORMATION
This Consumer Information is only a summary of some
important information about CLARUS®. Medicines are
sometimes prescribed for purposes other than those listed
in a Consumer Information. If you have any concerns or
questions about CLARUS®, ask your doctor. Do not use
CLARUS® for a condition for which it was not
prescribed.
The full product monograph prepared for health
professionals can be found at: http://www.mylan.ca, or by
contacting Mylan Pharmaceuticals ULC at: 1-800-5751379
IMPORTANT: PLEA
HOW TO STORE IT
 Keep out of reach from children.
 CLARUS® should be stored at controlled room
temperature (15°C to 30°C). Store in the original
package. Protect from exposure to heat and light.
 CLARUS® does not need to be refrigerated.
This leaflet was prepared by Mylan Pharmaceuticals
ULC.
Last revised: November 18, 2013
CLARUS® is a registered Trade-Mark of Mylan
Pharmaceuticals ULC.
SPECIAL HANDLING INSTRUCTIONS
For more information about birth control or for
confidential counselling call the toll-free number at 1-
40
877-776-7711 or visit the CLARUS® website at
www.clarusclearprogram.ca.
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