ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Arava 10 mg film-coated tablets
2.
Each tablet contains 10 mg of leflunomide.
Excipients:
Each tablet contains 78 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to almost white, round film-coated tablet, imprinted with ZBN on one side.
4.
Leflunomide is indicated for the treatment of adult patients with:
active rheumatoid arthritis
as a "disease-modifying antirheumatic drug" (DMARD),
active psoriatic arthritis.
Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may
result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide
treatment has to be carefully considered regarding these benefit/risk aspects.
Moreover, switching from leflunomide to another DMARD without following the washout procedure
(see section 4.4) may also increase the risk of serious adverse reactions even for a long time after the
switching.
The treatment should be initiated and supervised by specialists experienced in the treatment of
rheumatoid arthritis and psoriatic arthritis.
Alanine aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood
cell count, including a differential white blood cell count and a platelet count, must be checked
simultaneously and with the same frequency:
before initiation of leflunomide,
every two weeks during the first six months of treatment, and
every 8 weeks thereafter (see section 4.4).
2
Posology
Leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days.
The recommended maintenance dose for rheumatoid arthritis is leflunomide 10 mg to 20 mg
once daily. Patients may be started on leflunomide 10 mg or 20 mg depending on the severity
(activity) of the disease.
The recommended maintenance dose for patients with psoriatic arthritis is 20 mg once daily (see
section 5.1).
The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.
There is no dose adjustment recommended in patients with mild renal insufficiency.
No dosage adjustment is required in patients above 65 years of age.
Paediatric population
Arava is not recommended for use in patients below 18 years since efficacy and safety in juvenile
rheumatoid arthritis (JRA) have not been established (see sections 5.1 and 5.2).
Administration
Arava tablets should be swallowed whole with sufficient amounts of liquid. The extent of leflunomide
absorption is not affected if it is taken with food.
Hypersensitivity to the active substance (especially previous Stevens-Johnson syndrome, toxic
epidermal necrolysis, erythema multiforme) or to any of the excipients.
Patients with impairment of liver function.
Patients with severe immunodeficiency states, e.g. AIDS.
Patients with significantly impaired bone marrow function or significant anaemia, leucopenia,
neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis.
Patients with serious infections (see section 4.4).
Patients with moderate to severe renal insufficiency, because insufficient clinical experience is
available in this patient group.
Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.
Pregnant women, or women of childbearing potential who are not using reliable contraception
during treatment with leflunomide and thereafter as long as the plasma levels of the active
metabolite are above 0.02 mg/l (see section 4.6). Pregnancy must be excluded before start of
treatment with leflunomide.
Breast-feeding women (see section 4.6).
Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not
advisable.
3
The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious
undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below),
even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if
for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to
be followed. The procedure may be repeated as clinically necessary.
For washout procedures and other recommended actions in case of desired or unintended pregnancy,
see section 4.6.
Liver reactions
Rare cases of severe liver injury, including cases with fatal outcome, have been reported during
treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co-
treatment with other hepatotoxic medicinal products was frequently present. It is considered essential
that monitoring recommendations are strictly adhered to.
ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the
complete blood cell count (every two weeks) during the first six months of treatment and every
8 weeks thereafter.
For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from
20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT)
elevations of more than 2-fold the upper limit of normal persist or if ALT elevations of more than
3-fold the upper limit of normal are present, leflunomide must be discontinued and wash-out
procedures initiated. It is recommended that monitoring of liver enzymes be maintained after
discontinuation of leflunomide treatment, until liver enzyme levels have normalised.
Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be
avoided during treatment with leflunomide.
Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic
metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients
with hypoproteinaemia. Arava is contraindicated in patients with severe hypoproteinaemia or
impairment of liver function (see section 4.3).
Haematological reactions
Together with ALT, a complete blood cell count, including differential white blood cell count and
platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first
6 months of treatment and every 8 weeks thereafter.
In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with
impaired bone marrow function or those at risk of bone marrow suppression, the risk of
haematological disorders is increased. If such effects occur, a washout (see below) to reduce plasma
levels of A771726 should be considered.
In case of severe haematological reactions, including pancytopenia, Arava and any concomitant
myelosuppressive treatment must be discontinued and a leflunomide washout procedure initiated.
Combinations with other treatments
The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive agents (with the exception of methotrexate, see section 4.5) has not been studied
up to now. The risk associated with combination therapy, in particular in long-term treatment, is
4
unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or
haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolised by
CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
Switching to other treatments
As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate)
without performing the washout procedure (see below)
may raise the possibility of additive risks even
for a long time after the switching (i.e. kinetic interaction, organ toxicity).
Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate)
may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully
be considered regarding these benefit/risk aspects
and closer monitoring is recommended in the initial
phase after switching.
Skin reactions
In case of ulcerative stomatitis, leflunomide administration should be discontinued.
Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported in
patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise
the suspicion of such severe reactions, Arava and any other possibly associated treatment must be
discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is
essential in such cases. In such cases re-exposure to leflunomide is contra-indicated (see section 4.3).
Infections
It is known that medicinal products with immunosuppressive properties - like leflunomide - may cause
patients to be more susceptible to infections, including opportunistic infections. Infections may be
more severe in nature, and may, therefore, require early and vigorous treatment. In the event that
severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and
administer a washout procedure as described below.
Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients
receiving leflunomide among other immunosuppressants.
Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis
reactivation.
Respiratory reactions
Interstitial lung disease has been reported during treatment with leflunomide (see section 4.8).
Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy.
Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy
and for further investigation, as appropriate.
Blood pressure
Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Procreation (recommendations for men)
Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception
during treatment with leflunomide should also be guaranteed.
5
There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to
evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to
father a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 times
daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.
In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the
A771726 plasma concentration must be determined again after an interval of at least 14 days. If both
plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk of
foetal toxicity is very low.
Washout procedure
Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is
administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be
modified depending on clinical or laboratory variables.
Lactose
Arava contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Interactions studies have only been performed in adults.
Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic
drugs or when leflunomide treatment is followed by such drugs without a washout period (see also
guidance concerning combination with other treatments, section 4.4).
Therefore, closer monitoring of
liver enzymes and haematological parameters is recommended in the initial phase after switching.
In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with
methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of
30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of
leflunomide. A more than 3-fold increase was seen in another 5 patients. All of these also resolved, 2
with continuation of both drugs and 3 after discontinuation of leflunomide.
In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to
20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.
It is recommended that patients receiving leflunomide are not treated with colestyramine or activated
powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the
active metabolite of leflunomide; see also section 5) concentration. The mechanism is thought to be by
interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.
If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or
corticosteroids, these may be continued after starting leflunomide.
The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. An
in vivo
interaction study with cimetidine (non-specific cytochrome P450 inhibitor) has demonstrated a
lack of a significant interaction. Following concomitant administration of a single dose of leflunomide
to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer) A771726
peak levels were increased by approximately 40%, whereas the AUC was not significantly changed.
The mechanism of this effect is unclear.
6
In vitro
studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical
trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were
co-administered. Caution is advised when leflunomide is given together with drugs, other than
NSAIDs, metabolised by CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill
containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in
contraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges.
Vaccinations
No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment.
Vaccination with live attenuated vaccines is, however, not recommended. The long half-life of
leflunomide should be considered when contemplating administration of a live attenuated vaccine after
stopping Arava.
Pregnancy
The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when
administered during pregnancy. Arava is contraindicated in pregnancy (see section 4.3).
Women of childbearing potential have to use effective contraception during and up to 2 years after
treatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washout
period” below).
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect
pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the
physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the
blood level of the active metabolite, by instituting the drug elimination procedure described below, at
the first delay of menses may decrease the risk to the foetus from leflunomide.
In a small prospective study in women (n=64) who became inadvertently pregnant while taking
leflunomide for no more than three weeks after conception and followed by a drug elimination
procedure, no significant differences (p=0.13) were observed in the overall rate of major structural
defects (5.4%) compared to either of the comparison groups (4.2% in the disease matched group
[n=108] and 4.2% in healthy pregnant women [n=78]).
For women receiving leflunomide treatment and who wish to become pregnant, one of the following
procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations
of A771726 (target concentration below 0.02 mg/l):
Waiting period
A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. The
concentration may be expected to decrease below 0.02 mg/l about 2 years after stopping the treatment
with leflunomide.
After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least
14 days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.
For further information on the sample testing please contact the Marketing Authorisation Holder or its
local representative (see section 7).
7
Washout procedure
After stopping treatment with leflunomide:
colestyramine 8 g is administered 3 times daily for a period of 11 days,
alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of
11 days.
However, also following either of the washout procedures, verification by 2 separate tests at an
interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence
of a plasma concentration below 0.02 mg/l and fertilisation is required.
Women of childbearing potential should be told that a waiting period of 2 years after treatment
discontinuation is required before they may become pregnant. If a waiting period of up to
approximately 2 years under reliable contraception is considered unpractical, prophylactic institution
of a washout procedure may be advisable.
Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and
progestogens such that reliable contraception with oral contraceptives may not be guaranteed during
the washout procedure with colestyramine or activated powdered charcoal. Use of alternative
contraceptive methods is recommended.
Lactation
Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding
women must, therefore, not receive leflunomide.
In the case of side effects such as dizziness the patient's ability to concentrate and to react properly
may be impaired. In such cases patients should refrain from driving cars and using machines.
The most frequently adverse effects reported commonly (1/100 to <1/10) with leflunomide are: mild
increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting,
oral mucosal disorders (e.g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair
loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased,
anorexia, weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver
parameters (transaminases (especially ALT), less often gamma-GT, alkaline phosphatise, bilirubin)).
Classification of expected frequencies:
Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000
to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations
Rare:
severe infections, including sepsis which may be fatal
Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to
infections, including opportunistic infections (see also section 4.4). Thus, the overall incidence of
infections can increase (in particular of rhinitis, bronchitis and pneumonia).
8
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some
immunosuppressive agents.
Blood and lymphatic system disorders
Common: leucopenia (leucocytes >2 G/l)
Uncommon: anaemia, mild thrombocytopenia (platelets <100 G/l)
Rare:
pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes
<2 G/l), eosinophilia
Very rare:
agranulocytosis
Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a
higher risk of haematological effects.
Immune system disorders
Common: mild allergic reactions
Very rare:
severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous
necrotizing vasculitis
Metabolism and nutrition disorders
Common: CPK increased
Uncommon: hypokalaemia, hyperlipidemia, hypophosphataemia
Rare: LDH increased
Not known: hypouricemia
Psychiatric disorders
Uncommon: anxiety
Nervous system disorders
Common:
paraesthesia, headache, dizziness
Very rare:
peripheral neuropathy
Cardiac disorders
Common:
mild increase in blood pressure
Rare:
severe increase in blood pressure
Respiratory, thoracic and mediastinal disorders
Rare:
interstitial lung disease (including interstitial pneumonitis), which may be fatal
Gastrointestinal disorders
Common: diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth
ulceration), abdominal pain
Uncommon: taste disturbances
Very rare:
pancreatitis
Hepatobiliary disorders
Common:
elevation of liver parameters (transaminases [especially ALT], less often gamma-GT,
alkaline phosphatase, bilirubin)
Rare:
hepatitis, jaundice/cholestasis
Very rare:
severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal
Skin and subcutaneous tissue disorders
Common: increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin
Uncommon: urticaria
Very rare:
toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
9
Musculoskeletal and connective tissue disorders
Common: tenosynovitis
Uncommon: tendon rupture
Renal and urinary disorders
Not known: renal failure
Reproductive system and breast disorders
Not known: marginal (reversible) decreases in sperm concentration, total sperm count and rapid
progressive motility
General disorders and administration site conditions
Common:
anorexia, weight loss (usually insignificant), asthenia
Symptoms
There have been reports of chronic overdose in patients taking Arava at daily doses up to five times
the recommended daily dose, and reports of acute overdose in adults and children. There were no
adverse events reported in the majority of case reports of overdose. Adverse events consistent with the
safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes,
anaemia, leucopenia, pruritus and rash.
Management
In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate
elimination. Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy
volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to
65% in 48 hours.
Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube
(50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active
metabolite A771726 by 37% in 24 hours and by 48% in 48 hours.
These washout procedures may be repeated if clinically necessary.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that
A771726, the primary metabolite of leflunomide, is not dialysable.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.
Human pharmacology
Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.
Animal pharmacology
Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and
transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/
immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory
10
properties. Leflunomide exhibits the best protective effects on animal models of autoimmune diseases
when administered in the early phase of the disease progression.
In vivo
, it is rapidly and almost completely metabolised to A771726 which is active
in vitro
, and is
presumed to be responsible for the therapeutic effect.
Mode of action
A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase
(DHODH) and exhibits antiproliferative activity.
Rheumatoid arthritis
The efficacy of Arava in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials
(1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with active
rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/day
(n=104). The treatment duration was 6 months.
All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days.
Study MN301 randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=133), sulphasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months.
Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm,
resulting in a 12-month comparison of leflunomide and sulphasalazine.
Study MN302 randomised 999 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation
was optional and only used in 10% of patients. Treatment duration was 12-months.
Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All
patients received folate 1 mg bid. Treatment duration was 12 months.
Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301
and US301) was statistically significantly superior to placebo in reducing the signs and symptoms of
rheumatoid arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology)
response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5%
for 25 mg/day. In the phase III trials, the ACR response rates for leflunomide 20 mg/day vs. placebo
were 54.6% vs. 28.6% (study MN301), and 49.4% vs. 26.3% (study US301).After 12 months with
active treatment, the ACR response rates in leflunomide patients were 52.3% (studies MN301/303),
50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/303) in
sulphasalazine patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients. In
study MN302 leflunomide was significantly less effective than methotrexate. However, in study
US301 no significant differences were observed between leflunomide and methotrexate in the primary
efficacy parameters. No difference was observed between leflunomide and sulphasalazine (study
MN301). The leflunomide treatment effect was evident by 1 month, stabilised by 3 to 6 months and
continued throughout the course of treatment.
A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two
different daily maintenance doses of leflunomide, 10 mg and 20 mg. From the results it can be
concluded that efficacy results of the 20 mg maintenance dose were more favourable, on the other
hand, the safety results favoured the 10 mg daily maintenance dose.
Paediatrics
Leflunomide was studied in a single multicenter, randomized, double-blind, active-controlled trial in
94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3–17
years of age with active polyarticular course JRA regardless of onset type and naive to methotrexate or
leflunomide. In this trial, the loading dose and maintenance dose of leflunomide was based on three
weight categories: <20 kg, 20-40 kg, and >40 kg. After 16 weeks treatment, the difference in response
11
rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement
(DOI) 30% (p=0.02). In responders, this response was maintained during 48 weeks (see section 4.2).
The pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose used
in lighter subjects resulted in a relatively low exposure (see section 5.2). These data do not allow an
effective and safe dose recommendation.
Psoriatic arthritis
The efficacy of Arava was demonstrated in one controlled, randomised, double blind study 3L01 in
188 patients with psoriatic arthritis, treated at 20 mg/day. Treatment duration was 6 months.
Leflunomide 20 mg/day was significantly superior to placebo in reducing the symptoms of arthritis in
patients with psoriatic arthritis: the PsARC (Psoriatic Arthritis treatment Response Criteria) responders
were 59% in the leflunomide group and 29.7% in the placebo group by 6 months (p<0.0001). The
effect of leflunomide on improvement of function and on reduction of skin lesions was modest.
5.2 Pharmacokinetic properties
Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring
opening) in gut wall and liver. In a study with radiolabelled
14
C-leflunomide in three healthy
volunteers, no unchanged leflunomide was detected in plasma, urine or faeces. In other studies,
unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels.
The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for
essentially all the
in vivo
activity of Arava.
Absorption
Excretion data from the
14
C study indicated that at least about 82 to 95% of the dose is absorbed. The
time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur
between 1 hour and 24 hours after single administration. Leflunomide can be administered with food,
since the extent of absorption is comparable in the fed and fasting state. Due to the very long half-life
of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies
to facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it is
estimated that attainment of steady-state plasma concentrations would require nearly two months of
dosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters
of A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect was
closely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a dose
level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately
35 µg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.
Distribution
In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of
A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range.
Binding of A771726 appeared slightly reduced and more variable in plasma from patients with
rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could
lead to displacement of other highly-bound drugs.
In vitro
plasma protein binding interaction studies
with warfarin at clinically relevant concentrations, however, showed no interaction. Similar studies
showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of
A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced ibuprofen,
diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%.
There is no indication that these effects are of clinical relevance. Consistent with extensive protein
binding A771726 has a low apparent volume of distribution (approximately 11 litres). There is
no
preferential uptake in erythrocytes.
12
Metabolism
Leflunomide is metabolised to one primary (A771726) and many minor metabolites including TFMA
(4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and
subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur
in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific
cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that
in
vivo
CYP enzymes are involved in the metabolism of leflunomide only to a small extent.
Elimination
Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The
elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose
of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in
urine. A771726 was still detectable in urine and faeces 36 days after a single administration.
The
principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to
24 hour samples) and an oxanilic acid derivative of A771726. The principal faecal component was
A771726.
It has been shown in man that administration of an oral suspension of activated powdered charcoal or
colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in
plasma concentrations (see section 4.9). This is thought to be achieved by a gastrointestinal dialysis
mechanism and/or by interrupting enterohepatic recycling.
Pharmacokinetics in renal failure
Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients
on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects
appeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed in
haemodialysis subjects which was not due to extraction of drug in the dialysate.
Pharmacokinetics in liver failure
No data are available regarding treatment of patients with hepatic impairment. The active metabolite
A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These
processes may be affected by hepatic dysfunction.
Pharmacokinetics in paediatrics
The pharmacokinetics of A771726 following oral administration of leflunomide have been
investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA)
who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these
trials have demonstrated that pediatric patients with body weights 40 kg have a reduced systemic
exposure (measured by C
ss
) of A771726 relative to adult rheumatoid arthritis patients (see section 4.2).
Pharmacokinetics in elderly
Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in
younger adults.
5.3 Preclinical safety data
Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in
mice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogs
for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs
13
for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes.
The main effects were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect
the basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz
bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea and
respiratory tract could be explained as infections due to immunosuppression. Toxicity in animals was
found at doses equivalent to human therapeutic doses.
Leflunomide was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline)
caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its
potential to exert this effect
in vivo
.
In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a
carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of the
highest dose group, considered to be due to the immunosuppressive activity of leflunomide. In female
mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of the
lung was noted. The relevance of the findings in mice relative to the clinical use of leflunomide is
uncertain.
Leflunomide was not antigenic in animal models.
Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic
range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies.
Fertility was not reduced.
6.
6.1 List of excipients
Tablet core:
Maize starch
Povidone (E1201)
Crospovidone (E1202)
Silica colloidal anhydrous
Magnesium stearate (E470b)
Lactose monohydrate
Film-coating:
Talc (E553b)
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 8000
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Blister:
Store in the original package.
Bottle:
Keep the container tightly closed.
14
6.5 Nature and content
s
of container
Blister:
Aluminium / Aluminium blister. Pack sizes: 30 and 100 film-coated tablets.
Bottle:
100 ml HDPE-wide-necked bottle, with screw cap with integrated desiccant container,
containing either 30 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
8.
MARKETING AUTHORISATION
NUMBER(S)
EU/1/99/118/001-004
9.
Date of first authorisation: 02 September 1999
Date of latest renewal: 02 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
15
1.
Arava 20 mg film-coated tablets
2.
Each tablet contains 20 mg of leflunomide.
Excipients:
Each tablet contains 72 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Yellowish to ochre and triangular film-coated tablet, imprinted with ZBO on one side.
4.
Leflunomide is indicated for the treatment of adult patients with:
active rheumatoid arthritis as a "disease-modifying antirheumatic drug" (DMARD),
active psoriatic arthritis.
Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may
result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide
treatment has to be carefully considered regarding these benefit/risk aspects.
Moreover, switching from leflunomide to another DMARD without following the washout procedure
(see section 4.4) may also increase the risk of serious adverse reactions even for a long time after the
switching.
The treatment should be initiated and supervised by specialists experienced in the treatment of
rheumatoid arthritis and psoriatic arthritis.
Alanine aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood
cell count, including a differential white blood cell count and a platelet count, must be checked
simultaneously and with the same frequency:
before initiation of leflunomide,
every two weeks during the first six months of treatment, and
every 8 weeks thereafter (see section 4.4).
16
Posology
Leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days.
The recommended maintenance dose for rheumatoid arthritis is leflunomide 10 mg to 20 mg
once daily. Patients may be started on leflunomide 10 mg or 20 mg depending on the severity
(activity) of the disease.
The recommended maintenance dose for patients with psoriatic arthritis is 20 mg once daily (see
section 5.1).
The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.
There is no dose adjustment recommended in patients with mild renal insufficiency.
No dosage adjustment is required in patients above 65 years of age.
Paediatric population
Arava is not recommended for use in patients below 18 years since efficacy and safety in juvenile
rheumatoid arthritis (JRA) have not been established (see sections 5.1 and 5.2).
Administration
Arava tablets should be swallowed whole with sufficient amounts of liquid. The extent of leflunomide
absorption is not affected if it is taken with food.
Hypersensitivity to the active substance (especially previous Stevens-Johnson syndrome, toxic
epidermal necrolysis, erythema multiforme) or to any of the excipients.
Patients with impairment of liver function.
Patients with severe immunodeficiency states, e.g. AIDS.
Patients with significantly impaired bone marrow function or significant anaemia, leucopenia,
neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis.
Patients with serious infections (see section 4.4).
Patients with moderate to severe renal insufficiency, because insufficient clinical experience is
available in this patient group.
Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.
Pregnant women, or women of childbearing potential who are not using reliable contraception during
treatment with leflunomide and thereafter as long as the plasma levels of the active metabolite are
above 0.02 mg/l (see section 4.6). Pregnancy must be excluded before start of treatment with
leflunomide.
Breast-feeding women (see section 4.6).
Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not
advisable.
17
The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious
undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below),
even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if
for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to
be followed. The procedure may be repeated as clinically necessary.
For washout procedures and other recommended actions in case of desired or unintended pregnancy,
see section 4.6.
Liver reactions
Rare cases of severe liver injury, including cases with fatal outcome, have been reported during
treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co-
treatment with other hepatotoxic medicinal products was frequently present. It is considered essential
that monitoring recommendations are strictly adhered to.
ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the
complete blood cell count (every two weeks) during the first six months of treatment and every
8 weeks thereafter.
For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from
20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT)
elevations of more than 2-fold the upper limit of normal persist or if ALT elevations of more than
3-fold the upper limit of normal are present, leflunomide must be discontinued and wash-out
procedures initiated. It is recommended that monitoring of liver enzymes be maintained after
discontinuation of leflunomide treatment, until liver enzyme levels have normalised.
Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be
avoided during treatment with leflunomide.
Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic
metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients
with hypoproteinaemia. Arava is contraindicated in patients with severe hypoproteinaemia or
impairment of liver function (see section 4.3).
Haematological reactions
Together with ALT, a complete blood cell count, including differential white blood cell count and
platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first
6 months of treatment and every 8 weeks thereafter.
In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with
impaired bone marrow function or those at risk of bone marrow suppression, the risk of
haematological disorders is increased. If such effects occur, a washout (see below) to reduce plasma
levels of A771726 should be considered.
In case of severe haematological reactions, including pancytopenia, Arava and any concomitant
myelosuppressive treatment must be discontinued and a leflunomide washout procedure initiated.
Combinations with other treatments
The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive agents (with the exception of methotrexate, see section 4.5) has not been studied
up to now. The risk associated with combination therapy, in particular in long-term treatment, is
18
unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or
haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolised by
CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
Switching to other treatments
As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate)
without performing the washout procedure (see below) may raise the possibility of additive risks even
for a long time after the switching (i.e. kinetic interaction, organ toxicity).
Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate)
may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully
be considered regarding these benefit/risk aspects
and closer monitoring is recommended in the initial
phase after switching.
Skin reactions
In case of ulcerative stomatitis, leflunomide administration should be discontinued.
Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported in
patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise
the suspicion of such severe reactions, Arava and any other possibly associated treatment must be
discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is
essential in such cases. In such cases re-exposure to leflunomide is contra-indicated (see section 4.3).
Infections
It is known that medicinal products with immunosuppressive properties - like leflunomide - may cause
patients to be more susceptible to infections, including opportunistic infections. Infections may be
more severe in natureand may, therefore, require early and vigorous treatment. In the event that severe,
uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and administer a
washout procedure as described below.
Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients
receiving leflunomide among other immunosuppressants.
Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis
reactivation.
Respiratory reactions
Interstitial lung disease has been reported during treatment with leflunomide (see section 4.8).
Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy.
Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy
and for further investigation, as appropriate.
Blood pressure
Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Procreation (recommendations for men)
Male patients should be aware of the possible male-mediated foetal toxicity Reliable contraception
during treatment with leflunomide should also be guaranteed.
19
There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to
evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to
father a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 times
daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.
In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the
A771726 plasma concentration must be determined again after an interval of at least 14 days. If both
plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk of
foetal toxicity is very low.
Washout procedure
Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is
administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be
modified depending on clinical or laboratory variables.
Lactose
Arava contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Interactions studies have only been performed in adults.
Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic
drugs or when leflunomide treatment is followed by such drugs without a washout period (see also
guidance concerning combination with other treatments, section 4.4).
Therefore, closer monitoring of
liver enzymes and haematological parameters is recommended in the initial phase after switching.
In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with
methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of
30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of
leflunomide. A more than 3-fold increase was seen in another 5 patients. All of these also resolved, 2
with continuation of both drugs and 3 after discontinuation of leflunomide.
In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to
20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.
It is recommended that patients receiving leflunomide are not treated with colestyramine or activated
powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the
active metabolite of leflunomide; see also section 5) concentration. The mechanism is thought to be by
interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.
If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or
corticosteroids, these may be continued after starting leflunomide.
The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. An
in vivo
interaction study with cimetidine (non-specific cytochrome P450 inhibitor) has demonstrated a
lack of a significant interaction. Following concomitant administration of a single dose of leflunomide
to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer) A771726
peak levels were increased by approximately 40%, whereas the AUC was not significantly changed.
The mechanism of this effect is unclear.
In vitro
studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical
trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were
20
co-administered. Caution is advised when leflunomide is given together with drugs, other than
NSAIDs, metabolised by CYP2C9 such as phenytoin, warfarin,
phenprocoumon and tolbutamide.
In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill
containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in
contraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges.
Vaccinations
No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment.
Vaccination with live attenuated vaccines is, however, not recommended. The long half-life of
leflunomide should be considered when contemplating administration of a live attenuated vaccine after
stopping Arava.
Pregnancy
The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when
administered during pregnancy. Arava is contraindicated in pregnancy (see section 4.3).
Women of childbearing potential have to use effective contraception during and up to 2 years after
treatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washout
period” below).
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect
pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the
physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the
blood level of the active metabolite, by instituting the drug elimination procedure described below, at
the first delay of menses may decrease the risk to the foetus from leflunomide.
In a small prospective study in women (n=64) who became inadvertently pregnant while taking
leflunomide for no more than three weeks after conception and followed by a drug elimination
procedure, no significant differences (p=0.13) were observed in the overall rate of major structural
defects (5.4%) compared to either of the comparison groups (4.2% in the disease matched group
[n=108] and 4.2% in healthy pregnant women [n=78]).
For women receiving leflunomide treatment and who wish to become pregnant, one of the following
procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations
of A771726 (target concentration below 0.02 mg/l):
Waiting period
A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. The
concentration may be expected to decrease below 0.02 mg/l about 2 years after stopping the treatment
with leflunomide.
After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least
14 days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.
For further information on the sample testing please contact the Marketing Authorisation Holder or its
local representative (see section 7).
21
Washout procedure
After stopping treatment with leflunomide:
colestyramine 8 g is administered 3 times daily for a period of 11 days,
alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of
11 days.
However, also following either of the washout procedures, verification by 2 separate tests at an
interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence
of a plasma concentration below 0.02 mg/l and fertilisation is required.
Women of childbearing potential should be told that a waiting period of 2 years after treatment
discontinuation is required before they may become pregnant. If a waiting period of up to
approximately 2 years under reliable contraception is considered unpractical, prophylactic institution
of a washout procedure may be advisable.
Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and
progestogens such that reliable contraception with oral contraceptives may not be guaranteed during
the washout procedure with colestyramine or activated powdered charcoal. Use of alternative
contraceptive methods is recommended.
Lactation
Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding
women must, therefore, not receive leflunomide.
In the case of side effects such as dizziness the patient's ability to concentrate and to react properly
may be impaired. In such cases patients should refrain from driving cars and using machines.
The most frequently adverse effects reported commonly (1/100 to <1/10) with leflunomide are: mild
increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting,
oral mucosal disorders (e.g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair
loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased,
anorexia, weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver
parameters (transaminases (especially ALT), less often gamma-GT, alkaline phosphatise, bilirubin)).
Classification of expected frequencies:
Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000
to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations
Rare:
severe infections, including sepsis which may be fatal.
Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to
infections, including opportunistic infections (see also section 4.4). Thus, the overall incidence of
infections can increase (in particular of rhinitis, bronchitis and pneumonia).
22
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some
immunosuppressive agents.
Blood and lymphatic system disorders
Common: leucopenia (leucocytes >2 G/l)
Uncommon: anaemia, mild thrombocytopenia (platelets <100 G/l)
Rare:
pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes
<2 G/l), eosinophilia
Very rare:
agranulocytosis
Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a
higher risk of haematological effects.
Immune system disorders
Common: mild allergic reactions
Very rare:
severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous
necrotizing vasculitis
Metabolism and nutrition disorders
Common: CPK increased
Uncommon: hypokalaemia, hyperlipidemia, hypophosphataemia
Rare: LDH increased
Not known: hypouricemia
Psychiatric disorders
Uncommon: anxiety
Nervous system disorders
Common:
paraesthesia, headache, dizziness
Very rare:
peripheral neuropathy
Cardiac disorders
Common:
mild increase in blood pressure
Rare:
severe increase in blood pressure
Respiratory, thoracic and mediastinal disorders
Rare:
interstitial lung disease (including interstitial pneumonitis), which may be fatal.
Gastrointestinal disorders
Common: diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth
ulceration), abdominal pain
Uncommon: taste disturbances
Very rare:
pancreatitis
Hepatobiliary disorders
Common:
elevation of liver parameters (transaminases [especially ALT], less often gamma-GT,
alkaline phosphatase, bilirubin)
Rare:
hepatitis, jaundice/cholestasis
Very rare:
severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal
Skin and subcutaneous tissue disorders
Common: increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin
Uncommon: urticaria
Very rare:
toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
23
Musculoskeletal and connective tissue disorders
Common: tenosynovitis
Uncommon: tendon rupture
Renal and urinary disorders
Not known: renal failure
Reproductive system and breast disorders
Not known: marginal (reversible) decreases in sperm concentration, total sperm count and rapid
progressive motility
General disorders and administration site conditions
Common:
anorexia, weight loss (usually insignificant), asthenia
Symptoms
There have been reports of chronic overdose in patients taking Arava at daily doses up to five times
the recommended daily dose, and reports of acute overdose in adults and children. There were no
adverse events reported in the majority of case reports of overdose. Adverse events consistent with the
safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes,
anaemia, leucopenia, pruritus and rash.
Management
In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate
elimination. Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy
volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to
65% in 48 hours.
Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube
(50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active
metabolite A771726 by 37% in 24 hours and by 48% in 48 hours.
These washout procedures may be repeated if clinically necessary.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that
A771726, the primary metabolite of leflunomide, is not dialysable.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.
Human pharmacology
Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.
Animal pharmacology
Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and
transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/
immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory
24
properties. Leflunomide exhibits the best protective effects on animal models of autoimmune diseases
when administered in the early phase of the disease progression.
In vivo
, it is rapidly and almost completely metabolised to A771726 which is active
in vitro
, and is
presumed to be responsible for the therapeutic effect.
Mode of action
A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase
(DHODH) and exhibits antiproliferative activity.
Rheumatoid arthritis
The efficacy of Arava in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials
(1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with active
rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/day
(n=104). The treatment duration was 6 months.
All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days.
Study MN301 randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=133), sulphasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months.
Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm,
resulting in a 12-month comparison of leflunomide and sulphasalazine.
Study MN302 randomised 999 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation
was optional and only used in 10% of patients. Treatment duration was 12-months.
Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All
patients received folate 1 mg bid. Treatment duration was 12 months.
Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301
and US301) was statistically significantly superior to placebo in reducing the signs and symptoms of
rheumatoid arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology)
response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5%
for 25 mg/day. In the phase III trials, the ACR response rates for leflunomide 20 mg/day vs. placebo
were 54.6% vs. 28.6% (study MN301), and 49.4% vs. 26.3% (study US301).After 12 months with
active treatment, the ACR response rates in leflunomide patients were 52.3% (studies MN301/303),
50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/303) in
sulphasalazine patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients. In
study MN302 leflunomide was significantly less effective than methotrexate. However, in study
US301 no significant differences were observed between leflunomide and methotrexate in the primary
efficacy parameters. No difference was observed between leflunomide and sulphasalazine (study
MN301). The leflunomide treatment effect was evident by 1 month, stabilised by 3 to 6 months and
continued throughout the course of treatment.
A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two
different daily maintenance doses of leflunomide, 10 mg and 20 mg. From the results it can be
concluded that efficacy results of the 20 mg maintenance dose were more favourable, on the other
hand, the safety results favoured the 10 mg daily maintenance dose.
Paediatrics
Leflunomide was studied in a single multicenter, randomized, double-blind, active-controlled trial in
94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3–17
years of age with active polyarticular course JRA regardless of onset type and naive to methotrexate or
leflunomide. In this trial, the loading dose and maintenance dose of leflunomide was based on three
weight categories: <20 kg, 20-40 kg, and >40 kg. After 16 weeks treatment, the difference in response
25
rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement
(DOI) 30 % (p=0.02). In responders, this response was maintained during 48 weeks (see section 4.2).
The pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose used
in lighter subjects resulted in a relatively low exposure (see section 5.2). These data do not allow an
effective and safe dose recommendation.
Psoriatic arthritis
The efficacy of Arava was demonstrated in one controlled, randomised, double blind study 3L01 in
188 patients with psoriatic arthritis, treated at 20 mg/day. Treatment duration was 6 months.
Leflunomide 20 mg/day was significantly superior to placebo in reducing the symptoms of arthritis in
patients with psoriatic arthritis: the PsARC (Psoriatic Arthritis treatment Response Criteria) responders
were 59% in the leflunomide group and 29.7% in the placebo group by 6 months (p<0.0001). The
effect of leflunomide on improvement of function and on reduction of skin lesions was modest.
5.2 Pharmacokinetic properties
Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring
opening) in gut wall and liver. In a study with radiolabelled
14
C-leflunomide in three healthy
volunteers, no unchanged leflunomide was detected in plasma, urine or faeces. In other studies,
unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels.
The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for
essentially all the
in vivo
activity of Arava.
Absorption
Excretion data from the
14
C study indicated that at least about 82 to 95% of the dose is absorbed. The
time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur
between 1 hour and 24 hours after single administration. Leflunomide can be administered with food,
since the extent of absorption is comparable in the fed and fasting state. Due to the very long half-life
of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies
to facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it is
estimated that attainment of steady-state plasma concentrations would require nearly two months of
dosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters
of A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect was
closely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a dose
level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately
35 µg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.
Distribution
In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of
A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range.
Binding of A771726 appeared slightly reduced and more variable in plasma from patients with
rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could
lead to displacement of other highly-bound drugs.
In vitro
plasma protein binding interaction studies
with warfarin at clinically relevant concentrations, however, showed no interaction. Similar studies
showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of
A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced ibuprofen,
diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%.
There is no indication that these effects are of clinical relevance. Consistent with extensive protein
binding A771726 has a low apparent volume of distribution (approximately 11 litres). There is
no
preferential uptake in erythrocytes.
26
Metabolism
Leflunomide is metabolised to one primary (A771726) and many minor metabolites including TFMA
(4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and
subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur
in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific
cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that
in
vivo
CYP enzymes are involved in the metabolism of leflunomide only to a small extent.
Elimination
Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The
elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose
of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in
urine. A771726 was still detectable in urine and faeces 36 days after a single administration.
The
principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to
24 hour samples) and an oxanilic acid derivative of A771726. The principal faecal component was
A771726.
It has been shown in man that administration of an oral suspension of activated powdered charcoal or
colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in
plasma concentrations (see section 4.9). This is thought to be achieved by a gastrointestinal dialysis
mechanism and/or by interrupting enterohepatic recycling.
Pharmacokinetics in renal failure
Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients
on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects
appeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed in
haemodialysis subjects which was not due to extraction of drug in the dialysate.
Pharmacokinetics in liver failure
No data are available regarding treatment of patients with hepatic impairment. The active metabolite
A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These
processes may be affected by hepatic dysfunction.
Pharmacokinetics in paediatrics
The pharmacokinetics of A771726 following oral administration of leflunomide have been
investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA)
who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these
trials have demonstrated that pediatric patients with body weights 40 kg have a reduced systemic
exposure (measured by C
ss
) of A771726 relative to adult rheumatoid arthritis patients (see section 4.2).
Pharmacokinetics in elderly
Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in
younger adults.
5.3 Preclinical safety data
Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in
mice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogs
for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs
27
for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes.
The main effects were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect
the basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz
bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea and
respiratory tract could be explained as infections due to immunosuppression. Toxicity in animals was
found at doses equivalent to human therapeutic doses.
Leflunomide was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline)
caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its
potential to exert this effect
in vivo
.
In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a
carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of the
highest dose group, considered to be due to the immunosuppressive activity of leflunomide. In female
mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of the
lung was noted. The relevance of the findings in mice relative to the clinical use of leflunomide is
uncertain.
Leflunomide was not antigenic in animal models.
Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic
range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies.
Fertility was not reduced.
6.
6.1 List of excipients
Tablet core:
Maize starch
Povidone (E1201)
Crospovidone (E1202)
Silica colloidal anhydrous
Magnesium stearate (E470b)
Lactose monohydrate
Film-coating:
Talc(E553b)
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 8000
Yellow ferric oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Blister:
Store in the original package.
Bottle:
Keep the container tightly closed.
28
6.5 Nature and content
s
of container
Blister:
Aluminium / Aluminium blister. Pack sizes: 30 and 100 film-coated tablets.
Bottle:
100 ml HDPE-wide-necked bottle, with screw cap with integrated desiccant container,
containing either 30, 50 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
8.
MARKETING AUTHORISATION
NUMBER(S)
EU/1/99/118/005-008
EU/1/99/118/010
9.
Date of first authorisation: 02 September 1999
Date of latest renewal: 02 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
29
1.
Arava 100 mg film-coated tablets
2.
Each tablet contains 100 mg of leflunomide.
Excipients:
Each tablet contains 138.42 mg of lactose monohydrate
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to almost white, round film-coated tablet, imprinted with ZBP on one side.
4.
Leflunomide is indicated for the treatment of adult patients with:
active rheumatoid arthritis as a "disease-modifying antirheumatic drug" (DMARD),
active psoriatic arthritis.
Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may
result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide
treatment has to be carefully considered regarding these benefit/risk aspects.
Moreover, switching from leflunomide to another DMARD without following the washout procedure
(see section 4.4) may also increase the risk of serious adverse reactions even for a long time after the
switching.
The treatment should be initiated and supervised by specialists experienced in the treatment of
rheumatoid arthritis and psoriatic arthritis.
Alanine Aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood
cell count, including a differential white blood cell count and a platelet count, must be checked
simultaneously and with the same frequency:
before initiation of leflunomide
every two weeks during the first six months of treatment, and
every 8 weeks thereafter (see section 4.4).
30
Posology
Leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days.
The recommended maintenance dose for rheumatoid arthritis is leflunomide 10 mg to 20 mg
once daily. Patients may be started on leflunomide 10 mg or 20 mg depending on the severity
(activity) of the disease.
The recommended maintenance dose for patients with psoriatic arthritis is 20 mg once daily (see
section 5.1).
The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.
There is no dose adjustment recommended in patients with mild renal insufficiency.
No dosage adjustment is required in patients above 65 years of age.
Paediatric population
Arava is not recommended for use in patients below 18 years since efficacy and safety in juvenile
rheumatoid arthritis (JRA) have not been established (see sections 5.1 and 5.2).
Administration
Arava tablets should be swallowed whole with sufficient amounts of liquid. The extent of leflunomide
absorption is not affected if it is taken with food.
Hypersensitivity to the active substance (especially previous Stevens-Johnson syndrome, toxic
epidermal necrolysis, erythema multiforme) or to any of the excipients.
Patients with impairment of liver function.
Patients with severe immunodeficiency states, e.g. AIDS.
Patients with significantly impaired bone marrow function or significant anaemia, leucopenia,
neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis.
Patients with serious infections (see section 4.4).
Patients with moderate to severe renal insufficiency, because insufficient clinical experience is
available in this patient group.
Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.
Pregnant women, or women of childbearing potential who are not using reliable contraception
during treatment with leflunomide and thereafter as long as the plasma levels of the active
metabolite are above 0.02 mg/l (see section 4.6). Pregnancy must be excluded before start of
treatment with leflunomide.
Breast-feeding women (see section 4.6).
Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not
advisable.
The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious
undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below),
31
even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if
for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to
be followed. The procedure may be repeated as clinically necessary.
For washout procedures and other recommended actions in case of desired or unintended pregnancy,
see section 4.6.
Liver reactions
Rare cases of severe liver injury, including cases with fatal outcome, have been reported during
treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co-
treatment with other hepatotoxic medicinal products was frequently present. It is considered essential
that monitoring recommendations are strictly adhered to.
ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the
complete blood cell count (every two weeks) during the first six months of treatment and every
8 weeks thereafter.
For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from
20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT)
elevations of more than 2-fold the upper limit of normal persist or if ALT elevations of more than
3-fold the upper limit of normal are present, leflunomide must be discontinued and wash-out
procedures initiated. It is recommended that monitoring of liver enzymes be maintained after
discontinuation of leflunomide treatment, until liver enzyme levels have normalised.
Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be
avoided during treatment with leflunomide.
Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic
metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients
with hypoproteinaemia. Arava is contraindicated in patients with severe hypoproteinaemia or
impairment of liver function (see section 4.3).
Haematological reactions
Together with ALT, a complete blood cell count, including differential white blood cell count and
platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first
6 months of treatment and every 8 weeks thereafter.
In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with
impaired bone marrow function or those at risk of bone marrow suppression, the risk of
haematological disorders is increased. If such effects occur, a washout (see below) to reduce plasma
levels of A771726 should be considered.
In case of severe haematological reactions, including pancytopenia, Arava and any concomitant
myelosuppressive treatment must be discontinued and a leflunomide washout procedure initiated.
Combinations with other treatments
The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive agents (with the exception of methotrexate, see section 4.5) has not been studied
up to now. The risk associated with combination therapy, in particular in long-term treatment, is
unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or
haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.
32
Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolised by
CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
Switching to other treatments
As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate)
without performing the washout procedure (see below)
may raise the possibility of additive risks even
for a long time after the switching (i.e. kinetic interaction, organ toxicity).
Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate)
may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully
be considered regarding these benefit/risk aspects
and closer monitoring is recommended in the initial
phase after switching.
Skin reactions
In case of ulcerative stomatitis, leflunomide administration should be discontinued.
Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis have been reported in
patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise
the suspicion of such severe reactions, Arava and any other possibly associated treatment must be
discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is
essential in such cases. In such cases re-exposure to leflunomide is contra-indicated (see section 4.3).
Infections
It is known that medicinal products with immunosuppressive properties - like leflunomide – may
cause patients to be more susceptible to infections, including opportunistic infections. Infections may
be more severe in nature and may, therefore, require early and vigorous treatment. In the event that
severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and
administer a washout procedure as described below.
Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients
receiving leflunomide among other immunosuppressants.
Patients with tuberculin reactivity must be carefully monitored because of the risk of tuberculosis
reactivation.
Respiratory reactions
Interstitial lung disease has been reported during treatment with leflunomide (see section 4.8).
Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy.
Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy
and for further investigation, as appropriate.
Blood pressure
Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
Procreation (recommendations for men)
Male patients should be aware of the possible male-mediated foetal toxicity Reliable contraception
during treatment with leflunomide should also be guaranteed.
There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to
evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to
33
father a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 times
daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.
In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the
A771726 plasma concentration must be determined again after an interval of at least 14 days. If both
plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk of
foetal toxicity is very low.
Washout procedure
Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is
administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be
modified depending on clinical or laboratory variables.
Lactose
Arava contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Interactions studies have only been performed in adults.
Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic
drugs or when leflunomide treatment is followed by such drugs without a washout period (see also
guidance concerning combination with other treatments, section 4.4).
Therefore, closer monitoring of
liver enzymes and haematological parameters is recommended in the initial phase after switching.
In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with
methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of
30 patients. All elevations resolved 2 with continuation of both drugs and 3 after discontinuation of
leflunomide. A more than 3-fold increase was seen in another 5 patients. All of these also resolved, 2
with continuation of both drugs and 3 after discontinuation of leflunomide.
In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to
20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.
It is recommended that patients receiving leflunomide are not treated with colestyramine or activated
powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the
active metabolite of leflunomide; see also section 5) concentration. The mechanism is thought to be by
interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.
If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or
corticosteroids, these may be continued after starting leflunomide.
The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. An
in vivo
interaction study with cimetidine (non-specific cytochrome P450 inhibitor) has demonstrated a
lack of a significant interaction. Following concomitant administration of a single dose of leflunomide
to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer) A771726
peak levels were increased by approximately 40%, whereas the AUC was not significantly changed.
The mechanism of this effect is unclear.
In vitro
studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical
trials no safety problems were observed when leflunomide and NSAIDs metabolised by CYP2C9 were
co-administered. Caution is advised when leflunomide is given together with drugs, other than
NSAIDs, metabolised by CYP2C9 such as phenytoin, warfarin, phenprocoumon and tolbutamide.
34
In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill
containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in
contraceptive activity of the pill, and A771726 pharmacokinetics were within predicted ranges.
Vaccinations
No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment.
Vaccination with live attenuated vaccines is, however, not recommended. The long half-life of
leflunomide should be considered when contemplating administration of a live attenuated vaccine after
stopping Arava.
Pregnancy
The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when
administered during pregnancy. Arava is contraindicated in pregnancy(see section 4.3).
Women of childbearing potential have to use effective contraception during and up to 2 years after
treatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washout
period” below).
The patient must be advised that if there is any delay in onset of menses or any other reason to suspect
pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the
physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the
blood level of the active metabolite, by instituting the drug elimination procedure described below, at
the first delay of menses may decrease the risk to the foetus from leflunomide.
In a small prospective study in women (n=64) who became inadvertently pregnant while taking
leflunomide for no more than three weeks after conception and followed by a drug elimination
procedure, no significant differences (p=0.13) were observed in the overall rate of major structural
defects (5.4%) compared to either of the comparison groups (4.2% in the disease matched group
[n=108] and 4.2% in healthy pregnant women [n=78]).
For women receiving leflunomide treatment and who wish to become pregnant, one of the following
procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations
of A771726 (target concentration below 0.02 mg/l):
Waiting period
A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. The
concentration may be expected to decrease below 0.02 mg/l about 2 years after stopping the treatment
with leflunomide.
After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least
14 days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.
For further information on the sample testing please contact the Marketing Authorisation Holder or its
local representative (see section 7).
35
Washout procedure
After stopping treatment with leflunomide:
colestyramine 8 g is administered 3 times daily for a period of 11 days,
alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of
11 days.
However, also following either of the washout procedures, verification by 2 separate tests at an
interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence
of a plasma concentration below 0.02 mg/l and fertilisation is required.
Women of childbearing potential should be told that a waiting period of 2 years after treatment
discontinuation is required before they may become pregnant. If a waiting period of up to
approximately 2 years under reliable contraception is considered unpractical, prophylactic institution
of a washout procedure may be advisable.
Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and
progestogens such that reliable contraception with oral contraceptives may not be guaranteed during
the washout procedure with colestyramine or activated powdered charcoal. Use of alternative
contraceptive methods is recommended.
Lactation
Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding
women must, therefore, not receive leflunomide.
In the case of side effects such as dizziness the patient's ability to concentrate and to react properly
may be impaired. In such cases patients should refrain from driving cars and using machines.
The most frequently adverse effects reported commonly (1/100 to <1/10) with leflunomide are: mild
increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting,
oral mucosal disorders (e.g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair
loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased,
anorexia, weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver
parameters (transaminases (especially ALT), less often gamma-GT, alkaline phosphatise, bilirubin)).
Classification of expected frequencies:
Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000
to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations
Rare:
severe infections, including sepsis which may be fatal.
Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to
infections, including opportunistic infections (see also section 4.4). Thus, the overall incidence of
infections can increase (in particular of rhinitis, bronchitis and pneumonia).
36
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some
immunosuppressive agents.
Blood and lymphatic system disorders
Common: leucopenia (leucocytes >2 G/l)
Uncommon: anaemia, mild thrombocytopenia (platelets <100 G/l)
Rare:
pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes
<2 G/l), eosinophilia
Very rare:
agranulocytosis
Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a
higher risk of haematological effects.
Immune system disorders
Common: mild allergic reactions
Very rare:
severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous
necrotizing vasculitis
Metabolism and nutrition disorders
Common: CPK increased
Uncommon: hypokalaemia, hyperlipidemia, hypophosphataemia
Rare: LDH increased
Not known: hypouricemia
Psychiatric disorders
Uncommon: anxiety
Nervous system disorders
Common:
paraesthesia, headache, dizziness
Very rare:
peripheral neuropathy
Cardiac disorders
Common:
mild increase in blood pressure
Rare:
severe increase in blood pressure
Respiratory, thoracic and mediastinal disorders
Rare:
interstitial lung disease (including interstitial pneumonitis), which may be fatal.
Gastrointestinal disorders
Common: diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth
ulceration), abdominal pain
Uncommon: taste disturbances
Very rare:
pancreatitis
Hepatobiliary disorders
Common:
elevation of liver parameters (transaminases [especially ALT], less often gamma-GT,
alkaline phosphatase, bilirubin)
Rare:
hepatitis, jaundice/cholestasis
Very rare:
severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal
Skin and subcutaneous tissue disorders
Common: increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin
Uncommon: urticaria
Very rare:
toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
37
Musculoskeletal and connective tissue disorders
Common: tenosynovitis
Uncommon: tendon rupture
Renal and urinary disorders
Not known: renal failure
Reproductive system and breast disorders
Not known: marginal (reversible) decreases in sperm concentration, total sperm count and rapid
progressive motility
General disorders and administration site conditions
Common:
anorexia, weight loss (usually insignificant), asthenia
Symptoms
There have been reports of chronic overdose in patients taking Arava at daily doses up to five times
the recommended daily dose, and reports of acute overdose in adults and children. There were no
adverse events reported in the majority of case reports of overdose. Adverse events consistent with the
safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes,
anaemia, leucopenia, pruritus and rash.
Management
In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate
elimination. Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy
volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to
65% in 48 hours.
Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube
(50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active
metabolite A771726 by 37% in 24 hours and by 48% in 48 hours.
These washout procedures may be repeated if clinically necessary.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that
A771726, the primary metabolite of leflunomide, is not dialysable.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.
Human pharmacology
Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.
Animal pharmacology
Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and
transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/
immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory
38
properties. Leflunomide exhibits the best protective effects on animal models of autoimmune diseases
when administered in the early phase of the disease progression.
In vivo
, it is rapidly and almost completely metabolised to A771726 which is active
in vitro
, and is
presumed to be responsible for the therapeutic effect.
Mode of action
A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase
(DHODH) and exhibits antiproliferative activity.
Rheumatoid arthritis
The efficacy of Arava in the treatment of rheumatoid arthritis was demonstrated in 4 controlled trials
(1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with active
rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/day
(n=104). The treatment duration was 6 months.
All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days.
Study MN301 randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=133), sulphasalazine 2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months.
Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm,
resulting in a 12-month comparison of leflunomide and sulphasalazine.
Study MN302 randomised 999 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation
was optional and only used in 10% of patients. Treatment duration was 12-months.
Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/day
(n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All
patients received folate 1 mg bid. Treatment duration was 12 months.
Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301
and US301) was statistically significantly superior to placebo in reducing the signs and symptoms of
rheumatoid arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology)
response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5%
for 25 mg/day. In the phase III trials, the ACR response rates for leflunomide 20 mg/day vs. placebo
were 54.6% vs. 28.6% (study MN301), and 49.4% vs. 26.3% (study US301).After 12 months with
active treatment, the ACR response rates in leflunomide patients were 52.3% (studies MN301/303),
50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/303) in
sulphasalazine patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients. In
study MN302 leflunomide was significantly less effective than methotrexate. However, in study
US301 no significant differences were observed between leflunomide and methotrexate in the primary
efficacy parameters. No difference was observed between leflunomide and sulphasalazine (study
MN301). The leflunomide treatment effect was evident by 1 month, stabilised by 3 to 6 months and
continued throughout the course of treatment.
A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two
different daily maintenance doses of leflunomide, 10 mg and 20 mg. From the results it can be
concluded that efficacy results of the 20 mg maintenance dose were more favourable, on the other
hand, the safety results favoured the 10 mg daily maintenance dose.
Paediatrics
Leflunomide was studied in a single multicenter, randomized, double-blind, active-controlled trial in
94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3–17
years of age with active polyarticular course JRA regardless of onset type and naive to methotrexate or
leflunomide. In this trial, the loading dose and maintenance dose of leflunomide was based on three
weight categories: <20 kg, 20-40 kg, and >40 kg. After 16 weeks treatment, the difference in response
39
rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement
(DOI) 30 % (p=0.02). In responders, this response was maintained during 48 weeks (see section 4.2).
The pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose used
in lighter subjects resulted in a relatively low exposure (see section 5.2). These data do not allow an
effective and safe dose recommendation.
Psoriatic arthritis
The efficacy of Arava was demonstrated in one controlled, randomised, double blind study 3L01 in
188 patients with psoriatic arthritis, treated at 20 mg/day. Treatment duration was 6 months.
Leflunomide 20 mg/day was significantly superior to placebo in reducing the symptoms of arthritis in
patients with psoriatic arthritis: the PsARC (Psoriatic Arthritis treatment Response Criteria) responders
were 59% in the leflunomide group and 29.7% in the placebo group by 6 months (p<0.0001). The
effect of leflunomide on improvement of function and on reduction of skin lesions was modest.
5.2 Pharmacokinetic properties
Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring
opening) in gut wall and liver. In a study with radiolabelled
14
C-leflunomide in three healthy
volunteers, no unchanged leflunomide was detected in plasma, urine or faeces. In other studies,
unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels.
The only plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for
essentially all the
in vivo
activity of Arava.
Absorption
Excretion data from the
14
C study indicated that at least about 82 to 95% of the dose is absorbed. The
time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur
between 1 hour and 24 hours after single administration. Leflunomide can be administered with food,
since the extent of absorption is comparable in the fed and fasting state. Due to the very long half-life
of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies
to facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it is
estimated that attainment of steady-state plasma concentrations would require nearly two months of
dosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters
of A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect was
closely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a dose
level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately
35 µg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.
Distribution
In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of
A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range.
Binding of A771726 appeared slightly reduced and more variable in plasma from patients with
rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could
lead to displacement of other highly-bound drugs.
In vitro
plasma protein binding interaction studies
with warfarin at clinically relevant concentrations, however, showed no interaction. Similar studies
showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of
A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced ibuprofen,
diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%.
There is no indication that these effects are of clinical relevance. Consistent with extensive protein
binding A771726 has a low apparent volume of distribution (approximately 11 litres). There is
no
preferential uptake in erythrocytes.
40
Metabolism
Leflunomide is metabolised to one primary (A771726) and many minor metabolites including TFMA
(4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and
subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur
in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific
cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that
in
vivo
CYP enzymes are involved in the metabolism of leflunomide only to a small extent.
Elimination
Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The
elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose
of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in
urine. A771726 was still detectable in urine and faeces 36 days after a single administration.
The
principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to
24 hour samples) and an oxanilic acid derivative of A771726. The principal faecal component was
A771726.
It has been shown in man that administration of an oral suspension of activated powdered charcoal or
colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in
plasma concentrations (see section 4.9). This is thought to be achieved by a gastrointestinal dialysis
mechanism and/or by interrupting enterohepatic recycling.
Pharmacokinetics in renal failure
Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients
on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects
appeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed in
haemodialysis subjects which was not due to extraction of drug in the dialysate.
Pharmacokinetics in liver failure
No data are available regarding treatment of patients with hepatic impairment. The active metabolite
A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These
processes may be affected by hepatic dysfunction.
Pharmacokinetics in paediatrics
The pharmacokinetics of A771726 following oral administration of leflunomide have been
investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA)
who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these
trials have demonstrated that pediatric patients with body weights 40 kg have a reduced systemic
exposure (measured by C
ss
) of A771726 relative to adult rheumatoid arthritis patients (see section 4.2).
Pharmacokinetics in elderly
Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in
younger adults.
5.3 Preclinical safety data
Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in
mice and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogs
for up to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs
41
for toxicity were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes.
The main effects were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect
the basic mode of action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz
bodies and/or Howell-Jolly bodies were found. Other effects found on heart, liver, cornea and
respiratory tract could be explained as infections due to immunosuppression. Toxicity in animals was
found at doses equivalent to human therapeutic doses.
Leflunomide was not mutagenic. However, the minor metabolite TFMA (4-trifluoromethylaniline)
caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its
potential to exert this effect
in vivo
.
In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a
carcinogenicity study in mice an increased incidence of malignant lymphoma occurred in males of the
highest dose group, considered to be due to the immunosuppressive activity of leflunomide. In female
mice an increased incidence, dose-dependent, of bronchiolo-alveolar adenomas and carcinomas of the
lung was noted. The relevance of the findings in mice relative to the clinical use of leflunomide is
uncertain.
Leflunomide was not antigenic in animal models.
Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic
range and exerted adverse effects on male reproductive organs in repeated dose toxicity studies.
Fertility was not reduced.
6.
6.1 List of excipients
Tablet core:
Maize starch
Povidone (E1201)
Crospovidone (E1202)
Talc (E553b)
Silica colloidal anhydrous
Magnesium stearate (E470b)
Lactose monohydrate
Film-coating:
Talc (E553b)
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 8000.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package.
42
6.5 Nature and content
s
of container
Aluminium / Aluminium blister. Pack size: 3 film-coated tablets.
6.6 Special precautions for disposal
No special requirements.
7.
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
8.
MARKETING AUTHORISATION
NUMBER(S)
EU/1/99/118/009
9.
Date of first authorisation: 02 September 1999
Date of latest renewal: 02 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
43
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
44
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Sanofi Winthrop Industrie
56, Route de Choisy au Bac
F-60205 Compiegne Cedex
France
B.
CONDITIONS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall ensure that all physicians who are expected to
prescribe/use Arava are provided with a physician educational pack containing the following:
The Summary of Product Characteristics
Physician Leaflet
The Physician Leaflet should contain the following key messages:
That there is a risk of severe liver injury and so regular measurement of ALT (SGPT) levels to
monitor liver function is important. The information provided in the Physician Leaflet should
provide information on dose reduction, discontinuation and wash out procedures.
The identified risk of synergistic hepato- or haematotoxicity associated with combination
therapy with another Disease-Modifying Antirheumatic Drug (e.g. methotrexate)
That there is a risk of teratogenicity and so pregnancy must be avoided until leflunomide
plasma levels are at an appropriate level. Physicians and patients should be made aware that
there is an ad hoc advisory service available to provide information on leflunomide plasma
level laboratory testing
The risk of infections, including opportunistic infections, and the contraindication for use in
immuno-compromised patients.
The need to counsel patients on important risks associated with leflunomide therapy and
appropriate precautions when using the medicine.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 3.0 dated 04
February 2010 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.3 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
45
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the EMEA
PSURs
:
The MAH should submit annual PSURs.
46
ANNEX III
LABELLING AND PACKAGE LEAFLET
47
A. LABELLING
48
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/BLISTER PACK
1.
Arava 10 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 10 mg leflunomide.
3.
LIST OF EXCIPIENTS
This medicinal product contains lactose (see leaflet for further information).
4.
30 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package.
49
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
EU/1/99/118/001 30 tablets
EU/1/99/118/002 100 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Arava 10 mg
50
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Arava 10 mg film-coated tablets
Leflunomide
2.
Sanofi-Aventis
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
51
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/BOTTLE PACK
1.
Arava 10 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 10 mg leflunomide.
3.
LIST OF EXCIPIENTS
This medicinal product contains lactose (see leaflet for further information).
4.
30 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the container tightly closed.
52
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
EU/1/99/118/003 30 tablets
EU/1/99/118/004 100 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Arava 10 mg
53
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL
1.
Arava 10 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg leflunomide.
3.
LIST OF EXCIPIENTS
Also contains lactose.
4.
30 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the container tightly closed.
54
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
EU/1/99/118/003 30 tablets
EU/1/99/118/004 100 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
55
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/BLISTER PACK
1.
Arava 20 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 20 mg leflunomide.
3.
LIST OF EXCIPIENTS
This medicinal product contains lactose (see leaflet for further information).
4.
30 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package.
56
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
EU/1/99/118/005 30 tablets
EU/1/99/118/006 100 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Arava 20 mg
57
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Arava 20 mg film-coated tablets
Leflunomide
2.
Sanofi-Aventis
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
58
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/BOTTLE PACK
1.
Arava 20 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 20 mg leflunomide.
3.
LIST OF EXCIPIENTS
This medicinal product contains lactose (see leaflet for further information).
4.
30 film-coated tablets
50 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the container tightly closed.
59
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
EU/1/99/118/007 30 tablets
EU/1/99/118/010 50 tablets
EU/1/99/118/008 100 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Arava 20 mg
60
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL
1.
Arava 20 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 20 mg leflunomide.
3.
LIST OF EXCIPIENTS
Also contains lactose.
4.
30 film-coated tablets
50 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Keep the container tightly closed.
61
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
EU/1/99/118/007 30 tablets
EU/1/99/118/010 50 tablets
EU/1/99/118/008 100 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
62
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING/BLISTER PACK
1.
Arava 100 mg film-coated tablets
Leflunomide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 100 mg leflunomide.
3.
LIST OF EXCIPIENTS
This medicinal product contains lactose (see leaflet for further information).
4.
3 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package.
63
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
EU/1/99/118/009 3 tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Arava 100 mg
64
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Arava 100 mg film-coated tablets
Leflunomide
2.
Sanofi-Aventis
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
65
B. PACKAGE LEAFLET
66
PACKAGE LEAFLET: INFORMATION FOR THE USER
Arava 10 mg film-coated tablets
Leflunomide
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist
In this leaflet
:
1.
What Arava is and what it is used for
2.
Before you take Arava
3.
How to take Arava
4.
Possible side effects
5.
How to store Arava
6.
Further information
1.
WHAT ARAVA IS AND WHAT IT IS USED FOR
Arava belongs to a group of medicines called anti-rheumatic medicines.
Arava is used to treat adult patients with active rheumatoid arthritis or with active psoriatic arthritis.
Symptoms of rheumatoid arthritis include inflammation of joints, swelling, difficulty moving and
pain. Other symptoms that affect the entire body include loss of appetite, fever, loss of energy and
anaemia (lack of red blood cells).
Symptoms of active psoriatic arthritis include inflammation of joints, swelling, difficulty moving, pain
and patches of red, scaly skin (skin lesions).
2.
BEFORE YOU TAKE ARAVA
Do not take Arava
-
if you have ever had an
allergic
reaction to leflunomide (especially a serious skin reaction,
often accompanied by fever, joint pain, red skin stains, or blisters e.g. Steven-Johnson
syndrome) or to any of the other ingredients of Arava,
-
if you have any
liver problems
,
-
if you have moderate to severe
kidney problems
,
-
if you have severely low numbers of
proteins in your blood
(hypoproteinaemia),
-
if you suffer from any problem which affects your
immune system
(e.g. AIDS),
-
if you have any problem with your
bone marrow,
or if you have low numbers of red or white
cells in your blood or a reduced number of blood platelets,
-
if you are suffering from a
serious infection
,
-
if you are
pregnant
or breast-feeding.
67
Take special care with Arava
- if you have ever suffered from
tuberculosis
(a lung disease),
- if you are
male
and wish to father a child, as Arava can cause birth defects in new born infants.
To minimise any possible risk, men wishing to father a child should contact their doctor who may
advise you to stop taking Arava and take certain medicines to speed up the removal of Arava from
your body. You will then need a blood test to make sure that Arava has been sufficiently removed
from your body, and you should then wait for at least another 3 months.
Arava can occasionally cause some problems with your blood, liver or lungs. It may also cause some
serious allergic reactions, or increase the chance of a severe infection. For more information on these,
please read section 4 (Possible side effects).
Your doctor will carry out
blood tests
at regular intervals, before and during treatment with Arava, to
monitor your blood cells and liver. Your doctor will also check your blood pressure regularly as Arava
can cause an increase in blood pressure.
Arava is not recommended for use in children and adolescents below 18 years of age.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
This is especially important if you are taking:
-
other medicines for
rheumatoid arthritis
such as antimalarials (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive drugs (e.g. methotrexate) as these combinations are not advisable,
-
a medicine called colestyramine (used to reduce high cholesterol) or activated
charcoal
as
these medicines can reduce the amount of Arava which is absorbed by the body,
-
phenytoin
(used to treat epilepsy),
Warfarin
or
phenprocoumon
(used to thin the blood) or
tolbutamide
(used to treat type 2 diabetes) as these medicines may increase the risk of side
effects.
If you are already taking a non-steroidal
anti-inflammatory
drug (NSAID) and/or
corticosteroids
,
you may continue to take them after starting Arava.
Vaccinations
If you have to be vaccinated, ask your doctor for advice. Certain vaccinations should not be given
while taking Arava, and for a certain amount of time after stopping treatment.
Taking Arava with food and drink
Arava may be taken with or without food.
It is not recommended to drink alcohol during treatment with Arava. Drinking alcohol while taking
Arava may increase the chance of liver damage.
Pregnancy and breast-feeding
Do not
take Arava if you are, or think you may be
pregnant
. Women of childbearing potential must
not take Arava without using reliable contraceptive measures.
Tell your doctor if you plan to become pregnant after stopping treatment with Arava, as you need to
ensure that all traces of Arava have left your body before trying to become pregnant. This may take up
to 2 years. This may be reduced to a few weeks by taking certain medicines which speed up removal
of Arava from your body.
68
In either case it should be confirmed by a blood test that Arava has been sufficiently removed from
your body and you should then wait for at least another month before you become pregnant.
For further information on the laboratory testing please contact your doctor.
If you suspect that you are pregnant while taking Arava or in the two years after you have stopped
treatment, you must contact your doctor
immediately
for a pregnancy test. If the test confirms that
you are pregnant, your doctor may suggest treatment with certain medicines to speed up the removal
of Arava from the body, as this may decrease the risk to your baby.
Do not
take Arava when you are
breast feeding
, as leflunomide passes into the breast milk.
Driving and using machines
Arava can make you feel dizzy which may impair your ability to concentrate and react. If you are
affected, do not drive, or use machines.
Important information about some of the ingredients of Arava
Arava contains
lactose
. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE ARAVA
Always take Arava exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual starting dosage of Arava is one 100 mg tablet once daily for the first three days. After this,
most patients need a dose of:
For rheumatoid arthritis: 10 or 20 mg Arava once daily, depending on the severity of the
disease.
For psoriatic arthritis: 20 mg Arava once daily.
Swallow
the tablet
whole
and with plenty of
water
.
It may take about 4 weeks or longer until you start to feel an improvement in your condition. Some
patients may even still feel further improvements after 4 to 6 months of therapy.
You will normally take Arava over long periods of time.
If you take more Arava than you should
If you take more Arava than you should, contact your doctor or get other medical advice. If possible,
take your tablets or the box with you to show the doctor.
If you forget to take Arava
If you forget to take a dose, take it as soon as you remember, unless it is nearly time for your next
dose. Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Arava can cause side effects, although not everybody gets them.
69
Tell your doctor
immediately
and stop taking Arava:
-
if you experience
weakness
, feel light-headed or dizzy or have
difficulty breathing,
as these
may be signs of a serious allergic reaction,
-
if you develop a
skin rash
or
ulcers in your mouth
, as these may indicate severe, sometimes
life-threatening reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema
multiforme).
Tell your doctor
immediately
if you experience:
-
pale skin
,
tiredness,
or
bruising,
as these may indicate blood disorders caused by an imbalance
in the different types of blood cells which make up blood,
-
tiredness
,
abdominal pain
, or
jaundice
(yellow discolouration of the eyes or skin), as these
may indicate serious conditions such as liver failure, which may be fatal,
-
any symptoms of an
infection
such as
fever, sore throat
or
cough,
as Arava may increase the
chance of a severe infection which may be life-threatening,
-
a
cough
or
breathing problems
as these may indicate inflammation of the lung (interstitial lung
disease).
Common side effects (affects 1 to 10 users in 100)
-
a slight decrease in the number of white blood cells (leucopenia),
-
mild allergic reactions,
-
loss of appetite, weight loss (usually insignificant),
-
tiredness (asthenia),
-
headache, dizziness,
-
abnormal skin sensations like tingling (paraesthesia),
-
mild increase in blood pressure,
-
diarrhoea,
-
nausea, vomiting,
-
inflammation of the mouth or mouth ulcers,
-
abdominal pain,
-
an increase in some liver test results,
-
increased hair loss,
-
eczema, dry skin, rash, itching,
-
tendonitis (pain caused by inflammation in the membrane surrounding the tendons usually in the
feet or hands),
-
an increase of certain enzymes in the blood (creatine phosphokinase).
Uncommon side effects (affects 1 to 10 users in 1,000)
-
a decrease in the number of red blood cells (anaemia) and a decrease in the number of blood
platelets (thrombocytopenia),
-
a decrease in the levels of potassium in the blood,
-
anxiety,
-
taste disturbances,
-
urticaria (nettle rash),
-
tendon rupture,
-
an increase in the levels of fat in the blood (cholesterol and triglycerides),
-
a decrease in the levels of phosphate in the blood.
Rare side effects (affects 1 to 10 users in 10,000)
-
an increase in the numbers of blood cells called eosinophiles (eosinophilia); mild decrease in the
number of white blood cells (leucopenia); decrease in the number of all blood cells
(pancytopenia),
-
severe increase in blood pressure,
-
inflammation of the lung (interstitial lung disease),
-
an increase in some liver results which may develop into serious conditions such as hepatitis
and jaundice,
70
-
severe infections called sepsis which may be fatal,
-
an increase of certain enzymes in the blood (lactate dehydrogenase).
Very rare side effects (affects less than 1 user in 10,000)
-
a marked decrease of some white blood cells (agranulocytosis),
-
severe and potentially severe allergic reactions,
-
inflammation of the small vessels (vasculitis, including cutaneous necrotizing vasculitis),
-
problems in the nerves of the arms or legs (peripheral neuropathy),
-
inflammation of the pancreas (pancreatitis),
-
sever liver injury such as liver failure or necrosis which may be fatal,
-
severe sometimes life-threatening reactions (Stevens-Johnson syndrome, toxic epidermal
necrolysis, erythema multiforme).
Other side effects such as kidney failure, a decrease in the levels of uric acid in your blood, and male
infertility (which is reversible once treatment with Arava is stopped) may also occur with an unknown
frequency.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ARAVA
Keep out of the reach and sight of children.
Do not use Arava after the expiry date which is stated on the packaging. The expiry date refers to the
last day of that month.
Blister:
Store in the original package.
Bottle:
Keep the container tightly closed.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Arava contains
- The active substance is leflunomide. One film-coated tablet contains 10 mg of leflunomide.
- The other ingredients are: maize starch, povidone (E1201), crospovidone (E1202), silica
colloidal anhydrous, magnesium stearate (E470b), and lactose monohydrate in the tablet core, as well
as talc (E553b), hypromellose (E464), titanium dioxide (E171), and macrogol 8000 in the film-
coating.
What Arava looks like and contents of the pack
Arava 10 mg film-coated tablets are white to almost white and round.
Imprint on one side: ZBN.
The tablets are packed in blisters or bottles.
Packs of 30 and 100 tablets are available.
Not all pack size may be marketed.
71
Marketing Authorisation Holder
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
Manufacturer
Sanofi Winthrop Industrie
56, Route de Choisy au Bac
F-60205 Compiegne Cedex
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
sanofi-aventis Norge AS
Tlf: +47 67 10 71 00
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, S.A.
Tel: +351 21 35 89 400
France
sanofi-aventis france
Tél: 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0) 21 317 31 36
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
72
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 33 100 100
Italia
sanofi-aventis S.p.A.
Tel: +39 02 393 91
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/.
73
PACKAGE LEAFLET: INFORMATION FOR THE USER
Arava 20 mg film-coated tablets
Leflunomide
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist
In this leaflet
:
1.
What Arava is and what it is used for
2.
Before you take Arava
3.
How to take Arava
4.
Possible side effects
5.
How to store Arava
6.
Further information
1.
WHAT ARAVA IS AND WHAT IT IS USED FOR
Arava belongs to a group of medicines called anti-rheumatic medicines.
Arava is used to treat adult patients with active rheumatoid arthritis or with active psoriatic arthritis.
Symptoms of rheumatoid arthritis include inflammation of joints, swelling, difficulty moving and
pain. Other symptoms that affect the entire body include loss of appetite, fever, loss of energy and
anaemia (lack of red blood cells).
Symptoms of active psoriatic arthritis include inflammation of joints, swelling, difficulty moving, pain
and patches of red, scaly skin (skin lesions).
2.
BEFORE YOU TAKE ARAVA
Do not take Arava
-
if you have ever had an
allergic
reaction to leflunomide (especially a serious skin reaction,
often accompanied by fever, joint pain, red skin stains, or blisters e.g. Steven-Johnson
syndrome) or to any of the other ingredients of Arava,
-
if you have any
liver problems
,
-
if you have moderate to severe
kidney problems
,
-
if you have severely low numbers of
proteins in your blood
(hypoproteinaemia),
-
if you suffer from any problem which affects your
immune system
(e.g. AIDS),
-
if you have any problem with your
bone marrow,
or if you have low numbers of red or white
cells in your blood or a reduced number of blood platelets,
-
if you are suffering from a
serious infection
,
-
if you are
pregnant
or breast-feeding.
74
Take special care with Arava
-
if you have ever suffered from
tuberculosis
(a lung disease),
-
if you are
male
and wish to father a child, as Arava can cause birth defects in new born infants.
To minimise any possible risk, men wishing to father a child should contact their doctor who may
advise you to stop taking Arava and take certain medicines to speed up the removal of Arava from
your body. You will then need a blood test to make sure that Arava has been sufficiently removed
from your body, and you should then wait for at least another 3 months.
Arava can occasionally cause some problems with your blood, liver or lungs. It may also cause some
serious allergic reactions, or increase the chance of a severe infection. For more information on these,
please read section 4 (Possible side effects).
Your doctor will carry out
blood tests
at regular intervals, before and during treatment with Arava, to
monitor your blood cells and liver. Your doctor will also check your blood pressure regularly as Arava
can cause an increase in blood pressure.
Arava is not recommended for use in children and adolescents below 18 years of age.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
This is especially important if you are taking:
–
other medicines for
rheumatoid arthritis
such as antimalarials (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive drugs (e.g. methotrexate) as these combinations are not advisable,
–
a medicine called colestyramine (used to reduce high cholesterol) or activated
charcoal
as
these medicines can reduce the amount of Arava which is absorbed by the body,
–
phenytoin
(used to treat epilepsy),
Warfarin
or
phenprocoumon
(used to thin the blood) or
tolbutamide
(used to treat type 2 diabetes) as these medicines may increase the risk of side
effects.
If you are already taking a nonsteroidal
anti-inflammatory
drug (NSAID) and/or
corticosteroids
,
you may continue to take them after starting Arava.
Vaccinations
If you have to be vaccinated, ask your doctor for advice. Certain vaccinations should not be given
while taking Arava, and for a certain amount of time after stopping treatment.
Taking Arava with food and drink
Arava may be taken with or without food.
It is not recommended to drink alcohol during treatment with Arava. Drinking alcohol while taking
Arava may increase the chance of liver damage.
Pregnancy and breast -feeding
Do not
take Arava if you are, or think you may be
pregnant
. Women of childbearing potential must
not take Arava without using reliable contraceptive measures.
Tell your doctor if you plan to become pregnant after stopping treatment with Arava, as you need to
ensure that all traces of Arava have left your body before trying to become pregnant. This may take up
to 2 years. This may be reduced to a few weeks by taking certain medicines which speed up removal
of Arava from your body.
75
In either case it should be confirmed by a blood test that Arava has been sufficiently removed from
your body and you should then wait for at least another month before you become pregnant.
For further information on the laboratory testing please contact your doctor.
If you suspect that you are pregnant while taking Arava or in the two years after you have stopped
treatment, you must contact your doctor
immediately
for a pregnancy test. If the test confirms that
you are pregnant, your doctor may suggest treatment with certain medicines to speed up the removal
of Arava from the body, as this may decrease the risk to your baby.
Do not take Arava when you are
breast feeding
, as leflunomide passes into the breast milk.
Driving and using machines
Arava can make you feel dizzy which may impair your ability to concentrate and react. If you are
affected, do not drive, or use machines.
Important information about some of the ingredients of Arava
Arava contains
lactose
. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE ARAVA
Always take Arava exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual starting dosage of Arava is one 100 mg tablet once daily for the first three days. After this,
most patients need a dose of:
For rheumatoid arthritis: 10 or 20 mg Arava once daily, depending on the severity of the
disease.
For psoriatic arthritis: 20 mg Arava once daily.
Swallow
the tablet
whole
and with plenty of
water
.
It may take about 4 weeks or longer until you start to feel an improvement in your condition. Some
patients may even still feel further improvements after 4 to 6 months of therapy.
You will normally take Arava over long periods of time.
If you take more Arava than you should
If you take more Arava than you should, contact your doctor or get other medical advice. If possible,
take your tablets or the box with you to show the doctor.
If you forget to take Arava
If you forget to take a dose, take it as soon as you remember, unless it is nearly time for your next
dose. Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
76
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Arava can cause side effects, although not everybody gets them.
Tell your doctor
immediately
and stop taking Arava:
-
if you experience
weakness
, feel light-headed or dizzy or have
difficulty breathing,
as these
may be signs of a serious allergic reaction,
-
if you develop a
skin rash
or
ulcers in your mouth
, as these may indicate severe, sometimes
life-threatening reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema
multiforme).
Tell your doctor
immediately
if you experience:
-
pale skin
,
tiredness,
or
bruising,
as these may indicate blood disorders caused by an imbalance
in the different types of blood cells which make up blood,
-
tiredness
,
abdominal pain
, or
jaundice
(yellow discolouration of the eyes or skin), as these
may indicate serious conditions such as liver failure, which may be fatal,
-
any symptoms of an
infection
such as
fever, sore throat
or
cough,
as Arava may increase the
chance of a severe infection which may be life-threatening,
-
a
cough
or
breathing problems
as these may indicate inflammation of the lung (interstitial lung
disease).
Common side effects (affects 1 to 10 users in 100)
-
a slight decrease in the number of white blood cells (leucopenia),
-
mild allergic reactions,
-
loss of appetite, weight loss (usually insignificant),
-
tiredness (asthenia),
-
headache, dizziness,
-
abnormal skin sensations like tingling (paraesthesia),
-
mild increase in blood pressure,
-
diarrhoea,
-
nausea, vomiting,
-
inflammation of the mouth or mouth ulcers,
-
abdominal pain,
-
an increase in some liver test results,
-
increased hair loss,
-
eczema, dry skin, rash, itching,
-
tendonitis (pain caused by inflammation in the membrane surrounding the tendons usually in the
feet or hands),
-
an increase of certain enzymes in the blood (creatine phosphokinase).
Uncommon side effects (affects 1 to 10 users in 1,000)
-
a decrease in the number of red blood cells (anaemia) and a decrease in the number of blood
platelets (thrombocytopenia),
-
a decrease in the levels of potassium in the blood,
-
anxiety,
-
taste disturbances,
-
urticaria (nettle rash),
-
tendon rupture,
-
an increase in the levels of fat in the blood (cholesterol and triglycerides),
-
a decrease in the levels of phosphate in the blood.
Rare side effects (affects 1 to 10 users in 10,000)
-
an increase in the numbers of blood cells called eosinophiles (eosinophilia); mild decrease in the
number of white blood cells (leucopenia); decrease in the number of all blood cells
(pancytopenia),
77
-
severe increase in blood pressure,
-
inflammation of the lung (interstitial lung disease),
-
an increase in some liver results which may develop into serious conditions such as hepatitis
and jaundice,
-
severe infections called sepsis which may be fatal,
-
an increase of certain enzymes in the blood (lactate dehydrogenase).
Very rare side effects (affects less than 1 user in 10,000)
-
a marked decrease of some white blood cells (agranulocytosis),
-
severe and potentially severe allergic reactions,
-
inflammation of the small vessels (vasculitis, including cutaneous necrotizing vasculitis),
-
problems in the nerves of the arms or legs (peripheral neuropathy),
-
inflammation of the pancreas (pancreatitis),
-
sever liver injury such as liver failure or necrosis which may be fatal,
-
severe sometimes life-threatening reactions (Stevens-Johnson syndrome, toxic epidermal
necrolysis, erythema multiforme).
Other side effects such as kidney failure, a decrease in the levels of uric acid in your blood, and male
infertility (which is reversible once treatment with Arava is stopped) may also occur with an unknown
frequency.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ARAVA
Keep out of the reach and sight of children.
Do not use Arava after the expiry date which is stated on the packaging.
The expiry date refers to the last day of that month.
Blister:
Store in the original package.
Bottle:
Keep the container tightly closed.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Arava contains
-
The active substance is leflunomide. One film-coated tablet contains 20 mg of leflunomide
-
The other ingredients are: maize starch, povidone (E1201), crospovidone (E1202), silica
colloidal anhydrous, magnesium stearate (E470b), and lactose monohydrate in the tablet core, as
well as talc (E553b), hypromellose (E464), titanium dioxide (E171), macrogol 8000 and yellow
ferric oxide (E172) in the film-coating.
What Arava looks like and contents of the pack
Arava 20 mg film-coated tablets are yellowish to ochre and triangular.
Imprint on one side: ZBO.
The tablets are packed in blisters or bottles.
Packs of 30, 50 and 100 tablets are available.
78
Not all pack size may be marketed.
Marketing Authorisation Holder
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
Manufacturer
Sanofi Winthrop Industrie
56, Route de Choisy au Bac
F-60205 Compiegne Cedex
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
sanofi-aventis Norge AS
Tlf: +47 67 10 71 00
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, S.A.
Tel: +351 21 35 89 400
France
sanofi-aventis france
Tél: 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0) 21 317 31 36
79
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 33 100 100
Italia
sanofi-aventis S.p.A.
Tel: +39 02 393 91
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/.
80
PACKAGE LEAFLET: INFORMATION FOR THE USER
Arava 100 mg film-coated tablets
Leflunomide
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist
In this leaflet
:
1.
What Arava is and what it is used for
2.
Before you take Arava
3.
How to take Arava
4.
Possible side effects
5.
How to store Arava
6.
Further information
1.
WHAT ARAVA IS AND WHAT IT IS USED FOR
Arava belongs to a group of medicines called anti-rheumatic medicines.
Arava is used to treat adult patients with active rheumatoid arthritis or with active psoriatic arthritis.
Symptoms of rheumatoid arthritis include inflammation of joints, swelling, difficulty moving and
pain. Other symptoms that affect the entire body include loss of appetite, fever, loss of energy and
anaemia (lack of red blood cells).
Symptoms of active psoriatic arthritis include inflammation of joints, swelling, difficulty moving, pain
and patches of red, scaly skin (skin lesions).
2.
BEFORE YOU TAKE ARAVA
Do not take Arava
-
if you have ever had an
allergic
reaction to leflunomide (especially a serious skin reaction,
often accompanied by fever, joint pain, red skin stains, or blisters e.g. Steven-Johnson
syndrome) or to any of the other ingredients of Arava,
-
if you have any
liver problems,
-
if you have moderate to severe
kidney problems
,
-
if you have severely low numbers of
proteins in your blood
(hypoproteinaemia),
-
if you suffer from any problem which affects your
immune system
(e.g. AIDS),
-
if you have any problem with your
bone marrow,
or if you have low numbers of red or white
cells in your blood or a reduced number of blood platelets,
-
if you are suffering from a
serious infection
,
-
if you are
pregnant
or breast-feeding.
81
Take special care with Arava
- if you have ever suffered from
tuberculosis
(a lung disease),
- if you are male and wish to father a child, as Arava can cause birth defects in new born infants.
To minimise any possible risk, men wishing to father a child should contact their doctor who may
advise you to stop taking Arava and take certain medicines to speed up the removal of Arava from
your body. You will then need a blood test to make sure that Arava has been sufficiently removed
from your body, and you should then wait for at least another 3 months.
Arava can occasionally cause some problems with your blood, liver or lungs. It may also cause some
serious allergic reactions, or increase the chance of a severe infection. For more information on these,
please read section 4 (Possible side effects).
Your doctor will carry out
blood tests
at regular intervals, before and during treatment with Arava, to
monitor your blood cells and liver. Your doctor will also check your blood pressure regularly as Arava
can cause an increase in blood pressure.
Arava is not recommended for use in children and adolescents below 18 years of age.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
This is especially important if you are taking:
-
other medicines for
rheumatoid arthritis
such as antimalarials (e.g. chloroquine and
hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other
immunosuppressive drugs (e.g. methotrexate) as these combinations are not advisable,
-
a medicine called colestyramine (used to reduce high cholesterol) or activated
charcoal
as
these medicines can reduce the amount of Arava which is absorbed by the body,
-
phenytoin
(used to treat epilepsy),
Warfarin
or
phenprocoumon
(used to thin the blood) or
tolbutamide
(used to treat type 2 diabetes) as these medicines may increase the risk of side
effects.
If you are already taking a nonsteroidal
anti-inflammatory
drug (NSAID) and/or
corticosteroids
,
you may continue to take them after starting Arava.
Vaccinations
If you have to be vaccinated, ask your doctor for advice. Certain vaccinations should not be given
while taking Arava, and for a certain amount of time after stopping treatment.
Taking Arava with food and drink
Arava may be taken with or without food.
It is not recommended to drink alcohol during treatment with Arava. Drinking alcohol while taking
Arava may increase the chance of liver damage.
Pregnancy and breast-feeding
Do not
take Arava if you are, or think you may be
pregnant
. Women of childbearing potential must
not take Arava without using reliable contraceptive measures.
Tell your doctor if you plan to become pregnant after stopping treatment with Arava, as you need to
ensure that all traces of Arava have left your body before trying to become pregnant. This may take up
to 2 years. This may be reduced to a few weeks by taking certain medicines which speed up removal
of Arava from your body.
82
In either case it should be confirmed by a blood test that Arava has been sufficiently removed from
your body and you should then wait for at least another month before you become pregnant.
For further information on the laboratory testing please contact your doctor.
If you suspect that you are pregnant while taking Arava or in the two years after you have stopped
treatment, you must contact your doctor
immediately
for a pregnancy test. If the test confirms that
you are pregnant, your doctor may suggest treatment with certain medicines to speed up the removal
of Arava from the body, as this may decrease the risk to your baby.
Do not
take Arava when you are
breast feeding
, as leflunomide passes into the breast milk.
Driving and using machines
Arava can make you feel dizzy which may impair your ability to concentrate and react. If you are
affected, do not drive, or use machines.
Important information about some of the ingredients of Arava
Arava contains
lactose
. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE ARAVA
Always take Arava exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual starting dosage of Arava is one 100 mg tablet once daily for the first three days. After this,
most patients need a dose of:
For rheumatoid arthritis: 10 or 20 mg Arava once daily, depending on the severity of the
disease.
For psoriatic arthritis: 20 mg Arava once daily.
Swallow
the tablet
whole
and with plenty of
water
.
It may take about 4 weeks or longer until you start to feel an improvement in your condition. Some
patients may even still feel further improvements after 4 to 6 months of therapy.
You will normally take Arava over long periods of time.
If you take more Arava than you should
If you take more Arava than you should, contact your doctor or get other medical advice. If possible,
take your tablets or the box with you to show the doctor.
If you forget to take Arava
If you forget to take a dose, take it as soon as you remember, unless it is nearly time for your next
dose. Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
83
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Arava can cause side effects, although not everybody gets them.
Tell your doctor
immediately
and stop taking Arava:
-
if you experience
weakness
, feel light-headed or dizzy or have
difficulty breathing,
as these
may be signs of a serious allergic reaction,
-
if you develop a
skin rash
or
ulcers in your mouth
, as these may indicate severe, sometimes
life-threatening reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema
multiforme).
Tell your doctor
immediately
if you experience:
-
pale skin
,
tiredness,
or
bruising,
as these may indicate blood disorders caused by an imbalance
in the different types of blood cells which make up blood,
-
tiredness
,
abdominal pain
, or
jaundice
(yellow discolouration of the eyes or skin), as these
may indicate serious conditions such as liver failure, which may be fatal,
-
any symptoms of an
infection
such as
fever, sore throat
or
cough,
as Arava may increase the
chance of a severe infection which may be life-threatening,
-
a
cough
or
breathing problems
as these may indicate inflammation of the lung (interstitial lung
disease).
Common side effects (affects 1 to 10 users in 100)
-
a slight decrease in the number of white blood cells (leucopenia),
-
mild allergic reactions,
-
loss of appetite, weight loss (usually insignificant),
-
tiredness (asthenia),
-
headache, dizziness,
-
abnormal skin sensations like tingling (paraesthesia),
-
mild increase in blood pressure,
-
diarrhoea,
-
nausea, vomiting,
-
inflammation of the mouth or mouth ulcers,
-
abdominal pain,
-
an increase in some liver test results,
-
increased hair loss,
-
eczema, dry skin, rash, itching,
-
tendonitis (pain caused by inflammation in the membrane surrounding the tendons usually in the
feet or hands),
-
an increase of certain enzymes in the blood (creatine phosphokinase).
Uncommon side effects (affects 1 to 10 users in 1,000)
-
a decrease in the number of red blood cells (anaemia) and a decrease in the number of blood
platelets (thrombocytopenia),
-
a decrease in the levels of potassium in the blood,
-
anxiety,
-
taste disturbances,
-
urticaria (nettle rash),
-
tendon rupture,
-
an increase in the levels of fat in the blood (cholesterol and triglycerides),
-
a decrease in the levels of phosphate in the blood.
Rare side effects (affects 1 to 10 users in 10,000)
-
an increase in the numbers of blood cells called eosinophiles (eosinophilia); mild decrease in the
number of white blood cells (leucopenia); decrease in the number of all blood cells
(pancytopenia),
84
-
severe increase in blood pressure,
-
inflammation of the lung (interstitial lung disease),
-
an increase in some liver results which may develop into serious conditions such as hepatitis
and jaundice,
-
severe infections called sepsis which may be fatal,
-
an increase of certain enzymes in the blood (lactate dehydrogenase).
Very rare side effects (affects less than 1 user in 10,000)
-
a marked decrease of some white blood cells (agranulocytosis),
-
severe and potentially severe allergic reactions,
-
inflammation of the small vessels (vasculitis, including cutaneous necrotizing vasculitis),
-
problems in the nerves of the arms or legs (peripheral neuropathy),
-
inflammation of the pancreas (pancreatitis),
-
sever liver injury such as liver failure or necrosis which may be fatal,
-
severe sometimes life-threatening reactions (Stevens-Johnson syndrome, toxic epidermal
necrolysis, erythema multiforme).
Other side effects such as kidney failure, a decrease in the levels of uric acid in your blood, and male
infertility (which is reversible once treatment with Arava is stopped) may also occur with an unknown
frequency.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ARAVA
Keep out of the reach and sight of children.
Do not use Arava after the expiry date which is stated on the packaging.
The expiry date refers to the last day of that month.
Store in the original package
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Arava contains
-
The active substance is leflunomide. One film-coated tablet contains 100 mg of leflunomide.
-
The other ingredients are: maize starch, povidone (E1201), crospovidone (E1202), talc (E553b),
silica colloidal anhydrous, magnesium stearate (E470b), and lactose monohydrate in the tablet
core, as well as talc (E553b), hypromellose (E464), titanium dioxide (E171), and macrogol 8000
in the film-coating.
What Arava looks like and contents of the pack
Arava 100 mg film-coated tablets are white to almost white and round.
Imprint on one side: ZBP
The tablets are packed in blisters.
A pack of 3 tablets is available
85
Marketing Authorisation Holder
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
Manufacturer
Sanofi Winthrop Industrie
56, Route de Choisy au Bac
F-60205 Compiegne Cedex
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
sanofi-aventis Norge AS
Tlf: +47 67 10 71 00
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, S.A.
Tel: +351 21 35 89 400
France
sanofi-aventis france
Tél: 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0) 21 317 31 36
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
86
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 33 100 100
Italia
sanofi-aventis S.p.A.
Tel: +39 02 393 91
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/.
87
Source: European Medicines Agency
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