ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Esbriet 267 mg hard capsules
2.
Each capsule contains 267 mg pirfenidone.
For a full list of excipients, see section 6.1.
3.
Hard capsule (capsule).
Two piece capsules with a blue opaque body and gold opaque cap imprinted with “InterMune 267 mg”
in brown ink and containing a white to pale yellow powder.
4.
Esbriet is indicated in adults for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis
(IPF).
Treatment with Esbriet should be initiated and supervised by specialist physicians experienced in the
diagnosis and treatment of IPF.
Posology
Adults
Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine capsules
per day over a 14-day period as follows:
Days 1 to 7: one capsule, three times a day (801 mg/day)
Days 8 to 14: two capsules, three times a day (1602 mg/day)
Day 15 onward: three capsules, three times a day (2403 mg/day)
The recommended daily dose of Esbriet for patients with IPF is three 267 mg capsules three times a
day with food for a total of 2403 mg/day.
Doses above 2403 mg/day are not recommended for any patient.
Patients who miss 14 consecutive days or more of Esbriet treatment should re-initiate therapy by
undergoing the initial 2-week titration regimen up to the recommended daily dose.
For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous
recommended daily dose without titration.
Dose adjustments and other considerations for safe use
Gastrointestinal events:
In patients who experience intolerance to therapy due to gastrointestinal side
effects, patients should be reminded to take the medicinal product with food. If symptoms persist
Esbriet may be reduced to 1-2 capsules (267 mg – 534 mg) 2-3 times/day with food with re-escalation
to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to
interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.
2
Photosensitivity reaction or rash:
Patients who experience a mild to moderate photosensitivity
reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun
exposure (see section 4.4). The dose of Esbriet may be reduced to 3 capsules/day (1 capsule three
times a day). If the rash persists after 7 days, Esbriet should be discontinued for 15 days, with
re-escalation to the recommended daily dose in the same manner as the dose escalation period.
Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the
dose and to seek medical advice (see section 4.4). Once the rash has resolved, Esbriet may be
re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.
Hepatic function:
In the event of significant elevation of alanine and /or aspartate aminotransferases
(ALT/AST) with or without bilirubin elevation, the dose of Esbriet should be adjusted or treatment
discontinued according to the guidelines listed in section 4.4.
Special populations
Elderly
No dose adjustment is necessary in patients 65 years and older (see section 5.2).
Hepatic impairment
No dose adjustment is necessary in patients with mild to moderate hepatic impairment (i.e. Child-Pugh
Class A and B). However, since plasma levels of pirfenidone may be increased in some individuals
with mild to moderate hepatic impairment, caution should be used with Esbriet treatment in this
population. Patients should be monitored closely for signs of toxicity especially if they are
concomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2). Esbriet has not been
studied in patients with severe hepatic impairment or end stage liver disease, and it should not be used
in patients with these conditions (see sections 4.3, 4.4 and 5.2). It is recommended to monitor liver
function during treatment, and dose adjustments may be necessary in the event of elevations (see
sections 4.4 and 5.2).
Renal impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment. Esbriet therapy
should not be used in patients with severe renal impairment (CrCl <30 ml/min) or end stage renal
disease requiring dialysis (see sections 4.3 and 5.2).
Paediatric population
There is no relevant use of Esbriet in the paediatric population in the treatment of IPF.
Method of administration
Esbriet is to be swallowed whole with water and taken with food to reduce the possibility of nausea
and dizziness (see sections 4.8 and 5.2).
Hypersensitivity to the active substance or to any of the excipients,
concomitant use of fluvoxamine (see section 4.5),
severe hepatic impairment or end stage liver disease(see sections 4.2 and 4.4),
severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring
dialysis (see sections 4.2 and 4.4).
Hepatic function
Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients
receiving therapy with Esbriet. Liver function tests (ALT, AST and bilirubin) should be conducted
prior to the initiation of treatment with Esbriet, and subsequently at monthly intervals for the first
6 months and then every 3 months thereafter (see section 4.8). In the event of significant elevation of
liver aminotransferases the dose of Esbriet should be adjusted or treatment discontinued according to
3
the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during
treatment, the following dose adjustments may be necessary.
Recommendations in case of ALT/AST elevations
If a patient exhibits an aminotransferase elevation to >3 to ≤5 x ULN after starting Esbriet therapy,
confounding medicinal products should be discontinued, other causes excluded, and the patient
monitored closely. If clinically appropriate the dose of Esbriet should be reduced or interrupted. Once
liver function tests are within normal limits Esbriet may be re-escalated to the recommended daily
dose if tolerated.
If a patient exhibits an aminotransferase elevation to ≤5 x ULN accompanied by symptoms or
hyperbilirubinaemia, Esbriet should be discontinued and the patient should not be rechallenged.
If a patient exhibits an aminotransferase elevation to >5 x ULN, Esbriet should be discontinued and
the patient should not be rechallenged.
Hepatic impairment
In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), Esbriet exposure was
increased by 60%. Esbriet should be used with caution in patients with pre-existing mild to moderate
hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased Esbriet exposure.
Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a
known CYP1A2 inhibitor (see sections 4.5 and 5.2). Esbriet has not been studied in individuals with
severe hepatic impairment and Esbriet should not be used in patients with severe hepatic impairment.
Photosensitivity reaction and rash
Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment
with Esbriet. Patients should be instructed to use a sunblock daily, to wear clothing that protects
against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients
should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe
photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation
may be necessary in mild to severe cases of photosensitivity reaction or rash (see section 4.2).
Dizziness
Dizziness has been reported in patients taking Esbriet. Therefore, patients should know how they react
to this medicinal product before they engage in activities requiring mental alertness or coordination
(see section 4.7). In clinical studies, most patients who experienced dizziness had a single event, and
most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens
in severity, dose adjustment or even discontinuation of Esbriet may be warranted.
Fatigue
Fatigue has been reported in patients taking Esbriet. Therefore, patients should know how they react to
this medicinal product before they engage in activities requiring mental alertness or coordination (see
section 4.7).
Weight loss
Weight loss has been reported in patients treated with Esbriet (see section 4.8). Physicians should
monitor patients’ weight, and when appropriate encourage increased caloric intake if weight loss is
considered to be of clinical significance.
Pirfenidone is primarily metabolised by CYP1A2.
In vitro
metabolism studies with hepatic
microsomes indicate that approximately 48% of pirfenidone is metabolised via CYP1A2 with other
CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1 each contributing less than 13%.
Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided
during treatment with pirfenidone.
4
Fluvoxamine and inhibitors of CYP1A2
In a Phase 1 study, the co-administration of Esbriet and fluvoxamine (a strong inhibitor of CYP1A2
with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold
increase in exposure to pirfenidone in non-smokers.
Esbriet is contraindicated in patients with concomitant use of fluvoxamine (see section 4.3).
Fluvoxamine should be discontinued prior to the initiation of Esbriet therapy and avoided during
Esbriet therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both
CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone
(e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment.
Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent
inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as
CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine,
paroxetine).
Esbriet should be used with caution in patients treated with other moderate or strong inhibitors of
CYP1A2 (e.g. ciprofloxacin, amiodarone, propafenone).
Cigarette smoking and inducers of CYP1A2
A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the
pharmacokinetics of Esbriet. The exposure to pirfenidone in smokers was 50% of that observed in
non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase
medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2
including smoking should be avoided during Esbriet therapy based on the observed relationship
between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to
discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with
pirfenidone.
In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically
result in a lowering of pirfenidone plasma levels.
Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other
CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant
lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever
possible.
Pregnancy
There are no data from the use of Esbriet in pregnant women.
In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for
accumulation of pirfenidone and/or its metabolites in amniotic fluid.
At high doses (≥1000 mg/kg/day) rats exhibited prolongation of gestation and reduction in fetal
viability.
As a precautionary measure, it is preferable to avoid the use of Esbriet during pregnancy.
Breast-feeding
It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available
pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk
with the potential for accumulation of pirfenidone and/or its metabolites in milk (see section 5.3). A
risk to the suckling child cannot be excluded.
5
A decision must be made whether to discontinue breast-feeding or to discontinue from Esbriet therapy,
taking into account the benefit of breast-feeding for the child and the benefit of Esbriet therapy for the
mother.
Fertility
No adverse effects on fertility were observed in preclinical studies (see section 5.3).
No studies on the effects of the ability to drive and use machines have been performed. Esbriet may
cause dizziness and fatigue, which could influence the ability to drive or use machines.
The safety of Esbriet has been evaluated in clinical studies including 1345 healthy volunteers and
patients.
The most commonly reported (≥10%) adverse reactions during clinical study experience with Esbriet
at a dose of 2403 mg/day compared to placebo, respectively, were nausea (32.8% versus 13.3%), rash
(28.7% versus 8.6%), fatigue (22.3% versus 13.3%), diarrhoea (21.7% versus 13.5%), dyspepsia
(16.8% versus 5.5%), and photosensitivity reaction (12.2% versus 1.7%).
Serious adverse reactions were recorded at similar frequencies among patients treated with
2403 mg/day of Esbriet and placebo in clinical studies.
Table 1 shows the adverse reactions reported at a frequency of ≥2% in 345 patients receiving Esbriet
at the recommended dose of 2403 mg/day in two pivotal Phase 3 studies. Adverse reactions are listed
by System Organ Class and within each frequency grouping [Very common (≥1/10), Common
(≥1/100 to <1/10)] the adverse reactions are presented in order of decreasing seriousness.
Table 1
Adverse reactions by SOC and MedDRA frequency
Infections and infestations
Common: Upper respiratory tract infection; urinary tract infection
Metabolism and nutrition disorders
Common: Weight decreased; anorexia; decreased appetite
Psychiatric disorders
Common: Insomnia
Nervous system disorders
Common:
Dizziness; headache; somnolence; dysgeusia
Vascular disorders
Common: Hot flush
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea; cough; productive cough
Gastrointestinal disorders
Very Common: Dyspepsia; nausea; diarrhoea
Common: Gastroesophageal reflux disease; vomiting; abdominal distension; abdominal
discomfort; abdominal pain; abdominal pain upper; stomach discomfort;
gastritis; constipation; flatulence
Hepatobiliary disorders
Common: ALT increased; AST increased; gamma glutamyl transferase increased
Skin and subcutaneous tissue disorders
Very Common:
Photosensitivity reaction; rash
Common:
Pruritus; erythema; dry skin; rash erythematous; rash macular; rash pruritic
6
Table 1
Adverse reactions by SOC and MedDRA frequency
Musculoskeletal and connective tissue disorders
Common: Myalgia; arthralgia
General disorders and administration site conditions
Very Common:
Fatigue
Common:
Asthenia; non-cardiac chest pain
Injury poisoning and procedural complications
Common:
Sunburn
There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a dose of
4806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers
over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the
most frequently reported adverse reactions for pirfenidone.
In the event of a suspected overdose, supportive medical care should be provided including monitoring
of vital signs and close observation of the clinical status of the patient.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX05
The mechanism of action of pirfenidone has not been fully established. However, existing data suggest
that pirfenidone exerts both antifibrotic and anti-inflammatory properties in a variety of
in vitro
systems and animal models of pulmonary fibrosis (bleomycin- and transplant-induced fibrosis).
IPF is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release of
pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and interleukin-1–beta
(IL-1β) and pirfenidone has been shown to reduce the accumulation of inflammatory cells in response
to various stimuli.
Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins and
cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to
cytokine growth factors such as, transforming growth factor-beta (TGF-β) and platelet-derived growth
factor (PDGF).
Clinical efficacy
The clinical efficacy of Esbriet has been studied in three Phase 3, multicentre, randomised,
double-blind, placebo-controlled studies in patients with IPF. Two of the Phase 3 studies (PIPF-004
and PIPF-006) were multinational, and the third (SP3) was conducted in Japan.
PIPF-004 and PIPF-006 compared treatment with Esbriet 2403 mg/day to placebo. The studies were
nearly identical in design, with few exceptions including an intermediate dose group (1197 mg/day) in
PIPF-004. In both studies, treatment was administered three times daily for a minimum of 72 weeks.
The primary endpoint in both studies was the change from baseline to Week 72 in percent predicted
Forced Vital Capacity (FVC).
In study PIPF-004, the decline of percent predicted FVC from Baseline at Week 72 of treatment was
significantly reduced in patients receiving Esbriet (N=174) compared with patients receiving placebo
(N=174; p=0.001, rank ANCOVA). Treatment with Esbriet also significantly reduced the decline of
7
percent predicted FVC from Baseline at Weeks 24 (p=0.014), 36 (p<0.001), 48 (p<0.001), and
60 (p<0.001). At Week 72, a decline from baseline in percent predicted FVC of ≥10% (a threshold
indicative of the risk of mortality in IPF) was seen in 20% of patients receiving Esbriet compared to
35% receiving placebo (Table 2)
.
Table 2 Categorical assessment of change from Baseline to Week 72 in
percent predicted FVC in study PIPF-004
Pirfenidone
2403 mg/day
(N = 174)
Placebo
(N = 174)
Decline of ≥10% or death or lung transplant
35 (20%)
60 (35%)
Decline of less than 10%
97 (56%)
90 (52%)
No decline (FVC change ≥0%)
42 (24%)
24 (14%)
Although there was no difference between patients receiving Esbriet compared to placebo in change
from baseline to Week 72 of distance walked during a six minute walk test (6MWT) by the
prespecified rank ANCOVA, in an
ad hoc
analysis, 37% of patients receiving Esbriet showed a
decline of ≥50 m in 6MWT distance, compared to 47% of patients receiving placebo.
In study PIPF-006, treatment with Esbriet (N=171) did not reduce the decline of percent predicted
FVC from Baseline at Week 72 compared with placebo (N=173; p=0.501). However, treatment with
Esbriet reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p<0.001),
36 (p=0.011), and 48 (p=0.005). At Week 72, a decline in FVC of ≥10% was seen in 23% of patients
receiving Esbriet and 27% receiving placebo (Table 3).
Table 3 Categorical assessment of change from Baseline to Week 72 in
percent predicted FVC in study PIPF-006
Pirfenidone
2403 mg/day
(N = 171)
Placebo
(N = 173)
Decline of ≥10% or death or lung transplant
39 (23%)
46 (27%)
Decline of less than 10%
88 (52%)
89 (51%)
No decline
(FVC change ≥ 0%)
44 (26%)
38 (22%)
The decline in 6MWT distance from baseline to Week 72 was significantly reduced compared with
placebo in this study (p <0.001, rank ANCOVA). Additionally, in an
ad hoc
analysis, 33% of patients
receiving Esbriet showed a decline of ≥50 m in 6MWT distance, compared to 47% of patients
receiving placebo.
In a pooled analysis of survival in PIPF-004 and PIPF-006 the mortality rate with Esbriet
2403 mg/day group was 7.8% compared with 9.8% with placebo (HR 0.77 [95% CI, 0.47–1.28]).
The third study (SP3) in Japanese patients compared pirfenidone 1800 mg/day (comparable to
2403 mg/day in the US and European populations of PIPF-004/006 on a weight-normalised basis)
with placebo (N=110, N=109, respectively). Treatment with pirfenidone significantly reduced mean
decline in vital capacity (VC) at Week 52 (the primary endpoint) compared with placebo (-0.09±0.02 l
versus -0.16±0.02 l respectively, p=0.042).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Esbriet in all subsets of the paediatric population in IPF. See section 4.2 for information on paediatric
use.
5.2 Pharmacokinetic properties
Absorption
8
Administration of Esbriet with food results in a large reduction in Cmax (by 50%) and a smaller effect
on AUC, compared to the fasted state. Following oral administration of a single dose of 801 mg to
healthy older adult volunteers (50-66 years of age) in the fed state, the rate of pirfenidone absorption
slowed, while the AUC in the fed state was approximately 80-85% of the AUC observed in the fasted
state. A reduced incidence of adverse events (nausea and dizziness) was observed in fed subjects when
compared to the fasted group. Therefore, it is recommended that Esbriet be administered with food to
reduce the incidence of nausea and dizziness.
The bioavailability of pirfenidone has not been determined in humans.
Distribution
Pirfenidone binds to human plasma proteins, primarily to serum albumin. The overall mean binding
ranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 μg/ml). Mean
apparent oral steady-state volume of distribution is approximately 70 l, indicating that pirfenidone
distribution to tissues is modest.
Biotransformation
In vitro
metabolism studies with hepatic microsomes indicate that approximately 48% of pirfenidone
is metabolised via CYP1A2 with other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1
each contributing less than 13%.
In vitro
and
in vivo
studies to date have not detected any activity of
the major metabolite (5-carboxy-pirfenidone), even at concentrations or doses greatly above those
associated with activity of pirfenidone itself.
Elimination
The oral clearance of pirfenidone appears modestly saturable. In a multiple-dose, dose-ranging study
in healthy older adults administered doses ranging from 267 mg to 1335 mg three times a day, the
mean clearance decreased by approximately 25% above a dose of 801 mg three times a day. Following
single dose administration of pirfenidone in healthy older adults, the mean apparent terminal
elimination half-life was approximately 2.4 hours. Approximately 80% of an orally administered dose
of pirfenidone is cleared in the urine within 24 hours of dosing. The majority of pirfenidone is
excreted as the 5-carboxy-pirfenidone metabolite (>95% of that recovered), with less than 1% of
pirfenidone excreted unchanged in urine.
Special populations
Hepatic impairment
The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were compared in
subjects with moderate hepatic impairment (Child-Pugh Class B) and in subjects with normal hepatic
function. Results showed that there was a mean increase of 60% in pirfenidone exposure after a single
dose of 801 mg pirfenidone (3 x 267 mg capsule) in patients with moderate hepatic impairment.
Pirfenidone should be used with caution in patients with mild to moderate hepatic impairment and
patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a
known CYP1A2 inhibitor (see sections 4.2 and 4.4). Esbriet is contraindicated in severe hepatic
impairment and end stage liver disease (see sections 4.2 and 4.3).
Renal impairment
No clinically relevant differences in the pharmacokinetics of pirfenidone were observed in subjects
with mild to severe renal impairment compared with subjects with normal renal function. The parent
drug is predominantly metabolised to 5-carboxy-pirfenidone, and the pharmacokinetics of this
metabolite is altered in subjects with moderate to severe renal impairment. However, the predicted
amount of metabolite accumulation at steady state is not pharmacodynamically important because the
terminal elimination half-life is only 1–2 hours in these subjects. No dose adjustment is required in
patients with mild to moderate renal impairment who are receiving pirfenidone. The use of pirfenidone
is contraindicated in patients with severe renal impairment (CrCl <30ml/min) or end stage renal
disease requiring dialysis (see sections 4.2 and 4.3).
9
Population pharmacokinetic analyses from 4 studies in healthy subjects or subjects with renal
impairment and one study in patients with IPF showed no clinically relevant effect of age, gender or
body size on the pharmacokinetics of pirfenidone.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In repeated dose toxicity studies increases in liver weight were observed in mice, rats and dogs; this
was often accompanied by hepatic centrilobular hypertrophy. Reversibility was observed after
cessation of treatment. An increased incidence of liver tumours was observed in carcinogenicity
studies conducted in rats and mice. These hepatic findings are consistent with an induction of hepatic
microsomal enzymes, an effect which has not been observed in patients receiving Esbriet. These
findings are not considered relevant to humans.
A statistically significant increase in uterine tumours was observed in female rats administered
1500 mg/kg/day, 37 times the human dose of 2403 mg/day. The results of mechanistic studies indicate
that the occurrence of uterine tumours is probably related to a chronic dopamine-mediated sex
hormone imbalance involving a species specific endocrine mechanism in the rat which is not present
in humans.
Reproductive toxicology studies demonstrated no adverse effects on male and female fertility or
postnatal development of offspring in rats and there was no evidence of teratogenicity in rats
(1000 mg/kg/day) or rabbits (300 mg/kg/day). In animals placental transfer of pirfenidone and/or its
metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in
amniotic fluid. At high doses (≥450 mg/kg/day) rats exhibited a prolongation of oestrous cycle and a
high incidence of irregular cycles. At high doses (≥1000 mg/kg/day) rats exhibited a prolongation of
gestation and reduction in fetal viability. Studies in lactating rats indicate that pirfenidone and/or its
metabolites are excreted in milk with the potential for accumulation of pirfenidone and/or its
metabolites in milk.
Pirfenidone showed no indication of mutagenic or genotoxic activity in a standard battery of tests and
when tested under UV exposure was not mutagenic. When tested under UV exposure pirfenidone was
positive in
a photoclastogenic assay in Chinese hamster lung cells.
Phototoxicity and irritation was noted in guinea pigs after oral administration of pirfenidone and with
exposure to UVA/UVB light. The severity of phototoxic lesions was minimised by application of
sunscreen.
Environmental Risk Assessment (ERA)
Pirfenidone is not considered to present a potential risk to surface water, microorganisms and ground
water or to sediment-dwelling invertebrates.
6.
6.1 List of excipients
Capsule content
Microcrystalline cellulose
Croscarmellose sodium
Povidone
Magnesium stearate
10
Capsule shell: body
Indigo carmine (E132)
Titanium dioxide (E171)
Gelatin
Capsule shell: cap
Red iron oxide (E172)
Yellow iron oxide (E172)
Titanium Dioxide (E171)
Gelatin
Imprinting Ink
Brown S-1-16530 ink containing:
Shellac
Iron oxide black (E172)
Iron oxide red (E172)
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
6.5
Nature and contents of container
Pack sizes
2-week treatment initiation pack
1 x PVC/PE/PCTFE aluminium foil blister card containing 21 capsules, packaged together with
1 x PVC/PE/PCTFE aluminium foil blister card containing 42 capsules, for a total of 63 capsules per
pack.
4-week treatment maintenance pack
4 x 1-week treatment packs of PVC/PE/PCTFE aluminium foil blister cards each containing
63 capsules for a total of 252 capsules per pack.
250 ml white HDPE bottle with child-resistant closure containing 270 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal <and other handling>
No special requirements.
7.
InterMune UK Ltd.
4th Floor
One Victoria Street
11
Bristol
BS1 6AA
UK
Tel.: +44 (0) 207 893 3988
Fax.: +44 (0) 207 893 3983
8.
EU/1/11/667/001
EU/1/11/667/002
EU/1/11/667/003
9.
Date of first authorisation: 28 February 2011
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
12
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Catalent UK Packaging Limited (trading as Catalent Pharma Solutions),
Sedge Close,
Headway,
Great Oakley,
Corby,
Northamptonshire,
NN18 8HS, United Kingdom.
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
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 MAH shall set up a post-authorisation safety study (PASS) in the form of an observational
registry in order to collect information on demographics of patients prescribed Esbriet and suspected
adverse drug reactions. This is in order to further characterise the long term safety profile of
pirfenidone based on the important identified, potential risks and missing information as detailed in
the Esbriet Risk Management Plan.
The MAH must ensure that at launch all physicians who are expected to prescribe Esbriet are provided
with a physician information pack containing the following:
Product information (SPC)
Physician information (safety checklists)
Patient information (PIL)
The safety checklist about Esbriet should contain the following key elements related to liver function
and photosensitivity:
Liver function
Esbriet is contraindicated in patients with severe hepatic impairment or end stage liver disease.
Elevations of serum transaminases can occur during treatment with Esbriet.
There is a need to monitor liver function tests prior to initiation of treatment with Esbriet and at
regular intervals thereafter.
Close monitoring is required of any patients who develop liver enzyme elevation with
appropriate dose adjustment or discontinuation.
Photosensitivity
Patients should be informed that Esbriet is known to be associated with photosensitivity
reactions and that preventative measures have to be taken.
Patients are advised to avoid or reduce exposure to direct sunlight (including sunlamps).
14
Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun
exposure, and to avoid other medications known to cause photosensitivity.
The physician information should encourage the prescribers to report serious adverse
reactions and clinically significant ADRs of special interest including:
Photosensitivity
reactions and skin rashes
Abnormal
liver function tests
Any other clinically significant ADRs based on the judgment of the prescriber
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, 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 01 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates
of the RMP agreed by the CHMP.
In particular a PASS Registry will be used to collect additional data regarding all identified and
potential safety concerns, and for important missing information.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following 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 European Medicines Agency
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON - BOTTLE 250 ML
1.
Esbriet 267 mg hard capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
LIST OF EXCIPIENTS
4.
Hard capsule
270 capsules
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
Do not store above 30°C.
18
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
InterMune UK Ltd.
4th Floor
One Victoria Street
Bristol
BS1 6AA
United Kingdom
EU/1/11/667/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Esbriet
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON –2-WEEK TREATMENT INITIATION PACK
1.
Esbriet 267 mg hard capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
LIST OF EXCIPIENTS
4.
Hard capsule
Initiation Pack
2-week treatment initiation pack containing a total of 63 capsules:
Week 1 – 21 capsules
Week 2 – 42 capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet inside the pouch before use.
Oral use.
OPENING INSTRUCTIONS
Press and hold
1
Lift
Here
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
20
Pull and slide blister card out
2
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
InterMune UK Ltd.
4th Floor
One Victoria Street
Bristol
BS1 6AA
United Kingdom
EU/1/11/667/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Esbriet
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – 1-WEEK TREATMENT PACK OF 63 CAPSULES
1.
Esbriet 267 mg hard capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
LIST OF EXCIPIENTS
4.
Hard capsule
1-week treatment pack of 63 capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet inside the pouch before use.
Oral use.
OPENING INSTRUCTIONS
Press and hold
2
Lift
Here
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
22
Pull and slide blister card out
1
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
InterMune UK Ltd.
4th Floor
One Victoria Street
Bristol
BS1 6AA
United Kingdom
EU/1/11/667/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Esbriet
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON – 4-WEEK TREATMENT MAINTENANCE PACK CONTAINING
4 X 1-WEEK TREATMENT PACKS OF 63 CAPSULES
1.
Esbriet 267 mg hard capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
LIST OF EXCIPIENTS
4.
Hard capsule
4-week treatment pack of 252 capsules
63 capsules per week
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
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
24
InterMune UK Ltd.
4th Floor
One Victoria Street
Bristol
BS1 6AA
United Kingdom
EU/1/11/667/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Esbriet
25
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
LABEL - BOTTLE 250 ML
1.
Esbriet 267 mg hard capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
LIST OF EXCIPIENTS
4.
Hard capsule
270 capsules
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
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
26
InterMune
Bristol BS1 6AA, United Kingdom
EU/1/11/667/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
27
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER CARD – 2-WEEK TREATMENT INITIATION PACK
1.
Esbriet 267 mg capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
InterMune UK Ltd.
4.
EXPIRY DATE
EXP
5.
BATCH NUMBER
Lot
6.
OTHER
2-week pack
WEEK 1
WEEK 2
AM, Noon, PM
Day 1, Day 2, Day 3, Day 4, Day 5 Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13,
Day 14
28
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER CARD – 1-WEEK TREATMENT PACK OF 63 CAPSULES
1.
Esbriet 267 mg capsules
Pirfenidone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 267 mg pirfenidone.
3.
InterMune UK Ltd.
4 EXPIRY DATE
EXP
5 BATCH NUMBER
Lot
6.
OTHER
1-week pack
AM, Noon, PM
Day 1, Day 2, Day 3, Day 4, Day 5 Day 6, Day 7
29
B. PACKAGE LEAFLET
30
PACKAGE LEAFLET: INFORMATION FOR THE USER
Esbriet 267 mg hard capsules
Pirfenidone
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 Esbriet is and what it is used for
2. Before you take Esbriet
3. How to take Esbriet
4. Possible side effects
5.
How to store Esbriet
6.
Further information
1.
What Esbriet is and what it is used for
Esbriet contains the active substance pirfenidone and it is used for the treatment of mild to moderate
Idiopathic Pulmonary Fibrosis (IPF) in adults.
IPF is a condition in which the tissues in your lungs become swollen and scarred over time, and as a
result makes it difficult to breathe deeply. This makes it hard for your lungs to work properly. Esbriet
helps to reduce scarring and swelling in the lungs, and helps you breathe better.
2.
Before you take Esbriet
Do not take Esbriet
if you are allergic (hypersensitive) to the active substance pirfenidone or any of the other
ingredients in this medicine (for the full list of ingredients see section 6: Further information)
if you are taking a medicine called fluvoxamine (used to treat depression and obsessive
compulsive disorder (OCD))
if you have severe or end stage liver disease
if you have severe or end stage kidney disease requiring dialysis.
If any of the above affects you, do not take Esbriet. If you are unsure ask your doctor or pharmacist.
Take special care with Esbriet
You may become more
sensitive to sunlight
(
photosensitivity reaction) when taking Esbriet.
Avoid the sun (including sunlamps) whilst taking Esbriet. Wear sunblock daily and cover your
arms, legs and head to reduce exposure to sunlight (see section 4: Possible side effects).
You should not take other medicines, such
as tetracycline antibiotics (such as doxycycline),
which may make you more sensitive to sunlight.
You should tell your doctor if you suffer from mild to moderate liver problems.
You should stop smoking before and during treatment with Esbriet. Cigarette smoking can
reduce the effect of Esbriet.
Esbriet may cause dizziness and tiredness. Be careful if you have to take part in activities where
you have to be alert and co-ordinated.
Esbriet can cause weight loss. Your doctor will monitor your weight whilst you are taking this
medicine.
31
You will need a blood test before you start taking Esbriet and at monthly intervals for the first
6 months and then every 3 months thereafter whilst you are taking this medicine to check whether
your liver is working properly. It is important that you have these regular blood tests for as long as you
are taking Esbriet.
Children and adolescents
Do not give Esbriet to children and adolescents under the age of 18.
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 the following medicines, as they may change the effect
of Esbriet.
Medicines that may increase side effects of Esbriet:
ciprofloxacin (a type of antibiotic)
amiodarone (used to treat some types of heart disease)
propafenone (used to treat some types of heart disease).
Medicines that may reduce how well Esbriet works:
rifampicin (a type of antibiotic).
Ask your doctor or pharmacist for advice before taking any medicine.
Taking Esbriet with food and drink
Take this medicine during or after a meal to reduce the risk of side effects such as nausea (feeling sick)
and dizziness (see section 4: Possible side effects).
Do not drink grapefruit juice whilst taking this medicine. Grapefruit may prevent Esbriet from
working properly.
Pregnancy and breastfeeding
Do not take this medicine if you are pregnant, planning to become pregnant or think you might be
pregnant. The risk to the unborn child is unknown.
If you are breastfeeding, speak to your doctor or pharmacist before taking Esbriet. It is not known if
Esbriet passes into breast milk. If you are breastfeeding and you need to take Esbriet, your doctor will
discuss the risks and benefits of taking this medicine while breastfeeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Do not drive or use machines if you feel dizzy or tired after taking Esbriet.
3.
How to take Esbriet
Always take Esbriet exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Your medicine will usually be given to you in increasing doses as follows:
for the first 7 days take 1 capsule 3 times a day with food (a total of 801 mg/day)
from day 8 to 14 take 2 capsules, 3 times a day with food (a total of 1602 mg/day)
from day 15 onwards, take 3 capsules 3 times a day with food (a total of 2403 mg/day).
32
Swallow the capsules whole with a drink of water, during or after a meal to reduce the risk of
side effects such as nausea (feeling sick) and dizziness. If symptoms continue, see your doctor.
Dose reduction due to side effects
Your doctor may reduce your dose if you suffer from side effects such as, stomach problems, any skin
reactions to sunlight or sun lamps, or significant changes to your liver enzymes
.
If you take more Esbriet than you should
Contact your doctor, pharmacist or nearest hospital casualty department immediately
if you have taken
more capsules than you should, and take your medicine with you.
If you forget to take Esbriet
If you forget a dose take it as soon as you remember, but separate each dose by at least 3 hours. Do not
take a double dose to make up for a forgotten dose.
If you stop taking Esbriet
Do not stop taking Esbriet unless your doctor tells you to. If for any reason you have to stop taking
Esbriet for more than 14 consecutive days, your doctor will restart your treatment with 1 capsule
3 times a day, gradually increasing this to 3 capsules 3 times a day.
If you have any questions on the use of this medicine, ask your doctor or pharmacist.
4.
Possible side effects
Like all medicines, Esbriet can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1000).
Stop taking Esbriet and tell your doctor immediately
If you experience a serious allergic (hypersensitivity) reaction such as swelling of the face, lips
and/or tongue, difficulty breathing or wheezing.
If you experience a severe skin reaction to sunlight or sunlamps such as blistering and/or marked
peeling of the skin. Severe photosensitivity reactions are uncommon. Avoid the sun (including
sunlamps) whilst taking Esbriet, wear sunblock daily and cover your arms, legs and head to reduce
exposure to sunlight to limit this reaction
.
Other side effects may include
Tell your doctor or pharmacist as soon as possible if you notice any of the following side effects listed
below.
Very common side effects
(affects more than 1 user in 10):
skin reactions after going out in the sun or using sunlamps
feeling sick (nausea)
tiredness
diarrhoea
indigestion or stomach upset.
Common side effects
(affects 1 to 10 users in 100):
infections of the throat or the airways going into the lungs and/or sinusitis
bladder infections
weight loss
loss of appetite
difficulty sleeping
33
dizziness, headache
feeling sleepy
changes in taste
hot flushes
shortness of breath
cough
stomach problems such as acid reflux, vomiting, feeling bloated, abdominal pain and discomfort,
heart burn, feeling constipated and passing wind
blood tests may show increased levels of liver enzymes
skin problems such as itchy skin, skin redness or red skin, dry skin, skin rash
muscle pain, aching joints/joint pains
feeling weak or feeling low in energy
chest pain
sunburn.
If any of the side effects becomes serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
5.
How to store Esbriet
Keep out of the reach and sight of children.
Do not use Esbriet after the expiry date which is stated on the bottle label, blister and carton after
EXP. The expiry date refers to the last day of that month.
Do not store this medicine above 30ºC.
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 Esbriet contains
The active substance is pirfenidone. Each capsule contains 267 mg of pirfenidone.
The other ingredients are:
Capsule filling: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate
Capsule shell (body): gelatin, indigo carmine (E132), titanium dioxide (E171)
Capsule shell (cap): gelatin, red iron oxide (E172), yellow iron oxide (E172), titanium dioxide
(E171)
Capsule brown printing ink: shellac, iron oxide black (E172), iron oxide red (E172), iron oxide
yellow (E172).
What Esbriet looks like and contents of the pack
Esbriet hard capsules (capsules) have a blue opaque body and a gold opaque cap with ‘InterMune
267 mg’ printed in brown ink. The capsules contain a white to pale yellow powder.
Your medicine is provided in either a 2-week treatment initiation pack, a 4-week treatment pack or in
a bottle.
The 2-week treatment initiation pack contains a total of 63 capsules - a Week-1 blister card containing
21 capsules (1 capsule per pocket) and a Week-2 blister card containing 42 capsules (2 capsules per
pocket).
The 4-week treatment pack contains 4 x 1-week blister cards each containing 63 capsules (3 capsules
per pocket) for a total of 252 capsules.
34
The bottle pack contains 270 capsules.
Not all pack sizes may be marketed.
Marketing Authorisation holder and Manufacturer
Marketing Authorisation holder
InterMune UK Ltd., 4th Floor, One Victoria Street, Bristol,
BS1 6AA, United Kingdom.
Manufacturer
Catalent UK Packaging Limited (trading as Catalent Pharma Solutions), Sedge Close, Headway, Great
Oakley, Corby, Northamptonshire, NN18 8HS, United Kingdom.
This leaflet was last approved in
Detailed information on this medicine is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
There are also links to other websites about rare diseases and treatments.
35
Source: European Medicines Agency
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