Vantobra

Each single-dose ampoule of 1.7 ml contains 170 mg tobramycin.

d For the full list of excipients, see section 6.1.

e s i 3. PHARMACEUTICAL FORM r o Nebuliser solution.

h t A clear to slightly yellow solution.

u a

4. CLINICAL PARTICULARS r e g 4.1 Therapeutic indications

n Vantobra is indicated for the management of chronic pulmonaryo infection due to Pseudomonas aeruginosa l in patients aged 6 years and older with cystic fibrosis (CF).

o Consideration should be given to official guidance on the appropriate use of antibacterial agents.

n

t 4.2 Posology and method of administratiocn

pautients

Posology

d oₐₗ

The dose of Vantobra is the same for all within the approved age range, regardless of age or weight.

r The recommended dose is one ampoule (170 mg/1.7 ml) administered twice daily (i.e. total daily dose is 2 p ampoules) for 28 days. The dose interv should be as close as possible to 12 hours and not less than 6 hours. Vantobra is taken in alternlating cycles of 28 days. A cycle of 28 days of active therapy (on-treatment period) and 28 days of rest froma treatment (off-treatment period) should be maintained.

n Missed doses i

In case of a micssed dose with at least 6 hours remaining until the next dose, the patient should inhale the dose soon as poissible. If less than 6 hours remain to the next planned dose, the patient should wait for the next d and not inhale more to make up for the missed dose.

ᵃᵈˢᵒˢᵉ e

Duration of treatment

M

Treatment should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the treatment taking into account that long-term safety data are not available for

Vantobra. If clinical deterioration of pulmonary status is evident, additional or alternative anti-pseudomonal therapy should be considered. See also information on clinical benefit and tolerability in sections 4.4, 4.8 and 5.1.

Special populations

Elderly patients (≥65 years)

There are insufficient data in this population to support a recommendation for or against dose adjustment.

Renal impairment

There are no data in this population to support a recommendation for or against dose adjustment with Vantobra. Please also refer to nephrotoxicity information in section 4.4 and excretion information in section 5.2.

Hepatic impairment

No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolised, an effect of hepatic impairment on the exposure to tobramycin is not expected.

d Patients after organ transplantation

e Adequate data do not exist for the use of inhaled tobramycin in patients after organ transplantation. No s recommendation for or against dose adjustment can be made for patients after organ transplantation.

i r Paediatric population o

There is no relevant use of Vantobra in children below 6 years of age.

h t Method of administration u a Inhalation use.

r Vantobra is administered by inhalation using the Tolero nebuliser handset perovided in the pack. For detailed instructions on use see section 6.6. g n Vantobra must not be administered by any other route or using any other device than the one provided in the o pack. The use of an alternative untested nebuliser system may alter the pulmonary deposition of the active l substance. And this in turn may alter efficacy and safety of the product.

o Where patients are receiving several inhaled medicinal products and chest physiotherapy, it is recommended n that Vantobra is used last.

t c 4.3 Contraindications u

d Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

o r p 4.4 Special warnings and precautions for use

l Ototoxicity a

Ototoxicity, manifested as both auditory toxicity (hearing loss) and vestibular toxicity, has been reported n with parenteral aiminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Tinnitus may bce a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution.

i d toxicity, as measured by complaints of hearing loss or by audiometric evaluations, was observed Aʷuⁱᵗdʰite poarryenteral aminoglycosides and may be considered also for the inhalation route of administration. In open label studies and post-marketing experience, some patients with a history of prolonged previous or M

concomitant use of intravenous aminoglycosides have experienced hearing loss. Physicians should consider the potential for aminoglycosides to cause vestibular and cochlear toxicity and carry out appropriate assessments of auditory function during Vantobra therapy.

In patients with a predisposing risk due to previous prolonged systemic aminoglycoside therapy it may be necessary to consider audiological assessment before initiating Vantobra therapy. If a patient reports tinnitus or hearing loss during aminoglycoside therapy, the physician should consider referring them for audiological assessment.

Nephrotoxicity

Nephrotoxicity has been associated with parenteral aminoglycoside therapy. There was no evidence of nephrotoxicity during clinical trials with inhaled tobramycin and Vantobra. Caution should be exercised when prescribing Vantobra to patients with known or suspected renal dysfunction. According to current clinical practice baseline renal function should be assessed. Urea and creatinine levels should be reassessed after every 6 complete cycles of Vantobra therapy (180 days of nebulised aminoglycoside therapy).

Monitoring of serum tobramycin concentrations

Patients with known or suspected auditory or renal dysfunction should be monitored for serum tobramycin d concentrations. If oto- or nephrotoxicity occurs in a patient receiving Vantobra, tobramycin therapy should e be discontinued until serum concentration falls below 2 µg/ml.

s i Serum concentrations greater than 12 µg/ml are associated with tobramycin toxicity and treatment should be r discontinued if concentrations exceed this level.

o h Finger The serum concentration of tobramycin should only be monitored using validated methods. prick t blood sampling is not recommended due to the risk of contamination of the sample.

u Bronchospasm a

Bronchospasm can occur with inhalation of medicinal products and has been reported with the use of r nebulised tobramycin. Bronchospasm should be treated as medically appropriate.

e

The first dose of Vantobra should be used under supervision of a physgician, after taking a bronchodilator if this is part of the current regimen for the patient. FEV₁ should be menasured before and after nebulisation.

o If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether the l benefits of continued use of Vantobra outweighs the risks to the patient. If an allergic response is suspected, Vantobra should be discontinued. o n Neuromuscular disorders

t Vantobra should be used with great caution in patients with neuromuscular disorders such as Parkinsonism cy or other conditions characterized by myasthenia, including myasthenia gravis, as aminoglycosides may aggravate muscle weakness due to a potentuial curare-like effect on neuromuscular function.

haemoptysids ould

Haemoptysis

o Inhalation of nebulised tobramycin solutions ma induce a cough reflex. The treatment with Vantobra in r patients with active, severe sh be initiated only if the benefits of treatment are considered to p outweigh the risks of inducing further haemorrhage.

l Development of resistaance

The development n of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent potential risks asisociated with antibiotic therapy. Development of resistance during inhaled tobramycin therapy could c limit treatment options during acute exacerbations; this should be monitored.

i d precautions

Pᴼaᵗʰtiᵉeʳnets rTehceisiving concomitant parenteral aminoglycoside therapy (or any medicine affecting renal excretion, such as diuretics) should be monitored as clinically appropriate taking into account the risk of cumulative M

toxicity. includes monitoring of serum concentrations of tobramycin.

Safety and efficacy have not been studied in patients colonised with Burkholderia cepacia.

No interaction studies have been performed. Based on the interaction profile for tobramycin following intravenous and aerosolised administration, concurrent and/or sequential use of Vantobra is not recommended with other medicinal products with nephrotoxic or ototoxic potential, such as:

• amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity);
• platinum compounds (risk of increased nephrotoxicity and ototoxicity);

Concurrent use of Vantobra with diuretic compounds (such as ethacrynic acid, furosemide, urea or mannitol) is not recommended. Such compounds can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue (see section 4.4).

Other medicinal products that have been reported to increase the potential toxicity of parenterally administered aminoglycosides include:

d - anticholinesterases, botulinum toxin (neuromuscular effects).

e In clinical studies patients using inhaled tobramycin continued to take dornase alfa, bronchodilators, inshaled i corticosteroids and macrolides. No evidence of drug interactions with these medicines was identified.

r o h 4.6 Fertility, pregnancy and lactation

tₙₒ

u Pregnancy

cana

There are limited data from the parenteral use of tobramycin in pregnant women. There are adequate data from the use of tobramycin administered by inhalation in pregnant women. Animal studies do not indicate a r teratogenic effect of tobramycin (see section 5.3). However, aminoglycosides cause foetal harm (e.g., e congenital deafness and nephrotoxicity) when high systemic concentrations are achieved in a pregnant g woman. Systemic exposure following inhalation of Vantobra is very low (see section 5.2). If Vantobra is used during pregnancy, or if the patient becomes pregnant while takning Vantobra, she should be informed of the potential hazard to the foetus.

o l Vantobra should not be used during pregnancy unless the benefits to the mother outweigh the risks to the o foetus or baby.

n Breast-feeding

tecause

Tobramycin is excreted in human breast milk after systemic administration. The amount of tobramycin c excreted in human breast milk after administration by inhalation is not known, though it is estimated to be u very low considering the low systemic exposure. B of the potential for ototoxicity and nephrotoxicity in infants, a decision should be maded whether to terminate breast-feeding or discontinue treatment with Vantobra, taking into account the importance of the treatment to the mother.

o r Fertility

p No effect on male or female fertility was observed in animal studies after subcutaneous administration (see section 5.3). l a n 4.7 Effects on i ability to drive and use machines

c i has no or negligible influence on the ability to drive and use machines.

d Vantoebra

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Summary of the safety profile

In controlled clinical trials with Vantobra the most frequent adverse reactions in cystic fibrosis patients with P. aeruginosa infection were cough and dysphonia.

Clinical experience with tobramycin nebuliser solutions reports dysphonia and tinnitus in patients treated with tobramycin. The episodes of tinnitus were transient and resolved without discontinuation of tobramycin therapy.

Occasionally, patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides may experience hearing loss. Parenteral aminoglycosides have been associated with hypersensitivity, ototoxicity and nephrotoxicity (see section 4.4).

Long-term safety data are not available for Vantobra (see also section 5.1).

Tabulated list of adverse reactions

Adverse drug reactions reported for tobramycin nebuliser solution are listed in Table 1.

Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ d class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each e frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category is provided using the following convention: Very common (≥ s 1/10);

i Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); r Very rare (< 1/10,000). o h Table 1 Adverse reactions

t u

System Organ Class	Frequency category	Adverse Reactions a
Infections and infestations
	Rare	Laryrgindidiasisna tis
	Very rare	Fegal infectionun c gᴼʳᵃˡ
Blood and lymphatic system disorders	n
	Very rare	Lymphadenopathy
Immune system disorders	o
	l rare	Hypersensitivity
Metabolism and nutrition disorders	o
	ⱽᵃʳᵉ nᴿᵉʳʸ	Anorexia
Nervous system disorders
u	ᴿᵃtᵉVeʳyr c	Dizziness Aphonia Headache
d	rare	Somnolence
Ear and labyrinth disorders o
r p	Rare	Hearing loss Tinnitus
l	Very rare	Ear pain Ear disorder
Vascular disorders a n
i c	Rare	Haemoptysis Epistaxis
i and mediastinal d
Respies ry, thoracicdisorderorat M	Uncommon	Dyspnoea Dysphonia Pharyngitis Cough
	Rare	Asthma Lung disorder Chest discomfort Productive cough Rhinitis Bronchospasm
	Very rare	Hypoxia Hyperventilation
		Sinusitis
Gastrointestinal disorders
	Rare	Vomiting Mouth ulceration Nausea Dysgeusia
	Very rare	Diarrhoea Abdominal pain
Skin and subcutaneous tissue disorders
	Rare	Rash
	Very rare	Urticaria Pruritus
Musculoskeletal and connective tissue disorders		o
	Very rare	Back pain h
General disorders and administration site conditions		t u
	Rare	a AᵃⁱⁿriaaPyrexniᴾ sthe e pain
	Very rare	gChₜlatseMₛesiₜₑ a
Investigations	n
	Rare o l	Pulmonary function decreased

d e s i r

o Paediatric population

npediatric

There was no difference in the safety profile between and adult patient population treated with Vantobra. t c Reporting of suspected adverse reactions u

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows d continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked o to report any suspected adverse reactions via the national reporting system listed in Appendix V.

r p

a Administration by inhalation results in low systemic bioavailability of tobramycin. Symptoms of aerosol n overdose may incilude severe hoarseness.

c the event i of accidental ingestion of Vantobra, toxicity is unlikely as tobramycin is poorly absorbed from d bramycin intact gastrointestinal tract.

ᴵᵃⁿⁿ e

In the event of inadvertent administration of Vantobra by the intravenous route, signs and symptoms of M

parenteral to overdose may occur, including dizziness, tinnitus, vertigo, loss of hearing acuity, respiratory distress and/or neuromuscular blockage and renal impairment.

Acute toxicity should be treated with immediate withdrawal of Vantobra and baseline tests of renal function should be undertaken. Assessment of tobramycin serum concentrations may be helpful in monitoring overdose. In the case of any overdose, the possibility of drug interactions with alterations in the elimination of Vantobra or other medicinal products should be considered.

5.1 Farmakodynamika

Pharmacotherapeutic group: Antibacterials for systemic use, Aminoglycoside antibacterials.

ATC code: J01GB01

Mechanism of action

Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell d envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly greater than e inhibitory concentrations.

s i Breakpoints r Established susceptibility breakpoints for parenteral administration of tobramycin are inapproopriate in the aerosolised administration of the medicinal product. Sputum of cystic fibrosis patients exhibits an inhibitory hₗ

action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations t following treatment with aerosolised tobramycin to be ten to twentyfive-fold above the Minimum Inhibitory u Concentration (MIC) for both P. aeruginosa growth suppression and control of bactericida activity. In a controlled clinical trials, 97% of patients receiving tobramycin nebuliser solution achieved sputum concentrations 10-fold of the highest P. aeruginosa MIC cultured from the patient and 95% of patients r receiving tobramycin nebuliser solution achieved 25-fold of the highest MIC.

e g Susceptibility

In the absence of conventional susceptibility breakpoints for the nnebulised route of administration, caution must be exercised in defining organisms as susceptible or insusceoptible to nebulised tobramycin.

l In clinical studies with TOBI, most patients with P. aeruginosa isolates with tobramycin MICs < 128 µg/ml o at baseline showed improved lung function following treatment with TOBI. Patients with a P. aeruginosa isolate with MIC 128 µg/ml at baseline are less liknely to show a clinical response. However, seven of 13 patients (54%) in the placebo-controlled trials who acquired isolates with MICs of 128 µg/ml while using t TOBI had improvement in pulmonary function.

c u Based upon in-vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to Vadntobra therapy as follows:

Susceptible	oₑᵤₛ Pseudomonas aeruginosa r Haemophilus influenzae p aur
Insusceptible c	l BturallococausepaciaS aphy deric ckho Stenotrophomonas maltophilia n i Alcaligenes xylosoxidans

i d with the 28-days on and 28-days off dose regimen in clinical studies showed a small but clear in tobramycin, amikacin and gentamicin MICs for P. aeruginosa isolates tested. Each additional 6 Tᵐinrᵒcerⁿaeᵗtaʰmesˢeent of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months Mof controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P. aeruginosa isolated from chronically infected CF patients is impermeability, defined by a general lack of susceptibility to all aminoglycosides. P. aeruginosa isolated from CF patients has also been shown to exhibit adaptive aminoglycoside resistance that is characterised by a reversion to susceptibility when the antibiotic is removed.

Other information

There is no evidence that patients treated with up to 18 months with tobramycin nebuliser solution were at a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in untreated patients. Aspergillus species were more frequently recovered from the sputum of treated patients; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with similar frequency as in the control group.

Aerosol characteristics

Table 2: Comparative performance data for the clinical test and reference batches:

Vantobra /Tolero nebuliser handset¹, and TOBI/PARI LC PLUS².

Performance parameter/ Drug/Device combination*	Vantobra/Tolero	TOBI/PARI LC PLUS
Total Drug Delivered [mg±SD]	96 ± 4.4	101 ± 8.5
Fine Particle Mass < 5 µm [mg±SD]	72 ± 6.5	65 ± 7.1
Drug Delivery Rate [mg/min]	27 ± 5.0	7 ± 0.9
Mass Median Aerodynamic Diameter [µm ± SD]	3.8 ± 0.3	3.6 ± 0.4
Geometric Standard Deviation ±SD	1.5 ± 0.0	2.3 ± 0.2
Nebulisation Time [min]	3.9 ± 0.6	15.3 ± 0.6

d e s i r o h t *Results from breath simulation and cascade impactor measurements. u

¹ connected with an eBase controller or eFlow rapid controller

a ² connected with a PARI Boy SX compressor

r The drug delivery rate of Vantobra with the Tolero nebuliser is independent of the breathing pattern applied e i.e. adult or child in contrast to the PARI LC PLUS nebuliser.

g Clinical efficacy and safety n

Limited data from one controlled clinical study over one treatmoent cycle indicate that the improvement in lung function was maintained above baseline during the 28-dayl off-treatment period.

As a result of study 12012.101, lung function improvement FEV₁% predicted relative to baseline increased o by 8.2 ± 9.4% under Vantobra and by 4.8 ± 9.6% under the reference therapy in the first treatment cycle n showing non-inferior (p=0.0005) efficacy. CFU reduction as an indicator for suppression of P. aeruginosa was comparable for Vantobra and the reference prtoduct.

c u 5.2 Pharmacokinetic properties

d Absorption and distribution o

r The systemic exposure to ro toubtepra. mycin after inhalation of Vantobra is expected to emerge primarily from the inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable extent when l administered via a theero osroaall ₐₜₐ Inhalation of nebulised tobramycin produces high sputum concentrations and low plasma levels.

n i For comparativce d please refer to Table 2 in section 5.1 i th heou erndd of a 4-weeks dosing cycle of Vantobra (170 mg/1.7 ml twice daily) in cystic fibrosis patients, ᴬmᵗaximeum tobramycin plasma concentrations (Cmax) of 1.27 ± 0.81 µg/ml were reached at approximately one after inhalation. Sputum concentrations were higher and more variable with Cmax of 1,951 + 2,187 M

µg/g. After administering a single dose of Vantobra 170 mg to healthy volunteers Cmax of 1.1 + 0.4 µg/ml were reached after a tmax of approximately 4 hours.

Distribution

Less than 10% of tobramycin is bound to plasma proteins.

Biotransformation

Tobramycin is not metabolised and is primarily excreted unchanged in the urine.

Elimination

The elimination of tobramycin administered by the inhalation route has not been studied.

Following intravenous administration, systemically absorbed tobramycin is eliminated by glomerular filtration. The elimination half-life of tobramycin from serum is approximately 2 hours.

Unabsorbed tobramycin following administration by inhalation is probably eliminated primarily in expectorated sputum.

d 5.3 Preclinical safety data

e s Non-clinical data reveal that the main hazard for humans, based on conventional studies of safety i pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reprodurction and development, consists of renal toxicity and ototoxicity. In repeated dose toxicity studies it haso been shown that target organs of toxicity are the kidneys and vestibular/cochlear functions. In general, toxicity is seen at h higher systemic tobramycin levels than are achievable by inhalation of the recommended clinical dose.

t u No reproduction toxicology studies have been conducted with tobramycin administered by inhalation. a Subcutaneous administration at doses of 100 mg/kg/day in rats and the maximum tolerated dose of 20 mg/kg/day in rabbits during organogenesis was not teratogenic. Teratogenicity could not be assessed at r higher parenteral doses in rabbits as they induced maternal toxicity and abortion. Based on available data e from animals a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded. Tobramycin g did not impair fertility in male or female rats at subcutaneous doses up to 100 mg/kg/day.

n o 6. PHARMACEUTICAL PARTICULARS l

o 6.1 List of excipients

n Sodium chloride

t Calcium chloride

c Magnesium sulphate

u Sulphuric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)d

Water for injections o

r 6.2 Incompatibilities p

l In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal a products in the nebuliser.

n i 6.3 Shelf life

c i years d

ᵀ³ ʰᵉ e

contents of a single-dose ampoule should be used immediately after opening (see section 6.6).

M

Stability after opening of the pouch: 4 weeks when stored below 25 °C

6.4 Specjalne środki ostrożności podczas przechowywania

Store in a refrigerator (2 °C – 8 °C).

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Rodzaj i zawartość opakowania

Vantobra is supplied in polyethylene (PE) ampoules that are packed in sealed aluminium foil pouches (8 ampoules per pouch).

Outer carton contains:

• One carton with the medicinal product: 56 ampoules with nebuliser solution in 7 pouches.
• One carton with the Tolero nebuliser handset.

6.6 Special precautions for disposal and other handling d e The contents of one ampoule should be emptied into the medication reservoir of the Tolero nebuliser handset s be and administered by inhalation until no medicine is left in the reservoir. The Tolero nebuliser handset can i operated either with an eBase controller or with the eFlow rapid control unit. The performance prarameters from in vitro aerosol characterisation studies are identical for the two controllers and are showon in section 5.1, Table 2.

h t

• Nebulisation should take place in a well ventilated room. u
• The nebuliser handset must be kept horizontally during operation.

a

• The patient should sit in an upright position during inhalation. Inhalation should be performed by applying a normal breathing pattern without interruption. r
• The Tolero nebuliser handset must be cleaned and disinfected as descriebed in the instructions for use of the device.

g n Vantobra is a clear to slightly yellow solution, but some variability in colour may be observed, which does not indicate loss of activity if the product is stored as recommendoed.ly.

l Vantobra solution is a sterile, aqueous preparation for sinogle use on As it is preservative-free, the contents of the whole ampoule should be used immediately after opening and any unused solution should be n discarded. Opened ampoule should never be stored for re-use.

t Use a new Tolero nebuliser handset for eachc treatment cycle (28 days on-treatment) as provided with the medicine. u

d Any unused medicinal product or waste material should be disposed off in accordance with local o requirements.

r p 7. MARKETING AUlTHORISATION HOLDER

a PARI Pharma GmbH

n Moosstrasse 3 i

D-82319 Starncberg

i₀₎

d TGeelr.m: eany +49 (0) 89 – 74 28 46 - 10

Fax: +49 ( 89 – 74 28 46 - 30

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E-Mail: [email protected]

8. Numer pozwolenia

EU/1/14/932/001

9. Data wydania lub przedłużenia pozwolenia

18 March 2015

10. Data zatwierdzenia lub aktualizacji tekstu

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

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d e s i r o h t u a ANNEX II

r e g A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE n o B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE l o C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING n AUTHORISATION

t D. CONDITIONS OR RESTRICTIONcS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

PARI Pharma GmbH

Lochhamer Schlag 21

82166 Graefelfing

d GERMANY

e B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE s i r Medicinal products subject to medical prescription.

o h C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING t AUTHORISATION u a

• Periodic safety update reports r e The requirements for submission of periodic safety update reports for this medicinal product are set out in g the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines wneb-portal.

o l The marketing authorisation holder shall submit the first periodic safety update report for this product within 12 months following authorisation W. ITHo n

D. CONDITIONS OR RESTRICTIONS t REGARD TO THE SAFE AND EFFECTIVE c USE OF THE MEDICINAL PRODUCT

u

• Risk Management Plan (RMP) d o The MAH shall perform the requrired pharmacovigilance activities and interventions detailed in the p agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. l requesat

An updated RMP should be submitted:

Whenevern

At the i of the European Medicines Agency;

c i the risk management system is modified, especially as the result of new information

• • d being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

Mᵉ

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

d e s i ANNEX III r o LABELLING AND PACKAGE LEAFLET h t u a

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON