Leaflet ANDEMBRY 200mg solution for injection in pre-filled syringe
Indicated for: routine prevention of recurrent hereditary angioedema attacks
Route of administration: injectable
Substance: garadacimab (factor XIIa inhibitor monoclonal antibody)
ATC: B06AC07 (Blood and blood forming organs | Other hematological agents | Drugs used in hereditary angioedema)
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Use in children only as recommended in the leaflet or by a doctor.
Store in the refrigerator as instructed in the leaflet.
Store protected from light.
Garadacimab is a monoclonal antibody used to prevent attacks of hereditary angioedema in eligible patients. The disease causes episodes of painful swelling of the skin, digestive tract or airways. Garadacimab blocks factor XIIa, a component of the contact system, reducing activation of the cascade that leads to attacks.
It is given by subcutaneous injection according to the schedule set by the doctor. It is a preventive treatment, meaning it is used regularly to reduce attacks, not to rapidly treat an attack that has already started. Patients should still have an emergency plan and on-demand medicines, especially for throat swelling or breathing difficulty.
Side effects may include redness, pain, itching or bruising at the injection site, abdominal pain, blocked or runny nose, sore throat or cold-like symptoms. Like any biological medicine, it may cause hypersensitivity reactions. Not all long-term risks are known, and the doctor may monitor effectiveness and possible adverse reactions.
Seek urgent medical help if swelling of the tongue or throat, breathing difficulty, faintness, widespread hives, severe abdominal pain or rapid worsening of symptoms occurs. Tell the doctor if you are pregnant, breastfeeding, have infections, important allergies or a planned procedure. Regular administration is essential for prevention.
General data about ANDEMBRY 200mg
- Substance: garadacimab
- Product code: W71970001
- Concentration: 200mg
- Pharmaceutical form: solution for injection in pre-filled syringe
- Quantity: 1
- Product type: Generic medicine
- Prescription status: S - Medicines dispensed with a restricted medical prescription, reserved for use in certain specialized fields.
Leaflet ANDEMBRY 200mg
Contents of the package leaflet for the medicine ANDEMBRY 200mg solution for injection in pre-filled syringe
1. NAME OF THE MEDICINAL PRODUCT
ANDEMBRY 200 mg solution for injection in pre-filled syringe
ANDEMBRY 200 mg solution for injection in pre-filled pen
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
ANDEMBRY 200 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 200 mg of garadacimab* in 1.2 mL solution.
ANDEMBRY 200 mg solution for injection in pre-filled pen
Each pre-filled pen contains 200 mg of garadacimab* in 1.2 mL solution.
*Garadacimab is a fully human IgG4 monoclonal antibody produced in Chinese Hamster Ovary(CHO) cells by recombinant DNA technology.
Excipients with known effectEach pre-filled syringe/pen contains 19.3 mg of proline and 0.24 mg of polysorbate 80.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
The solution is a slightly opalescent to clear, brownish-yellow to yellow liquid.
The solution has a pH of approximately 6.1 and an osmolality of approximately 470 mOsm/kg.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
ANDEMBRY is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE)in adult and adolescent patients aged 12 years and older.
4.2 Posology and method of administration
This medicinal product should be initiated under the supervision of a healthcare professionalexperienced in the management of patients with HAE.
PosologyThe recommended dose of ANDEMBRY, in adults and children 12 years of age and above, is aninitial loading dose of 400 mg administered subcutaneously as two 200 mg injections on the first dayof treatment, followed by a monthly dose of 200 mg.
Consideration should be given to discontinuing treatment in patients with normal C1-INH HAE (nC1-
INH) who have shown insufficient reduction in attacks after 3 months of treatment (see section 4.4 and5.1).
ANDEMBRY is not intended for the treatment of acute HAE attacks (see section 4.4).
Missed dosesIf a dose of ANDEMBRY is missed, the patient should be instructed to administer the dose as soon aspossible.
Special populationsElderly
No dose adjustment is required for patients above 65 years of age (see section 5.2).
Renal and hepatic impairmentNo dose adjustment is required in patients with renal or hepatic impairment (see section 5.2).
Paediatric populationThe safety and efficacy of garadacimab in children less than 12 years have not been established.
No data are available.
Method of administrationANDEMBRY is intended for subcutaneous use only.
Each ANDEMBRY unit (pre-filled syringe or pre-filled pen) is intended for single use only (seesection 6.6).
The injection should be restricted to the following injection sites: the abdomen, the thighs and theupper outer arms (see section 5.2). Rotation of the injection site is recommended.
ANDEMBRY may be self-administered or administered by a caregiver only after training onsubcutaneous injection technique by a healthcare professional.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
Hypersensitivity reactionsHypersensitivity reactions have not been observed but may theoretically occur. In case of severehypersensitivity reactions, administration of garadacimab should be discontinued, and appropriatetreatment instituted.
GeneralANDEMBRY is not intended for treatment of acute HAE attacks. In case of breakthrough HAEattack, individualized treatment should be initiated with an approved rescue medicinal product.
There are limited data available on the use of garadacimab in HAE patients with nC1-INH (seesection 5.1).
Some subcategories of nC1-INH HAE may not respond to treatment with garadacimab due toalternative pathways that do not include FXII activation. It is recommended to perform genetic testing,if available, according to the current HAE guidelines and to discontinue the treatment if clinicalresponse is not observed (see sections 4.2 and 5.1).
Interference with coagulation test
ANDEMBRY can prolong activated partial thromboplastin time (aPTT) due to an interaction ofgaradacimab with the aPTT assay. The extent of aPTT prolongation could be variable depending ondrug exposure as well as additional parameters, such as natural variation in FXII levels, and othercoagulation factors. The reagents used in the aPTT laboratory test initiate intrinsic coagulation throughthe activation of FXII in the contact system, therefore inhibition of plasma FXIIa by ANDEMBRYcan prolong aPTT in this assay.
ExcipientsThis medicinal product contains 19.3 mg of proline in each pre-filled syringe/pen which is equivalentto 16.1 mg/mL. Proline may be harmful for patients with hyperprolinaemia, a rare genetic disorder inwhich proline builds up in the body.
This medicinal product contains 0.24 mg of polysorbate 80 in each pre-filled syringe/pen which isequivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
No dedicated drug-drug interaction studies have been conducted in humans. Garadacimab has onlybeen studied as a monotherapy and not in combination with other products indicated for long-termprophylaxis of HAE. The use of analgesic, antibacterial, antihistamine, anti-inflammatory andanti-rheumatic medications had no effect on the PK of garadacimab. For breakthrough HAE attacks,use of rescue medications such as plasma-derived and recombinant C1-INH or icatibant had no effecton the PK of garadacimab.
4.6 Fertility, pregnancy and lactation
There are no or limited amount of data from the use of garadacimab in pregnant women. Monoclonalantibodies such as garadacimab are transported across the placenta mainly during the third trimester ofpregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester ofpregnancy. A pre- and postnatal development study conducted in pregnant rabbits revealed noevidence of harm to the developing fetus. (see section 5.3). As a precautionary measure, it ispreferable to avoid the use of garadacimab during pregnancy.
Breast-feedingIt is unknown whether garadacimab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, and decrease to low concentrations soon afterwards.
Consequently, transfer of IgG antibodies to the newborns through milk may happen during the firstfew days. In this short period, a risk to the breast-fed child cannot be excluded. Afterwards,garadacimab could be used during breast-feeding if clinically needed.
FertilityEffect on fertility has not been evaluated in humans. Garadacimab had no effect on male or femalefertility in rabbits (see section 5.3).
4.7 Effects on ability to drive and use machines
ANDEMBRY has no or negligible influence on the ability to drive and use machines
4.8 Undesirable effects
The most commonly observed adverse reactions associated with ANDEMBRY were injection sitereactions (ISR) including injection site erythema, injection site bruising, injection site pruritus andinjection site urticaria, headache and abdominal pain.
Tabulated list of adverse reactionsTable 1 summarises adverse reactions observed in the VANGUARD pivotal trial, which included 39subjects with HAE who received at least 1 dose of ANDEMBRY.
The frequency of adverse reactions listed in Table 1 is defined using the following convention: verycommon (≥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).
Table 1: Adverse drug reactions (ADRs) obtained from clinical studies with ANDEMBRY
System organ class Adverse drug reaction Frequency
General disorders and administration site Injection site reactions* Commonconditions
Nervous system disorders Headache Common
Gastrointestinal disorders Abdominal pain Common
*Injection site reactions include, erythema, bruising, pruritus, and injection site urticaria
Paediatric populationThe safety of ANDEMBRY was evaluated in a subgroup of 11 subjects aged 12 to < 18 years old. Nodifference from the overall safety profile was seen between adults and children.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no available information to identify potential signs and symptoms of overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in hereditary angioedema, ATC code: B06AC07
Mechanism of actionGaradacimab is a fully human IgG4/lambda recombinant monoclonal antibody which binds to thecatalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. Theinhibition of FXIIa, the first factor activated in the contact system, prevents HAE attacks by blockingthe activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated withinflammation and swelling in HAE attacks.
Pharmacodynamic effectsConcentration-dependent inhibition of FXIIa-mediated kallikrein activity was demonstrated aftersubcutaneous administration of ANDEMBRY once monthly in patients with HAE.
Clinical efficacy and safetyVANGUARD pivotal study
The efficacy of ANDEMBRY for the routine prevention of recurrent attacks of hereditary angioedemain adult and adolescent patients 12 years of age and older with Type I or II HAE was studied in aphase 3, multicenter, randomised, double-blind, placebo-controlled parallel group study.
The study contained 64 patients aged 12 years and older including 58 adult and 6 pediatric patientswho experienced at least 2 attacks during the up to 2-month run-in period. Patients were randomisedinto 2 parallel treatment arms in a 3:2 ratio (garadacimab 200 mg monthly after an initial 400 mgloading dose or volume-match placebo) for a 6-month treatment period. Patients were required todiscontinue other prophylactic HAE treatment prior to entering the study. All patients were allowed touse on-demand medications for treatment of HAE attacks during the study.
Overall, 87.5% of patients had Type I HAE. A family history of HAE was reported for 89.1%, ahistory of laryngeal edema attacks for 59.4% of patients and 32.8% were on prior prophylactic HAEtreatments. During the study run-in period, attack rates of ≥ 3 attacks/month were observed in 59.4%of patients overall. Mean baseline number of attacks per month was 3.07 in the ANDEMBRY groupcompared to 2.52 in the placebo group.
The primary efficacy endpoint was the time-normalised number of HAE attacks from day 1 throughthe end of the 6-month treatment period. The key secondary endpoints were: the percent reduction inthe mean time-normalised number of HAE attacks, the number of subjects who were attack free fromday 1 through the end of the first 3-months the percent of subjects with good or excellent responses tothe SGART from day 1 through the end of the 6-month treatment period.
Table 2: Results of key primary and secondary efficacy measures (ITT analysis set)
ANDEMBRY 200 mg Placebo(N = 39) (N = 25)
Number of evaluable 39 24apatients, n
Primary endpoint
Total number of HAE attacks 63 264from Day 1 to 182
Time-normalised number of HAE attacks from Day 1 to 182
Mean (95% CI) 0.27 (0.05, 0.49) 2.01 (1.44, 2.57)
P-value* < 0.001
Adjusted LS meanb (95% CI) 0.22 (0.11, 0.47) 2.07 (1.49, 2.87)
Secondary endpoints
Percent reduction in time-normalised number of HAE attacksrelative to placeboc
Mean (95% CI) 86.51 (57.84, 95.68)
P-value* < 0.001
Percent (number) of subjects 71.79 (28) 8.33 (2)who were attack free fromday 1 through the end ofmonth 3
P-value* < 0.001
Percent (number) of subjects 82 (31) 33 (8)with good or excellentresponse to SGART at day
P-value* < 0.001
HAE - hereditary angioedema; ITT - intent to treat; N - number of patients in the ITT analysis set; LS- least squares; CI - confidence interval; SGART - Subjects Global Assessment of Response to
Therapya One patient had a treatment period of less than 30 Days and was therefore not included in theanalysisb After adjusting for baseline attack ratec Median percent reduction for this endpoint was 100
* A hierarchical testing procedure controls for the overall alpha level of 5% (2-sided)
Additional non-hierarchically tested secondary endpoints from day 1 to 182 were the mean (median)time-normalised number of HAE attacks requiring on-demand treatment, 0.23 (0.0) in subjects treatedwith ANDEMBRY compared to 1.86 (1.35) in the placebo group, and the mean (median)time-normalised number of moderate to severe HAE attacks, 0.13 (0.0) in subjects treated with
ANDEMBRY compared to 1.35 (0.83) in the placebo group.
The exploratory endpoint of Angioedema Quality of Life Questionnaire (AE-QoL) total and domain(functioning, fatigue/mood, fear/shame, and nutrition) scores, compared to the placebo at day 182(Table 3) showed improvement in the ANDEMBRY treated patients. A reduction of six points in the
AE-QoL has been defined as the minimal clinically important difference (MCID). Changes frombaseline greater than the MCID were observed in 88% of patients treated with ANDEMBRY.
Table 3: AE-QoL total score and domains change from baseline to day 182 (ITT analysis set)a
AE-QoL total score and ANDEMBRY 200 mg Placebodomains change from baseline (N=39) (N=25)to day 182b, mean (SD)
Patients Included in the 33 20
Analysis, n
Total Score -26.5 (17.9) -2.2 (19.1)
Functioning -35.8 (23.2) 1.9 (29.6)
Fatigue/Mood -21.1 (22.9) -5.8 (27.1)
Fears/Shame -28.0 (24.1) -2.5 (18.6)
Nutrition: -16.7 (23.3) -0.6 (16.5)
ITT = intention-to-treat; N = number of patients in the ITT Analysis Set; SD = standard deviation.a Angioedema Quality of Life is only answered by patients of age ≥ 18 years.b A lower AE-QoL score represents greater improvement
The efficacy profile in pediatric patients 12 years of age and older (n=6) was consistent with that ofthe overall population.
VANGUARD Open Label Extension Study
Patients who completed VANGUARD (n=57) in addition to patients from a phase 2 study (n=35)rolled over into the VANGUARD open-label extension study which also enrolled 69 new patients.
From the start of treatment through 16.7 months (median duration of exposure 9.49 months) 96/161(59.6%) patients remained attack-free. The safety and efficacy profile in adolescent patients ages 12years and older (n=10) was consistent with that of the overall population.
Normal C1-INH HAE population
Normal C1-INH HAE includes patients with known or unknown mutations. The safety and efficacy ofgaradacimab was evaluated in 6 patients with known mutations: HAE-FXII (n=3) or HAE-PLG(plasminogen) (n=3) in the phase 2 study 2001.
Among the three genetically confirmed HAE-FXII patients enrolled, one withdrew during the secondmonth of the treatment period due to lack of efficacy after showing a reduction in overall attack ratefrom 4.35 to 3.51 attacks per month and a reduction in severe attacks from 1.09 to 0.58 attacks permonth. The remaining two patients completed the initial 12-week treatment period, with onedemonstrating a reduction in attack rate from 3.24 to 0.36 attacks per month and the other becomingattack-free from an initial attack rate of 3.20 attacks per month. Both patients continued garadacimabfor the duration of the second treatment period of 20 and 17 months, after which both patients rolledover into the phase 3 extension study and received garadacimab for an additional 18 months andremained attack free.
Additionally, the 3 patients with HAE-PLG completed the initial 12-week treatment period and did notcontinue into the treatment extension period. One patient reported a decrease in their monthly overallattack rate to 1.75 and a severe attack rate to 0.35 during the treatment period, compared to 3.20 and1.60, respectively, during the run-in period. The remaining two patients reported an increase in theirmonthly attack rates to 6.8 and 3.17 during the treatment period compared to 2.28 and 1.45 during therun-in period respectively. None of the reported attacks was classified as severe attack.
Overall, the safety profile of garadacimab in patients with nC1-INH was similar to that observed inpatients with HAE-C1-INH.
ImmunogenicityTreatment with ANDEMBRY has been associated with development of low-titer treatment emergentanti-drug antibodies (ADA) in 2.9% (5/172) of treated subjects. Due to the low titer of ADA registeredin these subjects, neutralizing antibodies could not be detected. However, although the clinicalrelevance of ADA could not be fully established, available data indicate that there was no apparentimpact of the presence of ADA on safety or efficacy.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with
ANDEMBRY in one or more subsets of the paediatric population in the prevention of hereditaryangioedema attacks (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
In the VANGUARD pivotal trial, patients treated with 200 mg garadacimab subcutaneous oncemonthly presented mean (SD) area under the curve over the dosing interval at steady-state (AUCtau,ss),maximum concentration at steady-state (Cmax,ss), and minimum concentration at steady-state (Cmin,ss) of10300 (3380) mcg∙h/mL, 21.2 (6.58) mcg/mL, and 9.30 (3.73) mcg/mL, respectively. Steady-stateexposure of garadacimab was achieved after the initial subcutaneous administration of loading dose of400 mg (2 doses of 200 mg).
AbsorptionFollowing subcutaneous administration, the time to maximum concentration is approximately 6 days.
The site of subcutaneous injection (thigh, arm, or abdomen) did not affect the absorption ofgaradacimab. The absorption rate of garadacimab was 0.00824/h. The mean absolute bioavailability ofgaradacimab in HAE patients was 39.5% on the basis of the population pharmacokinetic analysis.
DistributionThe mean (SD) apparent volume of distribution of garadacimab in patients with HAE was 7.42 litres(4.20). Garadacimab is a monoclonal antibody and is not expected to bind to plasma proteins.
BiotransformationSimilar to other monoclonal antibodies, garadacimab is expected to be degraded by enzymaticproteolysis into small peptides and amino acids. Therefore, specific metabolism studies were notconducted with garadacimab.
EliminationGaradacimab had a mean (SD) apparent clearance of 0.0217 L/h (0.00793) and a terminal eliminationhalf-life of approximately 19 days.
Special populationsNo dedicated studies have been conducted to evaluate the pharmacokinetics of garadacimab in specialpatient populations including gender, age, pregnant women.
In a population pharmacokinetic analysis, after correcting for body weight (43.3 to 153 kg), noinfluence of gender, age (12 to 73 years), race, or ethnicity was apparent on clearance or volume ofdistribution of garadacimab.
Although body weight was identified as an important covariate describing the variability of clearanceand volume of distribution, the difference was not clinically relevant and no dose adjustments arerecommended.
Renal and hepatic impairmentDedicated studies on subjects with renal or hepatic impairment were not conducted.
As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment orhepatic impairment is not expected to influence clearance of garadacimab.
Based on population pharmacokinetic analysis, hepatic impairment had no effect on thepharmacokinetics of garadacimab.
In a population pharmacokinetic analysis, renal impairment (estimated glomerular filtration rate: ≥90mL/min [normal, N=149], 60 to <90 mL/min [mild, N=22], and 30 to <60 mL/min [moderate, N=1])had no effect on the pharmacokinetics of garadacimab.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated-dose toxicity.
Reproductive toxicityMale and female fertility were unaffected based upon no observed adverse findings on mating,fecundity, fertility indices, on maternal reproductive parameters, embryo survival or sperm assessmentin sexually mature rabbits that received garadacimab intravenously once every three days resulting inapproximately 83- and 103-fold the exposure (based on AUC) in females and males, respectively, atthe recommended human dose of 200 mg subcutaneously once monthly.
In a pre- and post-natal development study, pregnant rabbits were administered garadacimabsubcutaneously once every five days from implantation through weaning. There was no maternal andoff-spring, through six months of age, garadacimab-related toxicity in rabbits receiving subcutaneousgaradacimab resulting in approximately 53-fold the clinical exposure (based on AUC) at therecommended human dose of 200 mg subcutaneously once monthly.
Garadacimab crossed the placenta in rabbits. With subcutaneous administration of garadacimabcorresponding to approximately 53-fold the clinical exposure (based on AUC) at the recommendedhuman dose of 200 mg subcutaneously once monthly, at gestation day 29, fetal plasma concentrationswere 40.8% of maternal concentrations.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Histidine
Arginine monohydrochloride
Proline
Polysorbate 80 (E 433)
Water for injections
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
ANDEMBRY may be stored at room temperature (up to 25 °C) for a single period of up to 2 months,but not beyond the expiry date.
6.4 Special precautions for storage
Store in a refrigerator (2 ⁰C - 8 ⁰C).
Do not freeze.
Keep the pre-filled syringe or pre-filled pen in the outer carton in order to protect from light.
Do not return ANDEMBRY to refrigerated storage after storage at room temperature.
6.5 Nature and contents of container
ANDEMBRY 200 mg solution for injection in pre-filled syringe1.2 mL of solution in a pre-filled glass syringe (type I glass) with a bromobutyl stopper, 27G x 1/2 5Bspecial thin-walled (STW) staked needle, and is assembled with an extended finger flange and needlesafety device.
ANDEMBRY is available as unit packs containing 1 assembled pre-filled syringe and in multipackscontaining 3 (3 packs of 1) assembled pre-filled syringes.
ANDEMBRY 200 mg solution for injection in pre-filled pen1.2 mL of solution in a pre-filled glass syringe (type I glass) with a bromobutyl stopper, 27G x 1/2 5Bspecial thin-walled (STW) staked needle. Each pre-filled syringe is assembled with a pen.
ANDEMBRY is available as unit packs containing 1 assembled pre-filled pen and in multipackscontaining 3 (3 packs of 1) assembled pre-filled pens.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Before use, ANDEMBRY should be visually inspected for appearance by gentle inversion. Thesolution should be slightly opalescent to clear, brownish-yellow to yellow. Solutions that arediscoloured or contain particles should not be used.
Do not shake.
Administration steps
ANDEMBRY 200 mg solution for injection in pre-filled syringe
After removing the pre-filled syringe with needle safety device from the refrigerator, wait 30 minutesbefore injecting to allow the solution to reach room temperature. Inject ANDEMBRY subcutaneouslyinto the abdomen, thigh or upper arm. Rotation of the injection site is recommended (see section 4.2).
Each pre-filled syringe with needle safety device is for single use only. Discard the pre-filled syringewith needle safety device after injection is completed in a sharps container or closed puncture resistantcontainer.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
ANDEMBRY 200 mg solution for injection in pre-filled pen
After removing the pre-filled pen from the refrigerator, wait 30 minutes before injecting to allow thesolution to reach room temperature. Inject ANDEMBRY subcutaneously into the abdomen, thigh orupper arm. Rotation of the injection site is recommended (see section 4.2).
Injection with the pre-filled pen may take up to 15 seconds.
Listen for the first ‘click’ (this signals the start of injection, and the yellow plunger will start to moveacross the window). Keep pressing and watch the yellow plunger move down to fill the window. Asecond ‘click’ will be heard and the viewing window will be completely yellow. Wait an extra 5seconds to make sure the full dose was received.
Each pre-filled pen is for single use only. Discard the pre-filled pen after injection is completed in asharps container or closed puncture resistant container.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on the medicinal product is available on the website of the European Medicines
Agency https://ema.europa.eu