Leaflet XERAVA 100mg powder for concentrate infusion solution

Xerava 50 mg powder for concentrate for solution for infusion

Each vial contains 50 mg eravacycline.

After reconstitution, each mL contains 10 mg eravacycline.

After further dilution, 1 mL contains 0.3 mg eravacycline.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

Pale yellow to dark yellow cake.

Xerava is indicated in adolescents from the age of 12 years weighing at least 50 kg, and in adults, forthe treatment of complicated intra-abdominal infections (cIAI) (see sections 4.4 and 5.1).

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

The recommended dose regimen is 1 mg/kg eravacycline every 12 hours for 4 to 14 days.

In patients co-administered strong CYP3A4 inducers the recommended dose regimen is 1.5 mg/kgeravacycline every 12 hours for 4 to 14 days (see sections 4.4 and 4.5).

Elderly (≥ 65 years old)

No dose adjustment is required in elderly patients (see section 5.2).

No dose adjustment is necessary in patients with renal impairment or in patients undergoinghaemodialysis. Eravacycline may be administered without regard to the timing of haemodialysis (seesection 5.2).

No dose adjustment is necessary in patients with hepatic impairment (see sections 4.4, 4.5 and 5.2).

The safety and efficacy of Xerava in children less than 12 years of age or adolescents with bodyweight below 50 kg have not been established. Currently available data are described in section 4.8 butno recommendation on a posology can be made. Xerava should not be used in children aged under8 years because of the risk of tooth discolouration (see sections 4.4 and 4.6).

Xerava is administered only by intravenous infusion over approximately 1 hour (see section 4.4).

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

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

Hypersensitivity to tetracycline class antibiotics.

Anaphylactic reactions

Serious and occasionally fatal hypersensitivity reactions are possible and have been reported withother tetracycline class antibiotics (see section 4.3). In case of hypersensitivity reactions, treatmentwith eravacycline must be discontinued immediately and appropriate emergency measures must beinitiated.

Clostridioides difficile-associated diarrhoea

Antibiotic-associated colitis and pseudomembranous colitis have been reported with the use of nearlyall antibiotics and may range in severity from mild to life-threatening. It is important to consider thisdiagnosis in patients who present with diarrhoea during or subsequent to treatment with eravacycline(see section 4.8). In such circumstances, the discontinuation of eravacycline and the use of supportivemeasures together with the administration of specific treatment for Clostridioides difficile should beconsidered. Medicinal products that inhibit peristalsis should not be given.

Infusion-site reactions

Eravacycline is administered via intravenous infusion, using an infusion time of approximately 1 hourto minimise the risk of infusion-site reactions. Infusion-site erythema, pain/tenderness, phlebitis andthrombophlebitis were observed with intravenous eravacycline in clinical trials (see section 4.8). Incase of serious reactions, eravacycline should be discontinued until a new intravenous access site isestablished. Additional measures to reduce the occurrence and severity of infusion site reactionsinclude decreasing the eravacycline infusion rate and/or concentration.

Non-susceptible micro-organisms

Prolonged use may result in the overgrowth of non-susceptible micro-organisms, including fungi. Ifsuperinfection occurs during therapy, it may require interruption of treatment. Other appropriatemeasures should be taken and alternative antimicrobial treatment should be considered in accordancewith existing therapeutic guidelines.

Pancreatitis has been reported with eravacycline and has been severe in some cases (see section 4.8). Ifpancreatitis is suspected, eravacycline should be discontinued.

Xerava should not be used during tooth development (during the 2nd and 3rd trimester of pregnancy,and in children under 8 years of age) as it may cause permanent discolouration of the teeth (yellow-grey-brown) (see section 4.6).

Concomitant use of strong CYP3A4 inducers

Medicines that induce CYP3A4 are expected to increase the rate and extent of metabolism oferavacycline. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 inductionmay take at least 2 weeks to decline. Co-administration of a strong CYP3A4 inducer (such asphenobarbital, rifampicin, carbamazepine, phenytoin, St. John’s Wort) is expected to reduce the effectof eravacycline (see sections 4.2 and 4.5).

Patients with severe hepatic impairment

Exposure may be increased in patients with severe hepatic impairment (Child-Pugh Class C).

Therefore, such patients should be monitored for adverse reactions (see section 4.8), particularly ifthese patients are obese and/or are also being treated with strong CYP3A inhibitors where theexposure may be further increased (see sections 4.5 and 5.2). In these cases, no recommendation on aposology can be made.

Limitations of the clinical data

In clinical trials in cIAI, there were no immunocompromised patients, and the majority of patients(80%) had APACHE II scores <10 at baseline; 5.4% of the patients had concurrent bacteraemia atbaseline; 34% of the patients had complicated appendicitis.

Eravacycline may prolong both prothrombin time (PT) and activated partial thromboplastin time(aPTT). Additionally, hypofibrinogenaemia has been reported with the use of eravacycline. Therefore,blood coagulation parameters such as PT or other suitable anticoagulation test, including bloodfibrinogen, should be monitored prior to treatment initiation with eravacycline and regularly while ontreatment.

Potential for other medicinal products to affect the pharmacokinetics of eravacycline

Concomitant administration of the strong CYP 3A4/3A5 inducer rifampicin altered thepharmacokinetics of eravacycline, decreasing exposure by approximately 32% and increasing clearanceby approximately 54%. The eravacycline dose should be increased by approximately 50% (1.5 mg/kgintravenous q12h) when co-administered with rifampicin or other strong CYP3A inducers such asphenobarbital, carbamazepine, phenytoin and St. John’s Wort (see sections 4.2 and 4.4).

Concomitant administration of the strong CYP3A inhibitor itraconazole altered the pharmacokinetics oferavacycline, increasing Cmax by approximately 5% and AUC0-24 by approximately 23%, and decreasingclearance. The increased exposure is not likely to be clinically significant; thus, no dose adjustment isrequired when eravacycline is co-administered with CYP3A inhibitors. However, patients receivingstrong CYP3A inhibitors (for example ritonavir, itraconazole, clarithromycin) with a combination offactors that may increase the exposure, such as severe hepatic impairment and/or obesity should bemonitored for adverse reactions (see sections 4.4 and 4.8).

In vitro, eravacycline was shown to be a substrate for the transporters P-gp, OATP1B1 and OATP1B3.

A drug-drug interaction in vivo cannot be excluded and co-administration of eravacycline and othermedicinal products that inhibit these transporters (examples of OATP1B1/3 inhibitors; atazanavir,cyclosporine, lopinavir, and saquinavir) may increase the eravacycline plasma concentration.

Potential for eravacycline to affect the pharmacokinetics of other medicinal products

In vitro, eravacycline and its metabolites are not inhibitors or inducers of CYP enzymes or transportproteins (see section 5.2). Interactions with medicinal products that are substrates for these enzymes ortransporters are therefore unlikely.

There are limited data on the use of eravacycline in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). The potential risk for humans is unknown.

As for other tetracycline class antibiotics, eravacycline may induce permanent dental defects(discolouration and enamel defects) and a delay in ossification processes in foetuses exposed in uteroduring the 2nd and 3rd trimester, due to accumulation in tissues with a high calcium turnover andformation of calcium chelate complexes (see sections 4.4 and 5.3). Xerava should not be used duringpregnancy unless the clinical condition of the woman requires treatment with eravacycline.

Women of childbearing potential should avoid becoming pregnant while receiving eravacycline.

It is unknown whether eravacycline and its metabolites are excreted in human breast milk. Animalstudies have shown excretion of eravacycline and its metabolites in breast milk (see section 5.3).

Long term use of other tetracyclines during breast-feeding may result in significant absorption by thebreast-fed infant and is not recommended because of the risk of dental discolouration and delay inossification processes of the breast-fed infant.

A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with

Xerava should be made, taking into account the benefit of breast-feeding for the child, and the benefitof therapy for the woman.

There are no human data on the effect of eravacycline on fertility. Eravacycline did affect mating andfertility in male rats at clinically relevant exposures (see section 5.3).

Eravacycline may have a minor influence on the ability to drive and use machines. Dizziness mayoccur following administration of eravacycline (see section 4.8).

In clinical trials, the most common adverse reactions in patients with cIAI treated with eravacycline(n=576) were nausea (3.0%), vomiting, infusion site phlebitis (each 1.9%), phlebitis (1.4%), infusionsite thrombosis (0.9%), diarrhoea (0.7%), vessel puncture site erythema (0.5%), hyperhidrosis,thrombophlebitis, infusion site hypoaesthesia, and headache (each 0.3%), which were generally mildor moderate in severity.

The adverse reactions identified with eravacycline are presented in Table 1. Adverse reactions areclassified according to MedDRA system organ classification and frequency. Frequency categories arederived according to the following conventions: very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Tabulated list of adverse reactions to eravacycline in clinical trials

System Organ Class Common Uncommon

Blood and lymphatic system Hypofibrinogenaemiadisorders Increased internationalnormalised ratio (INR)

Prolonged activated partialthromboplastin time (aPTT)

Prolonged prothrombin time(PT)

Immune system disorders Hypersensitivity

Nervous system disorders Dizziness

Headachea

Vascular disorders Thrombophlebitis

Phlebitisb

Gastrointestinal disorders Nausea Pancreatitis

Vomiting Diarrhoea

Aspartate aminotransferase (AST)increased

Hepatobiliary disorders Alanine aminotransferase (ALT)increased

Skin and subcutaneous Rashtissue disorders Hyperhidrosis

General disorders andadministration site Infusion site reactioncconditions

a. Thrombophlebitis includes the preferred terms thrombophlebitis and infusion site thrombosis

b. Phlebitis includes the preferred terms phlebitis, infusion site phlebitis, superficial phlebitis and injectionsite phlebitis

c. Infusion site reaction includes the preferred terms injection site erythema, infusion site hypoaesthesia,vessel puncture site erythema and vessel puncture site pain

Infusion site reactions

Mild to moderate infusion site reactions, including pain or discomfort, erythema and swelling orinflammation at the injection site as well as superficial thrombophlebitis and/or phlebitis have beenreported in patients treated with eravacycline. Infusion site reactions can be mitigated by reducing theeravacycline infusion concentration or the infusion rate.

Tetracycline class effects

Tetracycline class adverse reactions include photosensitivity, pseudotumor cerebri, and anti-anabolicaction which have led to increased blood urea nitrogen , azotaemia, acidosis, and hyperphosphataemia.

Antibiotic class adverse reactions include pseudomembranous colitis, and overgrowth of non-susceptible organisms, including fungi (see section 4.4). In clinical trials, treatment-related diarrhoeaoccurred in 0.7% of patients; all cases were mild in severity.

In a phase I study to determine the pharmacokinetics and the safety of a single dose of intravenouseravacycline in children aged 8 to less than 18 years (n= 19, with 10 less than 12 years old) the mostfrequently reported adverse reactions were nausea (26.3%), vomiting (15.8%), headache (15.8%), andhyperhidrosis (10.5%). In general, adverse reactions were mild or moderate in severity and similar tothe adverse reactions observed in adults. Two events were assessed as severe including one event ofanaphylactic reaction and one event of pleural effusion, which was also assessed as serious.

Reporting 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.

In trials administering up to 3 mg/kg eravacycline to healthy volunteers it has been observed that doseshigher than the recommended dose lead to a higher rate of nausea and vomiting.

In the case of suspected overdose Xerava should be discontinued and the patient monitored for adversereactions.

Pharmacotherapeutic group: Antibacterials for systemic use, tetracyclines, ATC code: J01AA13.

The mechanism of action of eravacycline involves the disruption of bacterial protein synthesis bybinding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues intoelongating peptide chains.

The C-7 and C-9 substitutions in eravacycline are not present in any naturally occurring or semisynthetictetracyclines and the substitution pattern imparts microbiological activities including retention of in vitropotency against Gram-positive and Gram-negative strains expressing tetracycline-specific resistancemechanism(s) (i.e., efflux mediated by tet(A), tet(B), and tet(K); ribosomal protection as encoded bytet(M) and tet(Q)). Eravacycline is not a substrate for the MepA pump in Staphylococcus aureus that hasbeen described as a resistance mechanism for tigecycline. Eravacycline is also not affected byaminoglycoside inactivating or modifying enzymes.

Resistance to eravacycline has been observed in Enterococcus harbouring mutations in rpsJ. There isno target-based cross-resistance between eravacycline and other classes of antibiotics such asquinolones, penicillins, cephalosporins, and carbapenems.

Other bacterial resistance mechanisms that could potentially affect eravacycline are associated withupregulated, non-specific intrinsic multidrug-resistant (MDR) efflux.

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) foreravacycline and are listed here:https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

The area under the plasma concentration-time curve (AUC) divided by the minimum inhibitoryconcentration (MIC) of eravacycline has been shown to be the best predictor of efficacy in vitro,utilising human steady state exposures in a chemostat and confirmed in vivo in animal models ofinfection.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical trials against the pathogens listed for cIAI that weresusceptible to eravacycline in vitro:

* Escherichia coli

* Klebsiella pneumoniae

* Staphylococcus aureus

* Enterococcus faecalis

* Enterococcus faecium

* Viridans Streptococcus spp.

Antibacterial activity against other relevant pathogens

In vitro data indicate that the following pathogen is not susceptible to eravacycline:

* Pseudomonas aeruginosa

The European Medicines Agency has deferred the obligation to submit the results of trials with Xeravain one or more subsets of the paediatric population in cIAI (see section 4.2 for information onpaediatric use).

Eravacycline is administered intravenously and therefore has 100% bioavailability.

The mean pharmacokinetic parameters of eravacycline after single and multiple intravenous infusions(60 minutes) of 1 mg/ kg administered to healthy adults every 12 hours are presented in Table 2.

Table 2 Mean (%CV) plasma pharmacokinetic parameters of eravacycline after single andmultiple intravenous infusions to healthy adults

PK parameters

Eravacycline dosing arithmetic mean (%CV)

Cmax tmaxa AUC0-12b t1/2(ng/mL) (h) (ng*h/mL) (h)1.0 mg/kg intravenous every Day 1 2125 (15) 1.0 (1.0-1.0) 4305 (14) 9 (21)12 hours (n=6) Day 10 1825 (16) 1.0 (1.0-1.0) 6309 (15) 39 (32)a Mean (range) representedb AUC of Day 1 = AUC 0-12 after the first dose and AUC for Day 10 = steady state AUC0- 12

The in vitro binding of eravacycline to human plasma proteins increases with increasingconcentrations, with 79%, 86% and 90% (bound) at 0.1, 1 and10 µg/mL, respectively. The mean(%CV) volume of distribution at steady-state in healthy normal volunteers following 1 mg/kg every12h is approximately 321 L (6.35), which is greater than total body water.

Unchanged eravacycline is the major medicinal product-related component in human plasma andhuman urine. Eravacycline is metabolised primarily by CYP3A4- and FMO-mediated oxidation of thepyrrolidine ring to TP-6208, and by chemical epimerisation at C-4 to TP-498. Additional minormetabolites are formed by glucuronidation, oxidation and hydrolysis. TP-6208 and TP-498 are notconsidered to be pharmacologically active.

Eravacycline is a substrate for the transporters P-gp, OATP1B1 and OATP1B3 but not for BCRP.

Eravacycline is excreted in both urine and faeces. Renal clearance and biliary and direct intestinalexcretion account for approximately 35% and 48% of total body clearance after administration of asingle intravenous dose of 60 mg 14C-eravacycline, respectively.

The Cmax and AUC of eravacycline in healthy adults increase approximately in proportion to anincrease in dose. There is approximately a 45% accumulation following intravenous dosing of 1 mg/kgevery 12 hours.

Within the range of eravacycline multiple intravenous doses studied clinically, the pharmacokineticparameters AUC and Cmax demonstrate linearity, but with increasing doses the increase in both AUCand Cmax are slightly less than dose-proportional.

Potential for drug-drug interactions

Eravacycline and its metabolites are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6 or CYP3A4 in vitro. Eravacycline, TP-498 and TP-6208 are not inducers of

CYP1A2, CYP2B6 or CYP3A4.

Eravacycline, TP-498 and TP-6208 are not inhibitors of BCRP, BSEP, OATP1B1, OATP1B3, OAT1,

OAT3, OCT1, OCT2, MATE1 or MATE2-K transporters. The metabolites TP-498 and TP-6208 arenot inhibitors of P-gp in vitro.

The geometric least square mean Cmax for eravacycline was increased by 8.8% for subjects with endstage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric leastsquare mean AUC0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthysubjects with 90% CI -14.0, 12.3.

The geometric mean Cmax for eravacycline was increased by 13.9%, 16.3%, and 19.7% for subjectswith mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C)hepatic impairment versus healthy subjects, respectively. The geometric mean AUC0-inf foreravacycline was increased by 22.9%, 37.9%, and 110.3% for subjects with mild, moderate, andsevere hepatic impairment versus healthy subjects, respectively.

In a population pharmacokinetic analysis of eravacycline, no clinically relevant differences in AUC bygender were observed for eravacycline.

In a population pharmacokinetic analysis of eravacycline, no clinically relevant differences in thepharmacokinetics of eravacycline were observed with respect to age.

A popPK study was conducted. This was inconclusive and consequently the dose in children below12 years/50 kg could not be determined. Adolescents (12-17 years) weighing at least 50 kg areexpected to have comparable exposure to adults when treated with 1 mg/kg every 12 hours.

In a population pharmacokinetic analysis it was shown that eravacycline disposition (clearance andvolume) was dependent on body weight. However, the resulting difference in exposure to eravacyclinein terms of AUC does not warrant dose adjustments in the weight range studied. No data are availablefor patients weighing more than 137 kg. The potential influence of severe obesity on eravacyclineexposure has not been studied.

In repeated dose toxicity studies in rats, dogs and monkeys, lymphoid depletion/atrophy of lymphnodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets (dog andmonkey), in association with bone marrow hypocellularity, and adverse gastrointestinal effects (dogand monkey) were observed with eravacycline. These findings were reversible or partially reversibleduring recovery periods of 3- to 7-weeks.

Bone discolouration (in the absence of histological findings), which was not fully reversible overrecovery periods of up to 7-weeks, was observed in rats and monkeys after 13 weeks of dosing.

Intravenous administration of high doses of eravacycline has been associated with cutaneous responses(including hives, scratching, swelling, and/or skin erythema) in rat and dog studies.

In fertility studies in male rats, eravacycline administered at about 5 times the clinical exposure (basedon AUC), gave rise to a significantly reduced number of pregnancies. These findings were reversiblefollowing a 70-day (10-week) recovery period, equivalent to a spermatogenic cycle in the rat. Findingson the male reproductive organs were also observed in rats in the repeated dose toxicity studies for 14days or 13 weeks at exposures more than 10- or 5-fold the clinical exposure based on AUC. Theobservations included degeneration of the seminiferous tubules, oligospermia, and cellular debris inthe epididymides, spermatid retention in the seminiferous tubules, increase of spermatid head retentionin Sertoli cells, and vacuolation of Sertoli cells and decreased sperm counts. No adverse effects onmating or fertility were observed in female rats.

In embryo-foetal studies, no adverse effects were observed in rats at exposures comparable to clinicalexposure or in rabbits at exposures 1.9-fold higher than the clinical exposure (based on AUC) in ratsand rabbits respectively. Doses more than 2- or 4-fold higher than the clinical exposure (based on

AUC) were associated with maternal toxicity (clinical observations and reduced body weight gain andfood consumption), and reduced foetal body weights and delays in skeletal ossification in both speciesand abortion in the rabbit.

Animal studies indicate that eravacycline crosses the placenta and is found in foetal plasma.

Eravacycline (and metabolites) is excreted in the milk of lactating rats.

Eravacycline is not genotoxic. Carcinogenicity studies with eravacycline have not been conducted.

Xerava may have the potential to be very persistent in freshwater sediment.

Mannitol (E421)

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years

Chemical and physical in-use stability after reconstitution in the vial has been demonstrated for 1 hourat 25 °C.

Chemical and physical in-use stability after dilution has been demonstrated for 72 hours at 2 °C - 8 °Cand 12 hours at 25 °C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 72 hours at 2 °C - 8 °C, unless the method ofreconstitution/dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 °C - 8 °C). Keep the vial in the carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

10 mL Type I glass vial with chlorobutyl rubber stopper and aluminium cap.

Pack sizes: 1 vial and multipacks containing 12 (12 packs of 1) vials.

Not all pack sizes may be marketed.

Each vial is for single use only.

Aseptic technique must be followed when preparing the infusion solution.

The contents of the required number of vials should each be reconstituted with 5 mL water forinjections, and swirled gently until the powder has dissolved entirely. Shaking or rapid movementshould be avoided as it may cause foaming.

Reconstituted Xerava should be a clear, pale yellow to orange solution. The solution should not beused if any particles are noticed or the solution is cloudy.

Preparation of the infusion solution

For administration, the reconstituted solution must be further diluted using sodium chloride 9 mg/mL(0.9%) solution for injection. The calculated volume of the reconstituted solution should be added tothe infusion bag to a target concentration of 0.3 mg/mL, within a range of 0.2 to 0.6 mg/mL. Seeexample calculations in Table 3 (adults) and Table 4 (adolescents 12 - 17 years).

Gently invert the bag to mix the solution.

Table 3 Example calculations for adult patients weighing 40 kg to 200 kg1

Patient weight Total dose Number of vials to Total volume to be Recommended(kg) (mg) needed to reconstitute diluted (mL) infusion bag size(mL)40 40 1 4 10060 60 2 6 25080 80 2 8 250100 100 2 10 250150 150 3 15 500200 200 4 20 5001 The exact dose needs to be calculated based on the specific patient weight.

For adult patients weighing ≥ 40 kg - < 50 kg:

Calculate the required volume of the reconstituted solution based on the patient’s weight and injectinto a 100 mL infusion bag.

For adult patients weighing 50 kg - 100 kg:

Calculate the required volume of the reconstituted solution based on the patient’s weight and injectinto a 250 mL infusion bag.

For adult patients weighing >100 kg:

Calculate the required volume of the reconstituted solution based on the patient’s weight and injectinto a 500 mL infusion bag.

Table 4 Example calculations for adolescent patients (12 - 17 years) weighing 50 kg to 90 kg1

Patient weight Total dose Number of vials to Total volume to be Recommended(kg) (mg) needed to reconstitute diluted (mL) infusion bag size(mL)50 50 1 5 25060 60 2 6 25070 70 2 7 25080 80 2 8 25090 90 2 9 2501 The exact dose needs to be calculated based on the specific patient weight.

For adolescent patients weighing 50 kg - 90 kg:

Calculate the required volume of the reconstituted solution based on the patient’s weight and injectinto a 250 mL infusion bag.

Infusion

The ready to use solution should be inspected visually for particulate matter prior to administration.

Reconstituted and diluted solutions containing visible particles or that are cloudy in appearance shouldbe discarded.

Following dilution, Xerava is administered intravenously over approximately 1 hour.

The reconstituted and diluted solution must be administered as an intravenous infusion only. It mustnot be administered as an intravenous bolus.

If the same intravenous line is used for sequential infusion of several different medicinal products, theline should be flushed before and after infusion with sodium chloride 9 mg/mL (0.9%) solution forinjection.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

PAION Pharma GmbH

Heussstraße 2552078 Aachen

Germany

EU/1/18/1312/001

EU/1/18/1312/002

Date of first authorisation: 20 September 2018

Date of latest renewal: 12 April 2023

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

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