TROGARZO 200 MG CONCENTRATE FOR SOLUTION FOR INFUSION - summary of medicine characteristics

"V This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Trogarzo 200 mg concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 200 mg of ibalizumab (in 1.33 mL of solution).

Ibalizumab is produced in murine myeloma non-secreting (NS0) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Colourless to slightly yellow, clear to slightly opalescent aqueous solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Trogarzo, in combination with other antiretroviral(s), is indicated for the treatment of adults infected with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen (see section 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

The recommended dose of ibalizumab is a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks.

If the treating physician determines there is no additional clinical benefit for the patient in terms of viral load reduction, discontinuation of ibalizumab treatment should be considered, see section 5.1.

Missed dose

If a maintenance dose (800 mg) of ibalizumab is missed by 3 days or longer beyond the scheduled dosing day, a loading dose (2,000 mg) should be administered as early as possible. Resume maintenance dosing (800 mg) every 2 weeks thereafter.

Elderly

The safety and efficacy of ibalizumab in geriatric patients (> 65 years of age) have not been established.

Paediatric population

The safety and efficacy of ibalizumab in children under the age of 18 years have not yet been established. No data are available.

Method of administration

Intravenous use

Diluted ibalizumab solution should be administered by a healthcare professional.

Ibalizumab should be administered as an intravenous infusion. Ibalizumab should not be administered as an intravenous push or bolus.

The duration of the first infusion (loading dose) should be no less than 30 minutes. If no infusion-associated adverse reactions have occurred, the duration of the subsequent infusions (maintenance doses) can be decreased to no less than 15 minutes.

After the infusion is complete, flush with 30 mL of sodium chloride 9 mg/mL (0.9%) solution for injection.

All patients must be observed during and for 1 hour after completion of ibalizumab administration for at least the first infusion. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered.

Prophylactic medication is not warranted prior to each infusion. If the patient does not experience an infusion-associated adverse reaction, the post-infusion observation time can be reduced to 15 minutes thereafter.

For instructions on dilution of the medicinal product before administration, see section 6.6.

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

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Transmission of HIV

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Immune reconstitution inflammatory syndrome (IRIS)

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of cART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. IRIS was reported in 2 subjects out of 153 treated with ibalizumab in Phase 2b and 3 clinical studies (see section 4.8).

Excipients with known effect

Ibalizumab contains less than 1 mmol sodium (23 mg) in each loading dose of 2,000 mg or maintenance dose of 800 mg and therefore is essentially sodium-free.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Based on the mechanism of action and target-mediated drug disposition of ibalizumab, it is not expected that ibalizumab will have pharmacokinetic drug-drug interactions with other medicinal products.

4.6 Fertility, Pregnancy and lactation

Women of childbearing potential

It is recommended that women of childbearing potential use an effective method of contraception during treatment.

Pregnancy

There are no data from the use of ibalizumab in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Human immunoglobulin (IgG) is known to cross the placental barrier. Ibalizumab is not recommended during pregnancy.

Breast-feeding

It is unknown whether ibalizumab/me­tabolites are excreted in human milk. Human IgG is known to be excreted in breast milk during the first days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to breast-fed infants cannot be excluded during this short period and ibalizumab should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breast-feed their infants under any circumstances.

Fertility

There are no data on the effects of ibalizumab on human fertility.

4.7 Effects on ability to drive and use machines

Ibalizumab has a minor influence on the ability to drive and use machines. Dizziness, nausea, fatigue and headache have been reported during treatment with ibalizumab (see section 4.8). Patients experiencing these symptoms should be advised to use caution when driving or using machines until symptoms abate.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were rash (9.2%), diarrhoea (3.9%), dizziness (3.9%), headache (3.9%), nausea (3.9%), fatigue (2.0%) and vomiting (2.0%).

Tabulated list of adverse reactions

A tabulated list of adverse reactions is presented in Table 1. Frequencies are defined as 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. Tabulated summary of adverse reactions associated with ibalizumab

* Frequency was calculated based on 24 weeks of safety data from 153 subjects enrolled in Phase 2b study TMB-202 (n = 113) and Phase 3 study TMB-301 (n=40), as well as on at least 48 weeks of safety data from 27 subjects from TMB-301 that rolled-over into expanded access study TMB-311.

Includes pooled terms “rash”, “rash erythematous”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash pruritic” and “rash papular”.

Description of selected adverse reactions

Rash

Rashes were common. In general, rashes had an early onset (i.e. within 1 to 3 weeks of the first dose of ibalizumab), were mild to moderate in intensity, and resolved within 13 weeks with continued ibalizumab administration. In case of rash, it is recommended that the patient be monitored and symptomatic therapy be initiated when appropriate (e.g. cortisteroids and/or anti-histamine medicinal products).

Out of the 153 subjects in Phase 2b and 3 clinical studies, one subject experienced a severe rash (non-serious). This subject had 8 adverse reactions of rash, including 1 event of macular rash, 1 event of generalized rash and 6 events of maculo-papular rash at different times during treatment with ibalizumab. No action was taken with ibalizumab in response to these events.

Immune reconstitution inflammatory syndrome (IRIS)

Out of 153 subjects, two subjects developed immune reconstitution inflammatory syndrome (IRIS; see section 4.4) manifested as an exacerbation of progressive multifocal leukoencephalopathy (serious) and of cryptococcal cutaneous infection (serious), respectively. Both subjects were discontinued from ibalizumab treatment.

Hypersensitivity

One subject out of 153 was reported to have hypersensitivity (allergic reaction) on Day 21 (i.e. 7 days after the 2nd infusion of ibalizumab). As a result, ibalizumab was discontinued.

Immunogenicity

All 153 subjects enrolled in Phase 2b and 3 clinical trials were tested for the presence of anti-ibalizumab IgG antibodies throughout their participation. Only one subject was found to have anti-ibalizumab antibodies. The subject had no adverse reactions associated with the positive immunogenicity result. The subject received ibalizumab therapy for an additional 1.5 years before discontinuing voluntarily with an undetectable viral load (<50 copies/mL).

Laboratory abnormalities

Grade 3 creatinine elevations occurred frequently in subjects with underlying renal disease, risk factors for renal disease, and/or in subjects taking concomitant medications known to be nephrotoxic.

Reporting of suspected adverse reactions

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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no known antidote to ibalizumab overdose. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and given appropriate symptomatic treatment. Standard supportive measures should be applied as required, including monitoring of vital signs as well as observation of the clinical status of the patient.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals. ATC code: J05AX23

Mechanism of action

Ibalizumab, a humanized monoclonal antibody of immunoglobulin G type 4 (IgG4), is a CD4 domain 2-directed HIV-1 inhibitor. Ibalizumab blocks HIV-1 from infecting CD4+ T cells by binding to domain 2 of CD4 and interfering with the post-attachment steps required for the entry of HIV-1 virus particles into host cells and preventing the viral transmission that occurs via cell-cell fusion.

Epitope mapping studies indicate that ibalizumab binds to a conformational epitope located primarily in domain 2 of the extracellular portion of the CD4 receptor. This epitope is positioned on the surface of CD4 opposite to the site in domain 1 that is required for CD4 binding of the MHC class II molecules and, therefore, does not interfere with CD4-mediated immune functions.

Ibalizumab is active against HIV-1 group M isolates (subtypes A, B, C, D, E, or O). It is also active against HIV-1 resistant to currently approved antiretroviral medicinal products and exhibits antiretroviral activity against R5-tropic, X4-tropic, and dualtropic HIV-1.

Phenotypic and genotypic test results revealed no evidence of cross-resistance between ibalizumab and any of the approved classes of anti-retroviral medicinal products.

Resistance

Decreased susceptibility to ibalizumab, as defined by a decrease in Maximum Percent Inhibition (MPI), has been observed in most subjects experiencing virologic failure and may be associated with genotypic changes in the HIV-1 envelope coding sequence that results in the loss of potential N-linked glycosylation sites (PNGS) in the V5 loop of gp120. No relevant remaining effect of ibalizumab is expected in cases of resistance development. Decreased susceptibility to ibalizumab was a finding in the majority of patients who experienced virologic failure up to week 24 in the pivotal study.

Decreased susceptibility to ibalizumab does not alter susceptibility to other approved agents and does not result in the selection of CD4-independent viral isolates.

Clinical efficacy and safety

Trial TMB-301

Phase 3 trial TMB-301 was a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected subjects with multidrug resistant HIV-1. Subjects were required to have a viral load greater than 1,000 copies/mL and documented resistance to at least one antiretroviral medication from three classes of antiretroviral medications as measured by resistance testing. Subjects must have been treated with antiretrovirals for at least 6 months and be failing or had recently failed therapy (i.e., in the last 8 weeks).

The trial was composed of three discrete periods:

Control period (Day 0 to Day 6): Subjects were either monitored on their current failing therapy or received no therapy if they had failed and discontinued treatment within the 8 weeks preceding screening. This was an observational period to establish baseline HIV viral load.

Functional monotherapy period (Day 7 to Day 13): All subjects received a 2,000 mg loading dose of ibalizumab on Day 7. Subjects on a failing ART regimen continued to receive their failing regimen in addition to the loading dose of ibalizumab. This period was to establish the virologic activity of ibalizumab.

Maintenance period (Day 14 to Week 25): On Day 14 of the treatment period, viral load was assessed for the primary endpoint, and thereafter the background regimen was optimized to include at least one drug to which the subject’s virus was susceptible. The use of an investigational drug as a component of the optimized background regimen was allowed. Beginning at Day 21, an 800 mg maintenance dose of ibalizumab was administered every two weeks through Week 25. This period was to establish the safety and durability of virologic suppression of ibalizumab when used in combination with an optimized background regimen.

The majority of subjects in Trial TMB-301 were male (85%), white (55%) and between 23 and 65 years of age (mean [SD] age: 50.5 [11.0] years). At Baseline, median [Min – Max] viral load and CD4+ T cell counts were 35,350 [304 – 743,000] copies/mL and 73 [0 – 676] cells/mm3, respectively. The subjects were heavily treatment-experienced: 53% of participants had been treated with 10 or more antiretroviral drugs prior to trial enrolment; 98% percent had been treated with NRTIs, 98% with PIs, 80% with NNRTIs, 78% with INSTIs, 30% with gp41 fusion inhibitors, and 20% with CCR5 co-receptor antagonists.

The primary efficacy endpoint was the proportion of subjects achieving a > 0.5 logio decrease in viral load from the beginning to the end of the “Functional monotherapy period” as compared to the proportion of subjects achieving a > 0.5 logw decrease from the beginning to the end of the “Control period”, as defined above. The results of the primary endpoint analysis are shown in Table 2 below.

Table 2. Proportion of subjects achieving a > 0.5 log10 decrease in viral load at the end of the control and functional monotherapy periods

exact 95% confidence interval

p < 0.0001 based on McNemar’s test comparing the proportion of subjects achieving > 0.5 log10 decrease in viral load at the end of the control and functional monotherapy periods.

Fifty-five percent of subjects had a > 1 log10 reduction in viral load, and 48% of subjects had a > 2 log10 reduction in viral load at Week 25. An increase in the mean number of CD4+ T-cells of 62 cells/mm3 was observed from Baseline to Week25 (Intent-To-Treat (ITT) analysis). Week25 outcomes are shown in Table 3. Subjects with baseline CD4 counts < 50 cells/mm3 were less likely to achieve a HIV-1 RNA of <200 copies/mL (or < 50 copies/mL) than subjects with > 50 cells/mm3.

Table 3. Virologic response at week 25 by baseline CD4 cell count, integrase inhibitor resistance and Overall Susceptibility Score (OSS) for study TMB-301

* The OSS indicates the number of fully active drugs in a subject’s Optimized Background Regimen (OBR) based on both current and available historical resistance test results. Demonstrating drug susceptibility by both genotypic and phenotypic testing was required, when testing by both methods was technically feasible. As an example, an OSS of 2 would indicate that the HIV-1 isolate tested was fully susceptible to two drugs in the OBR.

Trial TNX-355.03

Study TNX-355.03 was a multicenter, randomized, double-blinded, placebo-controlled, multi-dose, 3-arm safety and efficacy study in 82 subjects with HIV-1 and who were failing or had failed highly active antiretroviral therapy. Subjects all received OBR plus 1 of the following regimens: alternating intravenous (IV) infusions of 15 mg/kg ibalizumab and placebo, weekly for the first 9 doses (through the Week 8 visit), then IV infusions of 15 mg/kg ibalizumab every 2 weeks (Arm A); 10 mg/kg ibalizumab IV infusions weekly for the first 9 doses (through the Week 8 visit), then IV infusions of 10 mg/kg ibalizumab every 2 weeks (Arm B); or weekly placebo IV infusions for the first 9 doses (through the Week 8 visit), then IV infusions of placebo every 2 weeks (Placebo arm). Patients in all three arms also received an OBR. As of Week 16, patients in Placebo arm who experienced virologic failure had the option of receiving 15 mg/kg open-label ibalizumab every 2 weeks and/or switching to a new OBR. Patients in Arm A and B arm who experienced virologic failure had the option of switching to a new OBR.

At Week 2, the mean viral load decrease was 0.87 log10 copies/mL in Arm A, 1.15 log10 copies/mL in Arm B and 0.38 log10 copies/mL in the Placebo arm (p=0.003 vs Arm A, p<0.001 vs Arm B).

By Week 16, i.e. prior to the possible switching of patients in the Placebo arm to the 15 mg/kg dose of ibalizumab every 2 weeks and/or to change in OBR for all patients, mean viral load decrease was 1.07 log10 copies/mL in Arm A, 1.33 log10 copies/mL in Arm B and 0.26 log10 copies/mL in the Placebo arm (p=0.002 vs Arm A, p<0.001 vs Arm B).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Trogarzo in one or more subsets of the paediatric population in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following the recommended dose regimen (a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks), ibalizumab concentrations reached steady-state levels after the first 800 mg maintenance dose with mean trough concentrations over 30 ^g/mL throughout the dosing interval. The median time to maximum serum concentration (Tmax) of 2,000 mg and 800 mg is 1 hr and 10 min, respectively. Ibalizumab is administered as an IV infusion. The bioavailability is 100% by definition.

Distribution

The volume of distribution of ibalizumab is approximately 4.8 L, which is comparable with vascular space, based on the performed population pharmacokinetics analysis.

Biotransformation

Specific metabolism studies were not conducted because ibalizumab is a protein. Ibalizumab is expected to degrade to small peptides and individual amino acids.

Elimination

Following single-dose administrations of 10 and 25 mg/kg of ibalizumab, clearance is 0.5 to 0.36 mL/h/kg and elimination half-life is 37.8 and 64.1 hours, respectively. The elimination is nonlinear and concentration-dependent.

Linearity/non-linearity

Ibalizumab administered as a single agent exhibits nonlinear pharmacokinetics at a dose range of 0.3–25 mg/kg. Following administration of ibalizumab, at the clinically relevant dose rage of 800–2,000 mg, the maximum serum concentration (Cmax) increased dose proportionally, whereas the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner. Such non-linear effects in clearance are common for monoclonal antibodies targeting cell surface molecules, such as CD4. This behaviour is characteristic of saturable (capacity-limited) elimination kinetics.

Special populations

A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates (age, body weight, sex, baseline CD4+ cell count) on ibalizumab pharmacokinetics. The results suggest that ibalizumab concentration decreases as body weight increases. The body weight range was very narrow in the population PK model, and the impact of body weight may not be precisely estimated. However, the effect is unlikely to impact virologic outcome and does not warrant a dose adjustment.

Renal impairment

No formal studies were conducted to examine the effects of renal impairment on the pharmacokinetics of ibalizumab. Renal impairment is not anticipated to impact the pharmacokinetics of ibalizumab.

Hepatic impairment

No formal studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of ibalizumab. Hepatic impairment is not anticipated to impact the pharmacokinetics of ibalizumab.

Paediatric population

Ibalizumab pharmacokinetics have not been evaluated in paediatric patients.

Elderly population

Ibalizumab pharmacokinetics in geriatric patients (> 65 years of age) is limited (n = 5). Results are similar to the adult population (> 18 to 65 years of age), however no definite conclusions can be drawn.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of in vitro and in vivo safety assessments.

Toxicity to reproduction and development

A pre- and post-natal developmental study was performed in cynomolgus monkeys. Ibalizumab was administered to pregnant females at a 110mg/kg weekly dose from gestation Day 20–22 until parturition (approximately 22 doses/animal). This dose was administered as it is at least 10-fold the estimated free clinical AUC and Cmax for the 800 mg Q2W dose. Ibalizumab was generally well tolerated in pregnant monkeys and in their offspring, when evaluated through 180 ± 2 days post-partum. There were no ibalizumab-related adverse effects (maternal, foetal, or infant) at 110 mg/kg (NoObserved-Adverse-Effect Level, NOAEL). However, CD4+ cells in infants of treated females were temporarily suppressed from BD14–91 compared to control, but there was no further impact on immunocompetence of the infants. The relevance of this effect for human pregnancy and lactation remains unknown. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for developmental effects was 110 mg/kg.

Genotoxicity, carcinogenic potential

Genotoxicity and carcinogenicity studies have not been conducted.

6.1 List of excipients

Sucrose

Sodium chloride

Polysorbate 80

Histidine

Hydrochloric acid (for pH-adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3

Shelf life

Unopened vial

5 years

Diluted solution

If not administered immediately, store the diluted ibalizumab solution below 25°C for up to 4 hours, or in a refrigerator (2°C to 8°C) for up to 24 hours. If refrigerated, allow the diluted ibalizumab solution to stand at room temperature (20°C to 25°C) for at least 30 minutes but no more than 4 hours prior to administration.

6.4 Special precautions for storage

Store and transport refrigerated (2°C to 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

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

6.5 Nature and contents of container

2 mL vial (Type I borosilicate glass) sealed with a stopper (butyl rubber) and an aluminum crimp cap.

Pack of 2 vials.

6.6 Special precautions for disposal

This medicinal product should be inspected visually for particulate matter and discoloration prior to administration. Vials containing non-diluted ibalizumab or infusion bag containing diluted ibalizumab must be discarded if solution is cloudy, if there is pronounced discoloration or if there is foreign particulate matter.

Ibalizumab is administered intravenously (IV), after diluting the appropriate number of vials in 250 mL of sodium chloride 9 mg/mL (0.9%) solution for injection. See Table 4 below for the appropriate number of vials required to prepare both the loading dose of 2,000 mg and the maintenance doses of 800 mg.

Table 4. Recommended ibalizumab dose and number of vials per administration

Ibalizumab concentrate for solution for infusion should be prepared by a healthcare professional using aseptic technique as follows:

Remove the flip-off cap from the vial and wipe with an alcohol swab.

Insert sterile syringe needle into the vial through the center of the stopper and withdraw 1.33 mL from each vial (NOTE: a small residual amount may remain in the vial, discard unused portion) and transfer into a 250 mL intravenous bag of sodium chloride 9 mg/mL (0.9%) solution for injection. Other intravenous diluents must not be used to prepare the ibalizumab solution for infusion.

Once diluted, the ibalizumab solution should be administered immediately.

Discard partially used vials or empty vials of ibalizumab and any unused portion of the diluted ibalizumab solution in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Theratechnologies Europe Limited

4th Floor, 2 Hume Street, Dublin 2, D02 DV24, Ireland

Tel: 00800 08250830

Tel.: +49 (0) 30 3119 6151

medinfo.eu@the­ratech.com

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 53915/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2021