LEMTRADA 12 mg concentrate for solution for infusion

Updates to the SmPC include:

• Update to section 4.4 Acquired heamophilia A - to add referral to a haematologist in case of a prolonged aPTT
• Update to section 4.4 to add a warning of the risk of pericarditis
• Update to section 4.4 to revise the warning of PML

Update to the SmPC in line with PSUSA procedure 201809 and addition of a Provisional Measure in Annex IID: “New treatment should only be initiated in adult patients with highly active relapsing remitting multiple sclerosis despite a full and adequate course of treatment with at least two other disease modifying treatments, or in adult patients with highly active relapsing remitting multiple sclerosis where all other disease modifying treatments are contraindicated or otherwise unsuitable.”

 

Updates to the SPC include:

• section 4.4 (warning and precautions) to add information on:
  • Autoimmune hepatitis
  • Other serious reactions temporally associated with Lemtrada infusion
    • Pulmonary alveolar haemorrhage
    • Myocardial infarction
    • Stroke
    • Cervicocephalic aerterial dissection
  • Haemophagocytic lymhohistiocytosis
• section 4.8 (undesirable effects) to update Table 1 with frequencies of adverse reactions for the above listed events, including severe neutropenia

Serious varicella zoster virus infections, including primary varicella and varicella zoster re-activation, have occurred more often in patients treated with LEMTRADA 12 mg (0.4%) in clinical trials as compared to IFNB-1a (0%). Cervical human papilloma virus (HPV) infection, including cervical dysplasia and anogenital warts, has also been reported in patients treated with LEMTRADA 12 mg (2%). It is recommended that HPV screening be completed annually for female patients.

 

Cytomegalovirus infections (CMV) including cases of CMV reactivation have been reported in LEMTRADA-treated patients. Most cases occurred within 2 months of alemtuzumab dosing. Before initiation of therapy, evaluation of immune serostatus could be considered according to local guidelines.

 

Tuberculosis has been reported for patients treated with LEMTRADA and IFNB-1a in controlled clinical trials. Active and latent tuberculosis, including a few cases of disseminated tuberculosis,  have been reported in 0.3% of the patients treated with LEMTRADA, most often in endemic regions. Before initiation of therapy, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection, according to local guidelines.

 

Table 1: Adverse reactions in study 1, 2, 3 and 4 observed in LEMTRADA 12 mg treated patients and post-marketing surveillance

System Organ Class	Very Common	Common	Uncommon	Not known
Infections and infestations	Upper respiratory tract infection, urinary tract infection, herpes virus infection,1	Herpes zoster infections2, lower respiratory tract infections, gastroenteritis, oral candidiasis, vulvovaginal candidiasis, influenza, ear infection, pneumonia, vaginal infection, tooth infection	Onychomycosis, gingivitis, fungal skin infection, tonsillitis, acute sinusitis, cellulitis, pneumonitis, tuberculosis, cytomegalovirus infection	Listeriosis/listeria meningitis

Section 4.4

Serious varicella zoster virus infections, including primary varicella and varicella zoster re-activation, have occurred more often in patients treated with LEMTRADA 12 mg (0.4%) in clinical trials as compared to IFNB-1a (0%). Cervical human papilloma virus (HPV) infection, including cervical dysplasia and anogenital warts, has also been reported in patients treated with LEMTRADA 12 mg (2%). It is recommended that HPV screening be completed annually for female patients.

 

Tuberculosis has been reported for patients treated with LEMTRADA and IFNB-1a in controlled clinical trials. Active and latent tuberculosis, including a few cases of disseminated tuberculosis,  have been reported in 0.3% of the patients treated with LEMTRADA, most often in endemic regions.

Acute acalculous cholecystitis

 

LEMTRADA may increase the risk of acute acalculous cholecystitis. In controlled clinical studies, 0.2% of LEMTRADA-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patients treated with INFB-1a. During postmarketing use, additional cases of acute acalculous cholecystitis have been reported in LEMTRADA-treated patients. Time to onset of symptoms ranged from less than 24 hours to 2 months after LEMTRADA infusion. Most patients were treated conservatively with antibiotics and recovered without surgical intervention, whereas others underwent cholecystectomy. Symptoms of acute acalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, and vomiting. Acute acalculous cholecystitis is a condition that may be associated with high morbidity and mortality rates if not diagnosed early and treated. If acute acalculous cholecystitis is suspected, evaluate and treat promptly.

 4.8

Table 1: Adverse reactions in study 1, 2, 3 and 4 observed in ≥0.5% of LEMTRADA 12 mg treated patients and post-marketing surveillanc- Table update

 

 

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Removal of Black Triangle

 

Section9

Addition of renewal approval date

Section 4.2 added and removed under various subtitles

2 initial treatment courses, with up to 2 additional treatment courses if needed.

Initial treatment of 2 courses:
• First

Up to two additional treatment courses, as needed, may be considered (see section 5.1):
• Third or fourth course: 12 mg/day on 3 consecutive days (36 mg total dose) administered at least 12 months after the prior treatment course in patients with MS disease activity defined by clinical or imaging features (see section 5.1).


Amendments to paragraph:-

Follow-up of patients
The therapy is recommended as an initial treatment of 2 courses with up to 2 additional treatment courses if needed (see posology) with safety follow-up of patients from initiation of the first treatment course and until 48 months after the last infusion of the second treatment course. If an additional third or fourth course is administered, continue safety follow-up until 48 months after the last infusion (see section 4.4).

Added:-

Pretreatment

Added under Elderly

61 years.

Section 4.4 added and removed under various subtitles

• follow- up from treatment initiation until 48-months
• after the last infusion of the second LEMTRADA. treatment course. If an additional course is administered, safety-follow up should be continued until 48 months after the last infusion.

Removed:-

of follow-up

Product name amended from alemtuzumub to LEMTRADA

Added:-

(corresponding to an annualised rate 4.7 events/1000 patient years). An additional 12 serious events of ITP has been observed through a median of 6.1 years (maximum 12 years) of follow-up (cumulative annualised rate of 2.8 events/1000 patient years). One

In 79.5% of cases, ITP onset occurred within 4 years after first exposure. However, in some cases ITP developed years later.

However, in some cases ITP developed year later.
6 % patients in clinical trials in MS through a median of 6.1 years (maximum 12 years) of follow-up

Thyroid endocrine disorders including autoimmune thyroid

Paragraph amended:-

Serious endocrine events occurred in 4.4% of patients, with Basedow’s disease (also known as Graves’ disease), hyperthyroidism, hypothyroidism, autoimmune thyroiditis, and goitre


Added:-

• 74% of patients with positive
• compared with 38% of patients with a baseline negative status.


Removed:-

• antibody status prior to treatment was not indicative for the development of a thyroid related adverse event. Half the patients who tested positive antibodies at baseline, and a quarter of patients who tested negative at baseline for anti-TPO antibodies

Added:-

• The incidence of IARs was higher in course 1 than in subsequent courses. Through all available follow-up, including patients who received additional treatment courses, the most common IARs

Removed:-

• Controlled

Added:-


and included cases of headache, tachycardia,

The cumulative annualised rate of infections was 0.99 through a median of 6.1 years (maximum 12 years) of follow-up from the first LEMTRADA exposure, as compared to 1.27 in controlled clinical trials.

Product name amended from alemtuzumab to LEMTRADA

Added:-

• Until

Section 4.8 added and removed under various subtitles

• in clinical studies
• A total of 486 patients treated with LEMTRADA (12 mg or 24 mg) constituted the safety population in a pooled analysis of MS clinical studies with a median follow-up of 6.1 years (maximum 12 years), resulting in 8,635 patient-years of safety follow-up
• all LEMTRADA 12 mg-treated patients during all available follow up in clinical trials.

Removed:-

• with relapsing remitting MS (RRMS)
• and a median follow up of 24 months.
• up to 24 months from RRMS patients treated with LEMTRADA 12 mg/day for 5 consecutive days at study entry and for 3 consecutive days at Study Month 12

TABLE 1

Amendments

Infections and infestations Upper respiratory tract infection, urinary tract infection, herpes virus infection,1
Herpes zoster infections2 Lower respiratory tract infections, herpes zoster, gastroenteritis, oral herpes, oral candidiasis, vulvovaginal candidiasis, influenza, ear infection, pneumonia, vaginal infection Tooth infection, genital herpestooth abscess, onychomycosis, gastroenteritis viral, gingivitis, fungal skin infection, tonsillitis, acute sinusitis, bacterial vaginosis, cellulitis
Blood and lymphatic system disorders Lymphopenia, leukopenia Lymphadenopathy, immune thrombocytopenic purpura, thrombocytopenia, white blood cell count increased, anaemia haematocrit decreased, neutrophilia, eosinophil count increase Immune thrombocytopenic purpura, thrombocytopenia haemoglobin decreased, haematocrit decreasedMonocytosis
Immune system disorders Cytokine release syndrome Hypersensitivity
Endocrine disorders Basedow’s disease, hyperthyrodisim, hypothyroidism Basedow’s disease, hyperthyroidism, autoimmuneAutoimmune thyroiditis, hypothyroidism, goitre, anti-thyroid antibody positive
Psychiatric disorders Insomnia*, anxiety, depression Depression
Nervous system disorders Headache* MS relapse, dizziness*, hypoaesthesia, paraesthesia, tremor, dysgeusia* Sensory disturbance, hyperaesthesia
Eye disorders VisionConjunctivitis, endocrine ophthalmopathy, vision blurred Conjunctivitis Diplopia
Ear and labyrinth disorders Vertigo Ear pain
Cardiac disorders Tachycardia* Tachycardia*, bradycardiaBradycardia*, palpitations
Vascular disorders Flushing* Hypotension*, hypertension
Respiratory, thoracic and mediastinal disorders Dyspnoea*, cough, epistaxis, hiccups, oropharyngeal pain Throat tightness, hiccups, throat irritation, asthma, productive cough
Gastrointestinal disorders Nausea* Abdominal pain, vomiting, diarrhoea dyspepsia*, stomatitis Constipation, gastro-oesophageal reflux disease, gingival bleeding, dry mouth, dysphagia, gastrointestinal disorder, haematochezia
Hepatobiliary disorders Aspartate aminotransferase increased, alanine aminotransferase increase Aspartate aminotransferase increased
Skin and subcutaneous tissue disorders Urticaria*, rash*, pruritus*, generalised rash* Generalised rash*, erythemaErythema, ecchymosis, alopecia, hyperhidrosis, acne Blister, night sweats, skin lesion, swelling face, eczema, dermatitis
Musculoskeletal and connective tissue disorders
Myalgia, muscle weakness, arthralgia, back pain, pain in extremity, muscle spasms, neck pain Musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, limb discomfort
Renal and urinary disorders Proteinuria, haematuria Nephrolithiasis, ketonuria
Reproductive system and breast disorders Menorrhagia, irregular menstruation Cervical dysplasia, amenorrhoea
General disorders and administration site conditions Pyrexia*, fatigue*, chills* Chest discomfort*, chills*, pain*, oedema peripheral, asthenia, influenza-like illness, malaise, infusion site pain
Investigations Blood creatinine increased, lymphocyte count increased, urine leukocyte esterase positive Weight decreasedWeight decreased, weight increased, red blood cell count decreased, bacterial test positive, CD4/CD8 ratio decreased, blood glucose increased, mean cell volume increase
Injury, poisoning and procedural complications Contusion, infusion related reaction
Metabolism and nutrition disorders Decreased appetite
Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Skin papilloma
1 Herpes virus infections include PTs: Oral herpes, Herpes simplex, Genital herpes, Herpes virus infection, Genital herpes simplex, Herpes dermatitis, Ophthalmic herpes simplex, Herpes simplex serology positive.
2 Herpes zoster infections include PTs: Herpes zoster, Herpes zoster cutaneous disseminated, Ophthalmic herpes zoster, Herpes ophthalmic, Herpes zoster infection neurological, Herpes zoster meningitis.

Section 4.8
Added:-

Safety profile in long-term follow-up
The type of adverse events including seriousness and severity observed in LEMTRADA treatment groups through all available follow-up including patients who received additional treatment courses were similar to those in the active-controlled studies. The incidence of IARs was higher in course 1 than in subsequent courses.

In patients continuing from controlled clinical studies and who did not receive any additional LEMTRADA after the initial 2 treatment courses, the rate (events per person-year) of most adverse reactions was comparable to or reduced in years 3-6 as compared to years 1 and 2. The rate of thyroid adverse reactions was highest in year three and declined thereafter.

Section 5.1
Added:-

and 1 uncontrolled, rater-blinded extension study

For studies 1 and 2, Study design/demographics for Studies 1, 2, 3 and results4 are shown in Table 2 and Table 3 respectively.

Table 2: Study Design and Baseline Characteristics for Studies 1, 2, 3 and 24
Study 1 Study 2 Study 3
Study name CAMMS323
(CARE-MS I) CAMMS32400507
(CARE-MS II) CAMMS223
Study design Controlled, randomised, rater-blinded Controlled, randomised, rater and dose-blinded Controlled, randomised, rater-blinded
Disease history Patients with active MS, defined as at least 2 relapses within the prior 2 years. Patients with active MS, defined as at least 2 relapses within the prior 2 years and 1 or more contrast-enhancing lesions
Follow-upDuration 2 years 3 years‡
Study population Treatment-naïve patients Patients with inadequate response to prior therapy* Treatment- naïve patients
Study 4
Study name CAMMS03409
Study design Uncontrolled, rater-blinded extension study
Study population Patients who participated in CAMMS223, CAMMS323, or CAMMS32400507
(see baseline characteristics above)
Duration of extension 4 years








SADCDW..
2 Time to onset of SAD2 CDW.
3 Estimated using a mixed model for repeated measures

Results for Studies 1 and 2 are shown in Table 3.



ofConfirmed (SRDimprovement (CDI)




Disability2
(Sustained Accumulation ofDisability1
(Confirmed Disability [SAD] ≥6 months1) Worsening [CDW] 2
Patients with 6-month SAD CDW
(95% CI)


8.0%
(5.7, 11.2)


11.1%
(7.3, 16.7)


12.7%
(9.9, 16.3)


21.1%
(15.9, 27.7)
Hazard ratio (95% CI)
0.70 (0.40, 1.23)
(p=0.22) 0.58 (0.38, 0.87)
(p=0.0084)
Patients who are relapse free at Year 2
(95% CI)

77.6%
(72.9, 81.606)
(p<0.0001) 58.7%
(51.1, 65.505) 65.4%
(60.6, 69.7)
(p<0.0001) 46.7
(39.5, 53.5)
Change from Baseline in EDSS at Year 223
Estimate (95% CI)

-0.14 (-0.25, -0.02)
(p=0.42)
-0.14 (-0.29, 0.01)
-0.17 (-0.29, -0.05)
(p<0.0001)
0.24 (0.07, 0.41)
Sustained reduction ofConfirmed (SRDimprovement (CDI)
SRDCDI SRDCDI SRDCDI studyStudy

SADCDWAlemtuzumabLEMTRADA

At 5 years, LEMTRADA reduced the risk of SAD by 69% (hazard ratio 0.31 [95% CI: 0.161, 0.598], p=0.0005) and reduced the ARR by 66% (rate ratio 0.34 [95% CI: 0.202, 0.569], p<0.0001) as compared to subcutaneous IFNB-1a.
Long-term efficacy data
Study 4, was a Phase 3, multicenter, open-label, rater-blinded, efficacy and safety extension study for patients with RRMS who participated in Study 1, 2, or 3 (prior phase 3 and 2 studies) to assess long-term efficacy and safety of Lemtrada. The study provides efficacy and safety through a median of 6 years from entry into Studies 1 and 2. Patients in the extension study (Study 4) were eligible to receive additional as-needed LEMTRADA treatment course(s) upon documentation of resumed disease activity, defined as the occurrence of ≥1 MS relapse and/or ≥2 new or enlarging brain or spinal lesions on magnetic resonance imaging (MRI). Additional
open-label follow-up of LEMTRADA clinical trials, some patients received additional “as needed” treatment with LEMTRADA upon documented evidence of resumed MS disease activity. The additional The benefits and risks of >2 treatment courses have not been fully established, but results suggest that the safety profile does not appear to change with additional courses. If additional treatment courses are to be given they must be administered at least 12 months after the prior course.

91.8% of the patients treated with LEMTRADA 12 mg in Studies 1 and 2 entered Study 4. 82.7% of these patients completed the study. Approximately half (51.2%) of patients initially treated with LEMTRADA 12 mg/day in Study 1 or 2 who enrolled in Study 4, received only the initial 2 courses of LEMTRADA and no other disease modifying treatment throughout 6 years of follow-up.

46.6% of the patients initially treated with LEMTRADA 12 mg/day in Study 1 or 2 received additional courses upon documented evidence of MS disease activity (relapse and/or MRI) and the treating physician’s decision to retreat. No characteristics at study entry identified patients who would later receive one or more additional courses.

Through 6 years from initial LEMTRADA treatment, patients continuing in follow-up showed rates of MS relapse, brain lesion formation on MRI, and brain volume loss consistent with LEMTRADA’s treatment effects during Studies 1 and 2 as well as predominantly stable or improved disability scores. Including follow-up in Study 4, patients originally treated with LEMTRADA in Studies 1 and 2, respectively, had ARRs 0.17 and 0.23, CDW was seen in 22.3% and 29.7%, while 32.7% and 42.5% achieved CDI. In each year of Study 4, patients from both studies continued to show a low risk of forming new T2 (27.4% to 33.2%) or gadolinium enhancing lesions (9.4% to 13.5%), and the median annual percent change in brain parenchymal fraction ranged from 0.19% to 0.09%.

Among patients who received one or two additional LEMTRADA treatment courses, improvements were seen in relapse rate, MRI activity and mean disability scores following a first or second LEMTRADA retreatment (Courses 3 and 4) when compared with outcomes in the preceding year. For these patients, the ARR declined from 0.79 in the year prior to Course 3 to 0.18 one year after, and the mean EDSS score from 2.89 to 2.69. The percentage of patients with new or enlarging T2 lesions declined from 50.8% the year prior to Course 3 to 35.9% one year after, and new gadolinium enhancing lesions from 32.2% to 11.9%. Similar improvements in ARR, mean EDSS score, and T2 and gadolinium-enhancing lesions were seen after Course 4 when compared with the prior year. These improvements were subsequently maintained, but no firm conclusions can be made with regards to the longer-term efficacy (e.g. 3 and 4 years after additional treatment courses) because many patients completed the study before reaching these time points.

The benefits and risks of 5 or more treatment courses have not been established.

Immunogenicity
controlled 92≥90% ThereThrough 2 treatment courses, there High titer anti-alemtuzumab antibodies observed in some patients were associated with incomplete lymphocyte depletion following a third or fourth treatment course, but there was no clear impact of anti-alemtuzumab antibodies on the clinical efficacy or safety profile of LEMTRADA.

Section 4.2: minor editorial update as below;

• Initial treatment course: 12 mg/day for on 5 consecutive days (60 mg total dose)
• Second treatment course: 12 mg/day for on 3 consecutive days (36 mg total dose) administered 12 months after the initial treatment course.

Section 4.4:

-          under Infusion-associated Reactions (IARs) addition of bradycardia

-          under infections addition of Listeriosis/Listeria meningitis as below;

Listeriosis/Listeria meningitis has been reported in LEMTRADA treated patients, generally within one month of LEMTRADA infusion. To reduce this risk, patients receiving LEMTRADA  should avoid ingestion of uncooked or undercooked meats, soft cheeses and unpasteurized dairy products for at least one month after LEMTRADA treatment.

Section 4.8:

-          Clarification that the adverse reaction bradycardia has been reported as an Infusion-associated Reaction (IAR)

In section 4.8: update to the HPRA adverse events reporting address.

None provided