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Koselugo 25 mg hard capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Treatment with Koselugo should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours.
Posology
The recommended dose of Koselugo is 25 mg/m2 of body surface area (BSA), taken orally twice daily (approximately every 12 hours).
Dosing is individualised based on BSA (mg/m2) and rounded to the nearest achievable 5 mg or 10 mg dose (up to a maximum single dose of 50 mg). Different strengths of Koselugo capsules can be combined to attain the desired dose (Table 1).
Table 1. Recommended dose based on body surface area
Body surface area (BSA) a
Recommended dose
0.55 – 0.69 m2
20 mg in the morning and 10 mg in the evening
0.70 – 0.89 m2
20 mg twice daily
0.90 – 1.09 m2
25 mg twice daily
1.10 – 1.29 m2
30 mg twice daily
1.30 – 1.49 m2
35 mg twice daily
1.50 – 1.69 m2
40 mg twice daily
1.70 – 1.89 m2
45 mg twice daily
≥ 1.90 m2
50 mg twice daily
a The recommended dose for patients with a BSA less than 0.55 m2 has not been established.
Treatment with Koselugo should continue as long as clinical benefit is observed, or until PN progression or the development of unacceptable toxicity. There is limited data in patients older than 18, therefore continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician. However, start of treatment with Koselugo in adults is not appropriate.
Missed dose
If a dose of Koselugo is missed, it should only be taken if it is more than 6 hours until the next scheduled dose.
Vomiting
If vomiting occurs after Koselugo is administered, an additional dose is not to be taken. The patient should continue with the next scheduled dose.
Dose adjustments
Interruption and/or dose reduction or permanent discontinuation of selumetinib may be required based on individual safety and tolerability (see sections 4.4 and 4.8). Recommended dose reductions are given in Table 2 and may require the daily dose to be divided into two administrations of different strength or for treatment to be given as a once daily dose.
Table 2. Recommended dose reductions for adverse reactions
Body surface area (BSA)
Initial Koselugo dosea
(mg/twice daily)
First dose reduction
(mg/dose)
Second dose reduction
(mg/dose)b
Morning
Evening
Morning
Evening
0.55 – 0.69 m2
20 mg in the morning and 10 mg in the evening
10
10
10 once daily
0.70 – 0.89 m2
20
20
10
10
10
0.90 – 1.09 m2
25
25
10
10
10
1.10 – 1.29 m2
30
25
20
20
10
1.30 – 1.49 m2
35
25
25
25
10
1.50 – 1.69 m2
40
30
30
25
20
1.70 – 1.89 m2
45
35
30
25
20
≥ 1.90 m2
50
35
35
25
25
a Based on BSA as shown in Table 1.
b Permanently discontinue treatment in patients unable to tolerate Koselugo after two dose reductions.
Dose modifications for the management of adverse reactions associated with this medicinal product are presented in Table 3.
Table 3. Recommended dose modifications for adverse reactions
CTCAE Grade*
Recommended dose modification
Grade 1 or 2 (tolerable – can be managed with supportive care)
Continue treatment and monitor as clinically indicated
Grade 2 (intolerable – cannot be managed with supportive care) or Grade 3
Interrupt treatment until toxicity is grade 0 or 1 and reduce by one dose level when resuming therapy (see Table 2)
Grade 4
Interrupt treatment until toxicity is grade 0 or 1, reduce by one dose level when resuming therapy (see Table 2). Consider discontinuation
* Common Terminology Criteria for Adverse Events (CTCAE)
Dose modification advice for left ventricular ejection fraction (LVEF) reduction
In cases of asymptomatic LVEF reduction of ≥ 10 percentage points from baseline and below the institutional lower level of normal (LLN), selumetinib treatment should be interrupted until resolution. Once resolved, selumetinib should be reduced by one dose level when resuming therapy (see Table 2).
In patients who develop symptomatic LVEF reduction or a grade 3 or 4 LVEF reduction, selumetinib should be discontinued and a prompt cardiology referral should be carried out (see section 4.4).
Dose modification advice for ocular toxicities
Selumetinib treatment should be interrupted in patients diagnosed with retinal pigment epithelial detachment (RPED) or central serous retinopathy (CSR) with reduced visual acuity until resolution; reduce selumetinib by one dose level when resuming therapy (see Table 2). In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. In patients who are diagnosed with retinal vein occlusion (RVO), treatment with selumetinib should be permanently discontinued (see section 4.4).
Dose adjustments for co-administration with CYP3A4 or CYP2C19 inhibitors
Concomitant use of strong or moderate CYP3A4 or CYP2C19 inhibitors is not recommended and alternative agents should be considered. If a strong or moderate CYP3A4 or CYP2C19 inhibitor must be co-administered, the recommended Koselugo dose reduction is as follows: If a patient is currently taking 25 mg/m2 twice daily, dose reduce to 20 mg/m2 twice daily. If a patient is currently taking 20 mg/m2 twice daily, dose reduce to 15 mg/m2 twice daily (see Table 4 and section 4.5).
Table 4. Recommended dose to achieve 20 mg/m2 or 15 mg/m2 twice daily dose level
Body Surface Area
20 mg/m2 twice daily (mg/dose)
15 mg/m2 twice daily (mg/dose)
Morning
Evening
Morning
Evening
0.55 – 0.69 m2
10
10
10 mg once a day
0.70 – 0.89 m2
20
10
10
10
0.90 – 1.09 m2
20
20
20
10
1.10 – 1.29 m2
25
25
25
10
1.30 – 1.49 m2
30
25
25
20
1.50 – 1.69 m2
35
30
25
25
1.70 – 1.89 m2
35
35
30
25
≥ 1.90 m2
40
40
30
30
Special populations
Renal impairment
Based on clinical trials no dose adjustment is recommended in patients with mild, moderate, severe renal impairment or those with end stage renal disease (ESRD) (see section 5.2).
Hepatic impairment
Based on clinical trials, no dose adjustment is recommended in patients with mild hepatic impairment. The starting dose should be reduced in patients with moderate hepatic impairment to 20 mg/m2 BSA, twice daily (see Table 4). Koselugo is contraindicated for use in patients with severe hepatic impairment (see sections 4.3 and 5.2).
Ethnicity
Increased systemic exposure has been seen in adult Asian subjects, although there is considerable overlap with Western subjects when corrected for body weight. No specific adjustment to the starting dose is recommended for paediatric Asian patients, however these patients, should be closely monitored for adverse events (see section 5.2).
Paediatric population
The safety and efficacy of Koselugo in children less than 3 years of age has not been established. No data are available.
Method of administration
Koselugo is for oral use. It should be taken on an empty stomach with no food or drink other than water 2 hours prior to dosing and 1 hour after dosing (see sections 4.5 and 5.2).
The capsules should be swallowed whole with water. The capsules should not be chewed, dissolved, or opened, because this could impair drug release and affect the absorption of selumetinib.
Koselugo should not be administered to patients who are unable or unwilling to swallow the capsule whole. Patients should be assessed for their ability to swallow a capsule before starting treatment. Standard medicine swallowing techniques are expected to be sufficient to swallow selumetinib capsules. For patients who have difficulties swallowing the capsule, referral to an appropriate health care professional such as a speech and language therapist could be considered to identify suitable methods that can be tailored to the particular patient.
4.3 |
Koselugo 25 mg hard capsules | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe hepatic impairment (see sections 4.2 and 5.2).
4.4 |
Koselugo 25 mg hard capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Left ventricular ejection fraction (LVEF) reduction
Asymptomatic decreases in ejection fraction have been reported in 22% of paediatric patients in the pivotal clinical trial. Median time to initial onset of these adverse reactions was 226 days. A small number of serious reports of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program (see section 4.8).
Paediatric patients with a history of impaired left ventricular function or a baseline LVEF below institutional LLN have not been studied. LVEF should be evaluated by echocardiogram before initiation of treatment to establish baseline values. Prior to starting selumetinib treatment, patients should have an ejection fraction above the institutional LLN.
LVEF should be evaluated at approximately 3-month intervals, or more frequently as clinically indicated, during treatment. Reduction in LVEF can be managed using treatment interruption, dose reduction or treatment discontinuation (see section 4.2).
Ocular toxicity
Patients should be advised to report any new visual disturbances. Adverse reactions of blurred vision have been reported in paediatric patients receiving selumetinib. Isolated cases of RPED, CSR and RVO in adult patients with multiple tumour types, receiving treatment with selumetinib monotherapy and in combination with other anti-cancer agents, and in a single paediatric patient with pilocytic astrocytoma on selumetinib monotherapy, have been observed (see section 4.8).
In line with clinical practice an ophthalmological evaluation prior to treatment initiation and at any time a patient reports new visual disturbances is recommended. In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. If RPED or CSR is diagnosed and visual acuity is affected, selumetinib therapy should be interrupted and the dose reduced when treatment is resumed (see section 4.2). If RVO is diagnosed, treatment with selumetinib should be permanently discontinued (see section 4.2).
Liver laboratory abnormalities
Liver laboratory abnormalities, specifically AST and ALT elevations, can occur with selumetinib (see section 4.8). Liver laboratory values should be monitored before initiation of selumetinib and at least monthly during the 6 first months of treatment, and thereafter as clinically indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see Table 2 in section 4.2).
Skin and subcutaneous disorders
Skin rash (including maculopapular rash and acneiform rash), paronychia and hair changes have been reported very commonly in the pivotal clinical study (see section 4.8). Pustular rash, hair colour changes and dry skin were seen more frequently in younger children (age 3-11 years) and acneiform rash was seen more frequently in post-pubertal children (age 12-16 years).
Vitamin E supplementation
Patients should be advised not to take any supplemental vitamin E. Koselugo 10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS. High doses of vitamin E may increase the risk of bleeding in patients taking concomitant anticoagulant or antiplatelet medicinal products (e.g., warfarin or acetylsalicylic acid). Anticoagulant assessments, including international normalised ratio or prothrombin time, should be conducted more frequently to detect when dose adjustments of the anticoagulant or antiplatelet medicinal products are warranted (see section 4.5).
Risk of choking
Selumetinib is available as a capsule which must be swallowed whole. Some patients, in particular children < 6 years of age, may be at risk of choking on a capsule formulation due to developmental, anatomical or psychological reasons. Therefore, selumetinib should not be administered to patients who are unable or unwilling to swallow the capsule whole (see section 4.2).
Women of child bearing potential
Koselugo is not recommended in women of child bearing potential who are not using contraception (see section 4.6).
4.5 |
Koselugo 25 mg hard capsules | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in healthy adults (aged ≥ 18 years).
Active substances that may increase selumetinib plasma concentrations
Co-administration with a strong CYP3A4 inhibitor (200 mg itraconazole twice daily for 4 days) increased selumetinib Cmax by 19% (90% CI 4, 35) and AUC by 49% (90% CI 40, 59) in healthy adult subjects.
Co-administration with a strong CYP2C19/moderate CYP3A4 inhibitor (200 mg fluconazole once daily for 4 days) increased selumetinib Cmax by 26% (90% CI 10, 43) and AUC by 53% (90% CI 44, 63) in healthy adult subjects, respectively.
Concomitant use of erythromycin (moderate CYP3A4 inhibitor) or fluoxetine (strong CYP2C19/CYP2D6 inhibitor) is predicted to increase selumetinib AUC by ~30-40% and Cmax by ~20%.
Co-administration with medicinal products that are strong inhibitors of CYP3A4 (e.g., clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (e.g., ticlopidine) should be avoided. Co-administration with medicinal products that are moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) and CYP2C19 (e.g., omeprazole) should be avoided.
If co-administration is unavoidable, patients should be carefully monitored for adverse events and the selumetinib dose should be reduced (see section 4.2 and Table 4).
Active substances that may decrease selumetinib plasma concentrations
Co-administration with a strong CYP3A4 inducer (600 mg rifampicin daily for 8 days) decreased selumetinib Cmax by -26% (90% CI -17, -34) and AUC by -51% (90% CI -47, -54).
Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) or moderate CYP3A4 inducers with Koselugo should be avoided.
Active substances whose plasma concentrations may be altered by selumetinib
In vitro, selumetinib is an inhibitor of OAT3. The potential for a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 (e.g., methotrexate and furosemide) cannot be excluded (see section 5.2).
TPGS is a P-gp inhibitor in vitro and it cannot be excluded that it may cause clinically relevant drug interactions with substrates of P-gp (e.g. digoxin or fexofenadine).
The effect of selumetinib on the exposure of oral contraceptives has not been evaluated. Therefore, use of an additional barrier method should be recommended to women using hormonal contraceptives (see section 4.6).
Effect of gastric acid reducing agents on selumetinib
Selumetinib capsules do not exhibit pH dependent dissolution. Koselugo can be used concomitantly with gastric pH modifying agents (i.e. H2-receptor antagonists and proton pump inhibitors) without restrictions, except for omeprazole which is a CYP2C19 inhibitor.
Vitamin E
Koselugo capsules contain vitamin E as the excipient TPGS. Therefore, patients should avoid taking supplemental vitamin E and anticoagulant assessments should be performed more frequently in patients taking concomitant anticoagulant or antiplatelet medicinal products (see section 4.4).
4.6 |
Koselugo 25 mg hard capsules | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Koselugo. It is recommended that a pregnancy test should be performed on women of childbearing potential prior to initiating treatment.
Both male and female patients (of reproductive potential) should be advised to use effective contraception during and for at least 1 week after completion of treatment with Koselugo. It cannot be excluded that selumetinib may reduce the effectiveness of oral contraceptives, therefore women using hormonal contraceptives should be recommended to add a barrier method (see section 4.5).
Pregnancy
There are no data on the use of selumetinib in pregnant women. Studies in animals have shown reproductive toxicity including embryofoetal death, structural defects and reduced foetal weights (see section 5.3). Koselugo is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 4.4).
If a female patient or a female partner of a male patient receiving Koselugo becomes pregnant, she should be apprised of the potential risk to the foetus.
Breast-feeding
It is not known whether selumetinib, or its metabolites, are excreted in human milk. Selumetinib and its active metabolite are excreted in the milk of lactating mice (see section 5.3). A risk to the breast-fed child cannot be excluded, therefore breast-feeding should be discontinued during treatment with Koselugo.
Fertility
There are no data on the effect of Koselugo on human fertility. Selumetinib had no impact on fertility and mating performance in male and female mice, although a reduction in embryonic survival was observed in female mice (see section 5.3).
4.7 |
Koselugo 25 mg hard capsules | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Koselugo may have a minor influence on the ability to drive and use machines. Fatigue, asthenia and visual disturbances have been reported during treatment with selumetinib and patients who experience these symptoms should observe caution when driving or using machines.
4.8 |
Koselugo 25 mg hard capsules | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The safety profile of selumetinib monotherapy in paediatric patients with NF1 who have inoperable PN has been determined following evaluation of a combined safety population of 74 paediatric patients (20-30 mg/m2 twice daily). This paediatric 'pool' of patients comprised 50 patients in SPRINT phase II stratum I, treated with selumetinib 25 mg/m2 twice daily (the pivotal dataset) and 24 patients in SPRINT phase I treated with 20 to 30 mg/m2 selumetinib twice daily (the dose finding study). There were no clinically relevant differences in the safety profile between SPRINT phase I and SPRINT phase II stratum I. This safety profile was also substantiated by a pool of safety data from 7 AstraZeneca sponsored studies in adult patients with multiple tumour types (N = 347) who received 75 to 100 mg twice daily).
In the paediatric pool, the median total duration of selumetinib treatment in paediatric patients with NF1 who have PN was 28 months (range: < 1 to 71 months), 23% of patients were exposed to selumetinib treatment for > 48 months. Patients aged ≥ 2 to 11 years (N = 45) had a higher incidence of the following adverse drug reactions (ADRs) compared to patients aged 12 to 18 years (N = 29): hypoalbuminaemia, dry skin, pyrexia, hair colour changes.
In the paediatric pool (N = 74; comprises 50 patients from the pivotal SPRINT phase II stratum 1 dataset and 24 patients from the supportive SPRINT phase I dataset), the most common adverse reactions of any grade (incidence ≥ 45%) were vomiting (82%), rash (80%), blood creatine phosphokinase increased (76%), diarrhoea (77%), nausea (73%), asthenic events (59%), dry skin (58%), pyrexia (57%), acneiform rash (54%), hypoalbuminaemia (50%), aspartate aminotransferase increased (50%) and paronychia (45%). Dose interruptions and reductions due to adverse events were reported in 78% and 32% of patients, respectively. The most commonly reported ADRs leading to dose modification (dose interrupted or dose reduced) of selumetinib were vomiting (26%), paronychia (16%), diarrhoea (15%) and nausea (11%). Permanent discontinuation due to adverse events was reported in 12% of the patients. The following serious adverse reactions were reported: diarrhoea (3%), anaemia (3%) pyrexia (3%), blood CPK increased (3%), blood creatinine increased (1%).
Tabulated list of adverse reactions
Table 5 presents the adverse reactions identified in the paediatric population with NF1 who have inoperable PN and in adult patients (see footnote to Table 5). The frequency is determined from the paediatric pool (N = 74); comprises 50 patients from the pivotal SPRINT phase II stratum 1 dataset and 24 patients from supportive SPRINT phase I dataset. Adverse drug reactions(ADRs) are organised by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions 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 < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from available data), including isolated reports.
Table 5. Adverse drug reactions reported in the paediatric pool (pivotal SPRINT phase II stratum 1 [N = 50] and supportive SPRINT phase I [N = 24]) and in other identified clinical trials in adult patients (N = 347)††
MedDRA SOC
MedDRA Term
Overall Frequency
(All CTCAE grades)
NF1 paediatric pool‡
(N = 74)
Frequency of CTCAE grade 3 and Above†
NF1 paediatric pool‡
(N = 74)
Eye disorders
Vision blurred^
Common (9%)
-
Respiratory, thoracic & mediastinal disorders
Dyspnoea*
Common (5%)
-
Gastrointestinal disorders
Vomiting^
Very common (82%)
Common (8%)
Diarrhoea^
Very common (77%)
Very common (15%)
Nausea^
Very common (73%)
Common (1%)
Stomatitis^
Very common (38%)
Common (1%)
Dry mouth
Common (5%)
-
Skin and subcutaneous tissue disorders
Rash ^ *
Very common (80%)
Common (5%)
Dry skin
Very common (58%)
-
Rash acneiform^ *
Very common (54%)
Common (3%)
Paronychia^
Very common (45%)
Common (9%)
Hair changes^ *
Very common (39%)
-
General disorders
Asthenic events*
Very common (59%)
-
Pyrexia
Very common (57%)
Common (8%)
Peripheral oedema*
Very common (12%)
-
Facial oedema*
Common (7%)
-
Investigations
Blood CPK increased^
Very common (76%)
Common (9%)
Hypoalbuminaemia
Very common (50%)
-
AST increased
Very common (50%)
Common (1%)
Haemoglobin decreased*
Very common (45%)
Common (3%)
ALT increased
Very common (36%)
Common (3%)
Blood creatinine increased
Very common (28%)
Common (1%)
Ejection fraction decreased^
Very common (23%)
Common (1%)
Increased blood pressure*
Very common (16%)
-
Eye disorders
Retinal pigment epithelial detachment (RPED)/ Central serous retinopathy (CSR)* ††
Uncommon (0.6%)
-
Retinal vein occlusion (RVO)* ††
Uncommon (0.3%)
-
Per National Cancer Institute CTCAE version 4.03
CPK = creatine phosphokinase; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
^ See Description of selected adverse reactions
†
All reactions were CTCAE grade 3, except for one CTCAE grade 4 event of blood CPK increased and one CTCAE grade 4 event of blood creatinine increased. There were no deaths.
†† Identified ADRs from other clinical trial experience in adult patients (N = 347), with multiple tumour types, receiving treatment with selumetinib (75 mg twice daily). These ADRs have not been reported in paediatric population with NF1 who have inoperable PN.
‡ Paediatric pool (N=74) percentage rounded to the nearest decimal.
*ADRs based on grouping of individual preferred terms (PT):
Asthenic events: asthenia, fatigue,
CSR/RPED: Detachment of macular retinal pigment epithelium, chorioretinopathy
Dyspnoea: dyspnoea exertional, dyspnoea, dyspnoea at rest
Facial oedema: face odema, periorbital oedema
Haemoglobin decreased: anaemia, haemoglobin decreased
Hair changes: alopecia, hair colour change
Increased blood pressure: blood pressure increased, hypertension
Peripheral oedema: oedema peripheral, oedema
Rash (acneiform): dermatitis acneiform
Rash: dermatitis acneiform, rash maculo-papular, rash papular, rash, rash erythematous, rash macular
RVO: retinal vascular disorder, retinal vein occlusion, retinal vein thrombosis
Description of selected adverse reactions
Left ventricular ejection fraction (LVEF) reduction
In SPRINT, phase II stratum 1, LVEF reduction (PT: ejection fraction decreased) was reported in 11 (22%) patients; all cases were grade 2, asymptomatic and did not lead to dose interruptions, reductions or discontinuation. Of the 11 patients, 6 patients recovered and for 5 patients the outcome was not reported. The median time to first occurrence of LVEF reduction was 226 days (median duration 78 days). The majority of LVEF reduction adverse reactions were reported as reductions from baseline (≥ 10% reduction) but were considered to remain in the normal range. Patients with LVEF lower than the institutional LLN at baseline were not included in the pivotal study. In addition, 2 serious cases of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program. For clinical management of LVEF reduction, see sections 4.2 and 4.4.
Ocular toxicity
In SPRINT, phase II stratum 1, grade 1 and 2 adverse reactions of blurred vision were reported in 4 (8%) patients. Two patients required dose interruption. All adverse reactions were managed without dose reduction. For clinical management of new visual disturbances, see sections 4.2 and 4.4.
In addition, a single event of RPED was reported in a paediatric patient receiving selumetinib monotherapy (25 mg/m2 twice daily) for pilocytic astrocytoma involving the optic pathway in an externally sponsored paediatric study (see sections 4.2 and 4.4).
Paronychia
In SPRINT, phase II stratum 1, paronychia was reported in 23 (46%) patients, the median time to first onset of maximum grade paronychia adverse reaction was 306 days and the median duration of adverse reactions was 96 days. The majority of these adverse reactions were grade 1 or 2 and were treated with supportive or symptomatic therapy and/or dose modification. Grade ≥ 3 events occurred in three (6%) patients. Seven patients (3 with a maximum grade 3 adverse reaction and 4 with a maximum grade 2 adverse reaction) had a selumetinib dose interruption for adverse reactions of paronychia, of whom 3 had dose interruption followed by dose reduction (2 patients required a second dose reduction). In one patient (2%) the event led to discontinuation.
Blood creatine phosphokinase (CPK) increase
Adverse reactions of blood CPK elevation occurred in 76% of patients in SPRINT phase II stratum 1. The median time to first onset of the maximum grade CPK increase was 106 days and the median duration of adverse reactions was 126 days. The majority of adverse reactions were grade 1 or 2 and resolved with no change in selumetinib dose. Grade ≥ 3 adverse reactions occurred in three (6%) patients. A grade 4 adverse reaction led to treatment interruption followed by dose reduction.
Gastrointestinal toxicities
In SPRINT, phase II stratum 1, vomiting (41 patients, 82%, median duration 3 days), diarrhoea (35 patients, 70%, median duration 5 days), nausea (33 patients, 66%, median duration 16 days), and stomatitis (25 patients, 50%, median duration 12 days) were the most commonly reported gastrointestinal (GI) reactions. The majority of these cases were grade 1 or 2 and did not require any dose interruptions or dose reductions.
Grade 3 adverse reactions were reported for diarrhoea (8 patients, 16%), nausea (1 patient, 2%), and vomiting (3 patients, 6%). For one patient diarrhoea led to dose reduction and subsequent discontinuation. No dose reduction or discontinuation was required for adverse reactions of nausea, vomiting or stomatitis.
Skin toxicities
In SPRINT, phase II stratum 1, acneiform rash was observed in 25 (50%) patients (median time to onset 13 days; median duration of 60 days for the maximum CTCAE grade event). The majority of these cases were grade 1 or 2, observed in post-pubertal patients (> 12 years) and did not require any dose interruptions or reductions. Grade 3 adverse reactions were reported for 4%.
Other (non-acneiform) rashes were observed in 35 (70%) patients in the pivotal study and were predominantly grade 1 or 2.
Hair changes
In SPRINT, phase II stratum 1, 32% of patients experienced hair changes (reported as hair lightening [PT: hair colour changes] in 11 patients (22%) and hair thinning [PT: alopecia]) in 12 patients (24%)); in 7 patients (14%) both alopecia and hair colour changes were reported during treatment. All cases were grade 1 and did not require dose interruption or dose reduction.
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 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 |
Koselugo 25 mg hard capsules | Clinical particulars - Overdose | Overdose
There is no specific treatment for overdose. If overdose occurs, patients should be closely monitored for signs and symptoms of adverse reactions and treated supportively with appropriate monitoring as necessary. Dialysis is ineffective in the treatment of overdose.
5. Pharmacological properties
5.1 |
Koselugo 25 mg hard capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
At the recommended dose of 25 mg/m2 twice daily in paediatric patients (3 to ≤ 18 years old), the geometric mean (coefficient of variation [CV%]) maximum plasma concentration (Cmax) was 731 (62%) ng/mL and that of the area under the plasma drug concentration curve (AUC0-12) following the first dose was 2009 (35%) ng·h/mL. Minimal accumulation of ~1.1-fold was observed at steady state upon twice daily dosing.
In paediatric patients, at a dose level of 25 mg/m2, selumetinib has an apparent oral clearance of 8.8 L/h, mean apparent volume of distribution at steady state of 78 L and mean elimination half-life of ~6.2 hours.
Absorption
In healthy adult subjects, the mean absolute oral bioavailability of selumetinib was 62%.
Following oral dosing, selumetinib is rapidly absorbed, producing peak steady state plasma concentrations (Tmax) between 1-1.5 hours post-dose.
Effect of food
In separate clinical studies, in healthy adult subjects and in adult patients with advanced solid malignancies at a dose of 75 mg, co-administration of selumetinib with a high-fat meal resulted in a mean decrease in Cmax of 50% and 62%, respectively, compared to fasting administration. Selumetinib mean AUC was reduced by 16% and 19%, respectively, and the time to reach maximum concentration (Tmax) was delayed by approximately 1.5 to 3 hours (see section 4.2).
In healthy adult subjects at a dose of 50 mg, co-administration of selumetinib with a low-fat meal resulted in 60% lower Cmax when compared to fasting administration. Selumetinib AUC was reduced by 38%, and the time to reach maximum concentration (Tmax) was delayed by approximately 0.9 hours (see section 4.2).
Distribution
The mean apparent volume of distribution at steady state of selumetinib across 20 to 30 mg/m2 ranged from 78 to 171 L in paediatric patients, indicating moderate distribution into tissue.
In vitro plasma protein binding is 98.4% in humans. Selumetinib mostly binds to serum albumin (96.1%) than α-1 acid glycoprotein (< 35%).
Biotransformation
In vitro, selumetinib undergoes phase 1 metabolic reactions including oxidation of the side chain, N-demethylation, and loss of the side chain to form amide and acid metabolites. CYP3A4 is the predominant isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP2C9, CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib also undergoes direct phase 2 metabolic reactions to form glucuronide conjugates principally involving the enzymes UGT1A1 and UGT1A3. Glucuronidation is a significant route of elimination for selumetinib phase 1 metabolites involving several UGT isoforms.
Following oral dosing of 14C-selumetinib to healthy male subjects, unchanged selumetinib (~40% of the radioactivity) with other metabolites including glucuronide of imidazoindazole metabolite (M2; 22%), selumetinib glucuronide (M4; 7%), N-desmethyl selumetinib (M8; 3%), and N-desmethyl carboxylic acid (M11; 4%) accounted for the majority of the circulating radioactivity in human plasma. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.
Interactions
In vitro, selumetinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP2E1. In vitro, selumetinib is not an inducer of CYP1A2 and CYP2B6. Selumetinib is an inducer of CYP3A4 in vitro, this is however not expected to be clinically relevant.
In vitro, selumetinib inhibits UGT1A3, UGT1A4, UGT1A6 and UGT1A9 however these effects are not expected to be clinically relevant.
Interactions with transport proteins
Based on in vitro studies, selumetinib is a substrate for BCRP and P-gp transporters but is unlikely to be subjected to clinically relevant drug interactions. In vitro studies suggest that selumetinib does not inhibit the breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, MATE1 and MATE2K at the recommended paediatric dose. A clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.
Elimination
In healthy adult subjects, following a single oral 75 mg dose of radiolabelled selumetinib, 59% of the dose was recovered in faeces (19% unchanged) while 33% of the administered dose (< 1% as parent) was found in urine by 9 days of sample collection.
Special populations
Renal impairment
The exposure of 50 mg oral selumetinib was investigated in adult subjects with normal renal function (n = 11) and subjects with ESRD (n = 12). The ESRD group showed 16% and 28% lower Cmax and AUC, respectively, with the fraction of unbound selumetinib being 35% higher in ESRD subjects. As a result, the unbound Cmax and AUC ratios were 0.97 and 1.13 in the ESRD group when compared to the group with normal renal function. A small increase, approximately 20% AUC, in the N-desmethyl metabolite to parent ratio was detected in the ESRD group when compared to the normal group. As exposure in ESRD subjects was similar to those with normal renal function, investigations in mild, moderate and severe renally impaired subjects were not performed. Renal impairment is expected to have no meaningful influence on the exposure of selumetinib (see section 4.2).
Hepatic impairment
Adult subjects with normal hepatic function (n = 8) and mild hepatic impairment (Child-Pugh A, n = 8) were dosed with 50 mg selumetinib, subjects with moderate hepatic impairment (Child-Pugh B, n = 8) were administered a 50 or 25 mg dose, and subjects with severe hepatic impairment (Child-Pugh C, n = 8) were administered a 20 mg dose. Selumetinib total dose normalised AUC and unbound AUC were 86% and 69% respectively, in mild hepatic impairment patients, compared to the AUC values for subjects with normal hepatic function. Selumetinib exposure (AUC) was higher in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment; the total AUC and unbound AUC values were 159% and 141% (Child-Pugh B) and 157% and 317% (Child-Pugh C), respectively, of subjects with normal hepatic function (see section 4.2). There was a trend of lower protein binding in subjects with severe hepatic impairment although the protein binding remained > 99% (see section 4.3).
Ethnicity
Following a single-dose, selumetinib exposure appears to be higher in Japanese, non-Japanese-Asian and Indian healthy adult subjects compared to Western adult subjects, however, there is considerable overlap with Western subjects when corrected for body weight or BSA (see section 4.2).
Adult patients (> 18 years old)
The PK parameters in adult healthy subjects and adult patients with advanced solid malignancies, are similar to those in paediatric patients (3 to ≤ 18 years old) with NF1.
In adult patients, Cmax and AUC increased dose proportionally over a 25 mg to 100 mg dose range.
5.3 |
Koselugo 25 mg hard capsules | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Genotoxicity
Selumetinib was positive in the mouse micronucleus study via an aneugenic mode of action. The free mean exposure (Cmax) at the no observed effect level (NOEL) was approximately 27-times greater than clinical free exposure at the maximum recommended human dose (MRHD) of 25 mg/m2.
Carcinogenicity
Selumetinib was not carcinogenic in rats or transgenic mice.
Repeat-dose toxicity
In repeat-dose toxicity studies in mice, rats and monkeys, the main effects seen after selumetinib exposure were in the skin, GI tract and bones. Scabs associated with microscopic erosions and ulceration at a free exposure similar to the clinical exposure (free AUC) at the MRHD were seen in rats. Inflammatory and ulcerative GI tract findings associated with secondary changes in the liver and lymphoreticular system at free exposures approximately 28 times the clinical free exposure at the MRHD were observed in mice. Growth plate (physeal) dysplasia was seen in male rats dosed for up to 3 months with selumetinib at a free exposure 11 times the clinical free exposure at the MRHD. GI findings showed evidence of reversibility following a recovery period. Reversibility for skin toxicities and physeal dysplasia was not evaluated. Vascular engorgement of the corpus cavernosum of the bulbocavernosus muscle were observed in male mice in a 26-week study at a dose of 40 mg/kg/day (28 times the free AUC in humans at the MRHD) leading to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.
Reproductive toxicology
Developmental and reproduction toxicity studies were conducted in mice. Fertility was not affected in male mice at up to 40 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD). In females, mating performance and fertility were not affected at up to 75 mg/kg/day, but a reversible decrease in the number of live fetuses was observed at this dose level; the NOAEL for effects on reproductive performance was 5 mg/kg/day (approximately 3.5-fold the free AUC in humans at the MRHD). A treatment-related increase in the incidence of external malformations (open eye, cleft palate) was reported in absence of maternal toxicity in embryo-fetal development studies at > 5 mg/kg/day, and in the pre- and post-natal development study at ≥ 1 mg/kg/day (corresponding to 0.4-fold the free Cmax in humans at the MRHD). The other treatment related effects observed at non-maternotoxic dose levels in these studies consisted of embryo-lethality and decreased fetal weight at ≥ 25 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD), reductions in post-natal pup growth and at weaning a lower number of pups met the pupil constriction criterion at 15 mg/kg/day (corresponding to 3.6-fold the free Cmax in humans at the MRHD). Selumetinib and its active metabolite were excreted in the milk of lactating mice at concentrations approximately the same as those in plasma.
6. |
Koselugo 25 mg hard capsules | Pharmaceutical particulars - List of excipients | List of excipients
Capsule content
Vitamin E polyethylene glycol succinate (D α-tocopheryl polyethylene glycol succinate).
Capsule shell
Hypromellose (E464)
Carrageenan (E407)
Potassium chloride (E508)
Titanium dioxide (E171)
Indigo carmine aluminium lake (E132)
Iron oxide yellow (E172)
Carnauba wax (E903)
Maize starch
Printing ink
Iron oxide red (E172)
Iron oxide yellow (E172)
Indigo carmine aluminium lake (E132)
Carnauba wax (E903)
Shellac, standard (E904)
Glyceryl mono-oleate
6.2 |
Koselugo 25 mg hard capsules | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Koselugo 25 mg hard capsules | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Koselugo 25 mg hard capsules | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 30 °C.
Store in the original bottle in order to protect from moisture and light.
Keep the bottle tightly closed.
6.5 |
Koselugo 25 mg hard capsules | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
High-density polyethylene (HDPE) plastic bottle with blue child-resistant polypropylene closure.
Each bottle contains 60 hard capsules and a silica gel desiccant. Each carton contains one bottle.
6.6 |
Koselugo 25 mg hard capsules | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Patients should be instructed not to remove the desiccant from the bottle.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Koselugo 25 mg hard capsules | Marketing authorisation holder | AstraZeneca UK Limited,
1 Francis Crick Avenue,
Cambridge,
CB2 0AA,
UK.
8. Marketing authorisation number(s)
PLGB 17901/0357
9. |
Koselugo 25 mg hard capsules | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 9th August 2021
Date of latest renewal: 10th August 2022
10. |
Koselugo 25 mg hard capsules | Date of revision of the text | 7th March 2023 |
Kwells 300 microgram tablets | Name of the medicinal product | Kwells 300 microgram tablets
2. |
Kwells 300 microgram tablets | Qualitative and quantitative composition | Hyoscine Hydrobromide 300 microgram
For excipients, see section 6.1
3. |
Kwells 300 microgram tablets | Pharmaceutical form | Tablet
Small pink circular, flat faced tablets with bevelled edges. One face is bisected by a score line and the other is plain.
4. |
Kwells 300 microgram tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
For the prevention of travel sickness.
4.2 |
Kwells 300 microgram tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Tablets to be sucked, chewed or swallowed.
Adults:
1 tablet every 6 hours if required. Do not take more than 3 tablets in 24 hours.
Elderly:
There is no special dosage regimen for the elderly and as such caution should be exercised
Children:
Children over 10: ½-1 tablet every 6 hours if required. Do not take more than 1½-3 tablets in 24 hours.
Tablets to be taken up to 30 minutes before the start of the journey to prevent travel sickness, or at the onset of nausea.
4.3 |
Kwells 300 microgram tablets | Clinical particulars - Contraindications | Contraindications
Prostatic enlargement, paralytic ileus, pyloric stenosis, glaucoma and myasthenia gravis.
In addition, Kwells should not be given to patients with a known sensitivity to hyoscine hydrobromide or any other component of the product.
4.4 |
Kwells 300 microgram tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
The elderly and patients under medical care (in particular those at risk of acute urinary retention, or with cardiovascular, metabolic, gastrointestinal, liver or renal disease, or suffering from CNS disorders such as seizures) should consult a doctor before taking this product.
In patients with ulcerative colitis its use may lead to ileus or megacolon.
Antimuscarinics should be used with caution in persons with Down's Syndrome.
Caution is advisable in patients with diarrhoea.
Hyperthermia can occur at high ambient temperatures due to decreased sweating, therefore, Kwells should be used with caution in patients with fever.
4.5 |
Kwells 300 microgram tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The effects of hyoscine may be enhanced by other drugs with anticholinergic properties (including amantadine, some antihistamines, phenothiazine antipsychotics and tricyclic antidepressants), therefore, combining these drugs with hyoscine should be avoided.
There may be an increased risk of side effects when given with MAOIs due to inhibition of drug-metabolising enzymes.
The sedative effect of Kwells may be enhanced with alcohol or CNS depressants.
The reduction in gastric motility caused by Kwells may also affect the absorption of other drugs. There is an antagonism of effect of domperidone and metoclopramide on gastro-intestinal activity.
There could be a reduced effect of sublingual nitrate tablets due to the failure to dissolve properly under the tongue owing to dry mouth.
4.6 |
Kwells 300 microgram tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
The safety of this medicine in pregnancy has not been established. It should only be used during pregnancy, particularly in the first trimester, if the expected benefit to the mother outweighs any potential risk to the developing foetus.
Caution is required during lactation as small amounts of this medicine may pass into breast milk.
4.7 |
Kwells 300 microgram tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
May cause drowsiness. If affected do not drive or operate machinery.
4.8 |
Kwells 300 microgram tablets | Clinical particulars - Undesirable effects | Undesirable effects
The listed adverse drug reactions are based on spontaneous reports, thus an organization according to CIOMS II categories of frequency is not pertinent.
General: hyperthermia at high temperatures due to decreased sweating.
Eye disorders: blurred vision, mydriasis.
Gastrointestinal disorders: dry mouth.
Immune system disorders: allergic reaction and anaphylactic reaction. Hypersensitivity reactions with respective laboratory and clinical manifestations, including asthma syndrome, mild to moderate reactions affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, and symptoms such as rash, urticaria, oedema, pruritus, cardio-respiratory distress, have been reported.
Nervous system disorders: drowsiness, dizziness, sedation and somnolence are commonly reported. Central nervous system stimulation including restlessness, hallucinations and confusion, have been less frequently reported following the administration of hyoscine.
There have been rare reports of an increase in seizure frequency in epileptic patients (the same caution for this patient population is included in Section 4.4).
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Kwells 300 microgram tablets | Clinical particulars - Overdose | Overdose
The symptoms of overdosage are tachycardia, arrhythmia, blurring of vision and photophobia, urinary retention. Drowsiness is usual but paradoxical stimulation with hallucinations may occur.
Treatment: gastric lavage or induced emesis and symptomatic treatment.
5. Pharmacological properties
5.1 |
Kwells 300 microgram tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Hyoscine hydrobromide is readily absorbed from the gastro-intestinal tract, and in circulation is bound to plasma proteins. Clinical studies have shown that oral hyoscine hydrobromide is effective in preventing motion sickness at plasma concentration of 50pg/ml (equivalent to 0.17nmol/l). This concentration is reached within 30 minutes following oral/buccal administration of 0.3 mg hyoscine hydrobromide and it is effective for about 4 hours. Hyoscine hydrobromide is almost entirely metabolised in the body.
5.3 |
Kwells 300 microgram tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Not applicable.
6. |
Kwells 300 microgram tablets | Pharmaceutical particulars - List of excipients | List of excipients
Mannitol
Potato Starch
Gelatin Powder
Aluminium Stearate
Saccharin Sodium
Ferric Oxide
Purified Water (not detectable)
6.2 |
Kwells 300 microgram tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known.
6.3 |
Kwells 300 microgram tablets | Pharmaceutical particulars - Shelf life | Shelf life
36 months.
6.4 |
Kwells 300 microgram tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
6.5 |
Kwells 300 microgram tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Blister packs made up of 250µm opaque white PVC coated with 40 gsm PVDC and 20µm hard tempered aluminium foil.
a. Two strips of six tablets in cardboard carton.
b. One strip of twelve tablets in cardboard carton
c. Strip of two tablets stapled into a cardboard carton.
Pack sizes: 12, 2.
6.6 |
Kwells 300 microgram tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special precautions necessary.
7. |
Kwells 300 microgram tablets | Marketing authorisation holder | Dexcel®-Pharma Ltd.
7 Sopwith Way
Drayton Fields, Daventry
Northamptonshire NN11 8PB
UK
8. Marketing authorisation number(s)
PL 14017/0299
9. |
Kwells 300 microgram tablets | Date of first authorisation/renewal of the authorisation | 12/10/2005
10. |
Kwells 300 microgram tablets | Date of revision of the text | 27/08/2020 |
Kwells Kids 150 microgram tablets | Name of the medicinal product | Kwells Kids 150 microgram tablets
2. |
Kwells Kids 150 microgram tablets | Qualitative and quantitative composition | Hyoscine Hydrobromide: 150 micrograms
For excipients, see 6.1
3. |
Kwells Kids 150 microgram tablets | Pharmaceutical form | Tablet
Small white circular, flat faced tablets with bevelled edges. One face is bisected by a score line and the other is plain.
4. |
Kwells Kids 150 microgram tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
For the prevention of travel sickness.
4.2 |
Kwells Kids 150 microgram tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Tablets to be sucked, chewed or swallowed.
Tablets to be taken up to 30 minutes before the start of the journey to prevent travel sickness, or at the onset of nausea.
Adults:
Not applicable.
Elderly persons:
Not applicable.
Children:
Children over 10: 1-2 tablets every 6 hours if required. Do not take more than 3-6 tablets in 24 hours.
Children 4-10: ½-1 tablet every 6 hours if required. Do not take more than 1½-3 tablets in 24 hours.
4.3 |
Kwells Kids 150 microgram tablets | Clinical particulars - Contraindications | Contraindications
Prostatic enlargement, paralytic ileus, pyloric stenosis, glaucoma and myasthenia gravis.
In addition, Kwells should not be given to patients with a known sensitivity to hyoscine hydrobromide or any other component of the product.
4.4 |
Kwells Kids 150 microgram tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
The elderly and patients under medical care (in particular those at risk of acute urinary retention, or with cardiovascular, metabolic, gastrointestinal, liver or renal disease, or suffering from CNS disorders such as seizures) should consult a doctor before taking this product.
In patients with ulcerative colitis its use may lead to ileus or megacolon.
Antimuscarinics should be used with caution in persons with Down's Syndrome. Caution is advisable in patients with diarrhoea.
Hyperthermia can occur at high ambient temperatures due to decreased sweating, therefore, Kwells should be used with caution in patients with fever.
4.5 |
Kwells Kids 150 microgram tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The effects of hyoscine may be enhanced by other drugs with anticholinergic properties (including amantadine, some antihistamines, phenothiazine antipsychotics and tricyclic antidepressants), therefore, combining these drugs with hyoscine should be avoided.
There may be an increased risk of side effects when given with MAOIs due to inhibition of drug-metabolising enzymes.
The sedative effect of Kwells may be enhanced with alcohol or CNS depressants.
The reduction in gastric motility caused by Kwells may also affect the absorption of other drugs. There is an antagonism of effect of domperidone and metoclopramide on gastro-intestinal activity.
There could be a reduced effect of sublingual nitrate tablets due to the failure to dissolve properly under the tongue owing to dry mouth.
4.6 |
Kwells Kids 150 microgram tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
The safety of this medicine in pregnancy has not been established. It should only be used during pregnancy, particularly in the first trimester, if the expected benefit to the mother outweighs any potential risk to the developing foetus.
Caution is required during lactation as small amounts of this medicine may pass into breast milk.
4.7 |
Kwells Kids 150 microgram tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
May cause drowsiness. If affected do not drive or operate machinery.
4.8 |
Kwells Kids 150 microgram tablets | Clinical particulars - Undesirable effects | Undesirable effects
The listed adverse drug reactions are based on spontaneous reports, thus an organization according to CIOMS II categories of frequency is not pertinent.
General: hyperthermia at high temperatures due to decreased sweating.
Eye disorders: blurred vision, mydriasis.
Gastrointestinal disorders: dry mouth.
Immune system disorders: allergic reaction and anaphylactic reaction. Hypersensitivity reactions with respective laboratory and clinical manifestations, including asthma syndrome, mild to moderate reactions affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, and symptoms such as rash, urticaria, oedema, pruritus, cardio-respiratory distress, have been reported.
Nervous system disorders: drowsiness, dizziness, sedation and sonmolence are commonly reported. Central nervous system stimulation including restlessness, hallucinations and confusion, have been less frequently reported following the administration of hyoscine.
There have been rare reports of an increase in seizure frequency in epileptic patients (the same caution for this patient population is included in Section 4.4).
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 Yellow Card Scheme at: www.mhra.gov.uk!yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Kwells Kids 150 microgram tablets | Clinical particulars - Overdose | Overdose
The symptoms of overdosage are tachycardia, arrhythmia, blurring of vision and photophobia, urinary retention. Drowsiness is usual, but paradoxical stimulation with hallucinations may occur.
Treatment: gastric lavage or induced emesis and symptomatic treatment.
5. Pharmacological properties
5.1 |
Kwells Kids 150 microgram tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Hyoscine hydrobromide is readily absorbed from the gastro-intestinal tract, and in circulation is bound to plasma proteins. Clinical studies have shown that oral hyoscine hydrobromide is effective in preventing motion sickness at plasma concentration of 50 pg/ml (equivalent to 0.17 nmol/1). This concentration is reached within 30 minutes following oral/buccal administration of 0.3 mg hyoscine hydrobromide and it is effective for about 4 hours. Hyoscine hydrobromide is almost entirely metabolised in the body.
5.3 |
Kwells Kids 150 microgram tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Not applicable
6. |
Kwells Kids 150 microgram tablets | Pharmaceutical particulars - List of excipients | List of excipients
Mannitol
Potato Starch part dried
Gelatin Powder
Aluminium Stearate
Saccharin Sodium
6.2 |
Kwells Kids 150 microgram tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known
6.3 |
Kwells Kids 150 microgram tablets | Pharmaceutical particulars - Shelf life | Shelf life
36 months
6.4 |
Kwells Kids 150 microgram tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
6.5 |
Kwells Kids 150 microgram tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Blister packs made up of 250µm opaque white PVC coated with 40 gsm PVDC and 20µm hard tempered aluminium foil.
a. Two strips of six tablets in cardboard carton.
b. One strip of twelve tablets in cardboard carton
Pack sizes: 12
6.6 |
Kwells Kids 150 microgram tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
None
7. |
Kwells Kids 150 microgram tablets | Marketing authorisation holder | Dexcel®-Pharma Ltd.
7 Sopwith Way
Drayton Fields, Daventry
Northamptonshire NN11 8PB
UK
8. Marketing authorisation number(s)
PL 14017/0300
9. |
Kwells Kids 150 microgram tablets | Date of first authorisation/renewal of the authorisation | 10/06/1988
10. |
Kwells Kids 150 microgram tablets | Date of revision of the text | 27/08/2020 |
Kyleena 19.5 mg intrauterine delivery system | Name of the medicinal product | Kyleena 19.5 mg intrauterine delivery system.
2. |
Kyleena 19.5 mg intrauterine delivery system | Qualitative and quantitative composition | The intrauterine delivery system contains 19.5 mg levonorgestrel.
For the full list of excipients, see section 6.1.
For details of release rates, see section 5.2.
3. |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical form | Intrauterine delivery system (IUS).
The product consists of a whitish or pale yellow drug core covered with a semi-opaque membrane, which is mounted on the vertical stem of a T-body. In addition, the vertical stem contains a silver ring located close to the horizontal arms. The white T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. The blue coloured removal threads are attached to the loop. The vertical stem of the IUS is loaded in the insertion tube at the tip of the inserter. The inserter consists of a handle and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. The removal threads are located within the insertion tube and handle.
Dimensions of Kyleena: 28 x 30 x 1.55 mm
4. |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Therapeutic indications | Therapeutic indications
Contraception for up to 5 years.
4.2 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Kyleena is inserted into the uterine cavity and is effective for up to 5 years.
Insertion
It is recommended that Kyleena should only be inserted by healthcare professionals who are experienced in IUS insertions and/ or have undergone training on the Kyleena insertion procedure.
Table 1: When to insert Kyleena in women of fertile age
Starting Kyleena
- Exclude pregnancy before insertion (see section 4.3 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Contraindications | Contraindications). Consider the possibility of ovulation and conception before using this product. Kyleena is not suitable for use as a post-coital contraceptive.
- Kyleena should be inserted into the uterine cavity within 7 days of the onset of menstruation. In this case Kyleena provides contraceptive protection upon insertion and no back-up contraception is needed.
- If insertion within 7 days of the onset of menstruation is not possible or the woman does not experience regular menses, Kyleena may be inserted at any time during the menstrual cycle provided that the healthcare professional can reliably exclude the possibility of prior conception. Following insertion, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for the next 7 days to prevent pregnancy.
Postpartum insertion
In addition to the instructions above (Starting Kyleena):
Postpartum insertions should be postponed until the uterus is fully involuted, however should not be performed earlier than 6 weeks after delivery. If involution is substantially delayed, consider waiting until 12 weeks postpartum.
Insertion after first trimester abortion
Kyleena can be inserted immediately after first trimester abortion. In this case no back-up contraception is needed.
Replacing Kyleena
Kyleena can be replaced by a new system at any time in the menstrual cycle. In this case no back up contraception is needed.
In case of a difficult insertion and/ or exceptional pain or bleeding during or after insertion, the possibility of perforation should be considered and appropriate steps should be taken, such as physical examination and ultrasound. Physical examination may not be sufficient to exclude partial perforation.
Kyleena can be distinguished from other IUSs by the combination of the visibility of the silver ring on ultrasound and the blue colour of the removal threads. The T-frame of Kyleena contains barium sulfate which makes it visible in X-ray examination.
Removal/Replacement
Kyleena is removed by gently pulling on the threads with a forceps. If the threads are not visible and the system is found to be in the uterine cavity on ultrasound examination, it may be removed using a narrow forceps. This may require dilatation of the cervical canal or surgical intervention.
The system should be removed no later than by the end of the fifth year. If the woman wishes to continue using the same method, a new system can be inserted immediately following removal of the original system.
If pregnancy is not desired, the removal should be carried out within 7 days of the onset of menstruation, provided the woman is experiencing regular menses. If the system is removed at some other time during the cycle or the woman does not experience regular menses and the woman has had intercourse within a week, she is at risk of pregnancy. To ensure continuous contraception a new system should be immediately inserted or an alternative contraceptive method should have been initiated.
After removal of Kyleena, the system should be examined to ensure that it is intact.
Elderly
Kyleena is not indicated for use in postmenopausal women.
Hepatic impairment
Kyleena has not been studied in women with hepatic impairment. Kyleena is contraindicated in women with acute liver disease or liver tumour (see section 4.3).
Renal impairment
Kyleena has not been studied in women with renal impairment.
Paediatric population
Use of this product before menarche is not indicated. For data on safety and efficacy in adolescents, see section 5.1.
Method of administration
To be inserted by a healthcare professional using aseptic technique.
Kyleena is supplied in a sterile package within an integrated inserter that enables single handed loading. The package should not be opened until needed for insertion. Do not resterilize. As supplied, Kyleena is for single use only. Do not use if the blister is damaged or open. Do not insert after the expiry date which is stated on the carton and the blister after EXP.
Any unused product or waste material should be disposed of in accordance with local requirements.
Kyleena is supplied with a patient reminder card in the outer carton. Complete the patient reminder card and give it to the patient, after insertion.
Preparation for insertion
- Examine the patient to establish the size and position of the uterus, in order to detect any signs of acute genital infections or other contraindications for the insertion of Kyleena. If there is any doubt regarding pregnancy, a pregnancy test should be performed.
- Insert a speculum, visualize the cervix, and then thoroughly cleanse the cervix and vagina with a suitable antiseptic solution.
- Employ an assistant as necessary.
- Grasp the anterior lip of the cervix with a tenaculum or other forceps to stabilize the uterus. If the uterus is retroverted, it may be more appropriate to grasp the posterior lip of the cervix. Gentle traction on the forceps can be applied to straighten the cervical canal. The forceps should remain in position and gentle counter traction on the cervix should be maintained throughout the insertion procedure.
- Advance a uterine sound through the cervical canal to the fundus to measure the depth and confirm the direction of the uterine cavity and to exclude any evidence of intrauterine abnormalities (e.g., septum, submucous fibroids) or a previously inserted intrauterine contraceptive which has not been removed. If difficulty is encountered, consider dilatation of the canal. If cervical dilatation is required, consider using analgesics and/or a paracervical block.
4.3 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Special warnings and precautions for use | Contraindications
• Pregnancy (see section 4.6);
• Acute or recurrent pelvic inflammatory disease or conditions associated with increased risk for pelvic infections;
• Acute cervicitis or vaginitis;
• Postpartum endometritis or infected abortion during the past three months;
• Cervical intraepithelial neoplasia until resolved;
• Uterine or cervical malignancy;
• Progestogen-sensitive tumours, e.g. breast cancer;
• Abnormal uterine bleeding of unknown etiology;
• Congenital or acquired uterine anomaly including fibroids which would interfere with insertion and / or retention of the intrauterine system (i.e. if they distort the uterine cavity);
• Acute liver disease or liver tumour;
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Special warnings and precautions for use
Kyleena should be used with caution after specialist consultation, or removal of the system should be considered if any of the following conditions exist or arise for the first time:
• migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia
• exceptionally severe headache
• jaundice
• marked increase of blood pressure
• severe arterial disease such as stroke or myocardial infarction
Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Kyleena. However, there is generally no need to alter the therapeutic regimen in diabetics using levonorgestrel- IUS.
Medical examination/consultation
Before insertion, a woman must be informed of the benefits and risks of Kyleena, including the signs and symptoms of perforation and the risk of ectopic pregnancy, see below. A physical examination including pelvic examination and examination of the breasts should be conducted. Cervical smear should be performed as needed, according to healthcare professional's evaluation. Pregnancy and sexually transmitted diseases should be excluded. Genital infections should be successfully treated prior to insertion. The position of the uterus and the size of the uterine cavity should be determined. Fundal positioning of Kyleena is important in order to maximize the efficacy and reduce the risk of expulsion. The instructions for the insertion should be followed carefully.
Emphasis should be given to training in the correct insertion technique.
Insertion and removal may be associated with some pain and bleeding. The procedure may precipitate a vasovagal reaction (e.g. syncope, or a seizure in an epileptic patient).
A woman should be re-examined 4 to 6 weeks after insertion to check the threads and ensure that the system is in the correct position. Follow-up visits are recommended once a year thereafter, or more frequently if clinically indicated.
Kyleena is not for use as a post-coital contraceptive.
The use of Kyleena for the treatment of heavy menstrual bleeding or protection from endometrial hyperplasia during estrogen replacement therapy has not been established. Therefore it is not recommended for use in these conditions.
Ectopic pregnancy
In clinical trials, the overall incidence of ectopic pregnancy with Kyleena was approximately 0.20 per 100 women-years. Approximately half of the pregnancies that occur during Kyleena use are likely to be ectopic.
Women considering Kyleena should be counselled on the signs, symptoms and risks of ectopic pregnancy. For women who become pregnant while using Kyleena, the possibility of an ectopic pregnancy must be considered and evaluated.
Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry an increased risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered in the case of lower abdominal pain, especially in connection with missed periods or if an amenorrhoeic woman starts bleeding.
Because an ectopic pregnancy may impact future fertility the benefits and risks of using Kyleena should be carefully evaluated on an individual woman basis.
Effects on the menstrual bleeding pattern
Effects on the menstrual bleeding pattern are expected in most users of Kyleena. Those alterations are a result of the direct action of levonorgestrel on the endometrium and may not correlate with the ovarian activity.
Irregular bleeding and spotting are common in the first months of use. Thereafter, the strong suppression of the endometrium results in the reduction of the duration and volume of menstrual bleeding. Scanty flow frequently develops into oligomenorrhoea or amenorrhoea.
In clinical trials, infrequent bleeding and/or amenorrhoea developed gradually. By the end of the fifth year about 26.4% and 22.6% of the users developed infrequent bleeding and/or amenorrhoea, respectively. Pregnancy should be considered if menstruation does not occur within 6 weeks of the onset of previous menstruation. A repeated pregnancy test is not necessary in subjects who remain amenorrhoeic unless indicated by other signs of pregnancy.
If bleeding becomes heavier and/or more irregular over time, appropriate diagnostic measures should be taken as irregular bleeding may be a symptom of endometrial polyps, hyperplasia or cancer and heavy bleeding may be a sign of unnoticed expulsion of the IUS.
Pelvic infection
Pelvic infection has been reported during use of any IUS or IUD. While Kyleena and the inserter are sterile they may, due to bacterial contamination during insertion, become a vehicle for microbial transport in the upper genital tract. In clinical trials, pelvic inflammatory disease (PID) was observed more frequently at the beginning of Kyleena use, which is consistent with published data for copper IUDs, where the highest rate of PID occurs during the first 3 weeks after insertion and decreases thereafter.
Before electing use of Kyleena, patients should be fully evaluated for risk factors associated with pelvic infection (e.g. multiple sexual partners, sexually transmitted infections, prior history of PID). Pelvic infections such as PID may have serious consequences and may impair fertility and increase the risk of ectopic pregnancy.
As with other gynecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can occur following IUD insertion, although this is extremely rare.
If a woman experiences recurrent endometritis or pelvic inflammatory disease or if an acute infection is severe or does not respond to treatment, Kyleena must be removed.
Bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms indicative of infections.
Expulsion
In clinical trials with Kyleena, the incidence of expulsion was low (<4% of insertions) and in the same range as reported for other IUDs and IUSs. Symptoms of partial or complete expulsion of Kyleena may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it, leading to loss of contraceptive protection. As Kyleena decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.
Risk of expulsion is increased in
- Women with history of heavy menstrual bleeding
- Women with greater than normal BMI at the time of insertion; this risk increases gradually with increasing BMI
Women should be counselled on possible signs of expulsion and how to check the threads of Kyleena and advised to contact a healthcare professional if the threads cannot be felt. A barrier contraceptive (such as a condom) should be used until the location of Kyleena has been confirmed.
Partial expulsion may decrease the effectiveness of Kyleena.
A partially expelled Kyleena should be removed. A new system can be inserted at the time of removal, provided pregnancy has been excluded.
Perforation
Perforation or penetration of the uterine corpus or cervix by an intrauterine contraceptive may occur, most often during insertion, although it may not be detected until sometime later, and may decrease the effectiveness of Kyleena. In case of a difficult insertion and/or exceptional pain or bleeding during or after insertion, appropriate steps should be taken immediately to exclude perforation, such as physical examination and ultrasound. Such a system must be removed; surgery may be required.
In a large prospective comparative non-interventional cohort study in users of other IUDs (N=61448 women) with a 1-year observational period, the incidence of perforation was 1.3 (95% CI: 1.1-1.6) per 1000 insertions in the entire study cohort; 1.4 (95% CI: 1.1-1.8) per 1000 insertions in the cohort of another levonorgestrel-IUS and 1.1 (95% CI: 0.7-1.6) per 1000 insertions in the copper IUD cohort.
The study showed that both breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were associated with an increased risk of perforation (see Table 2). Both risk factors were independent of the type of IUD inserted.
Table 2: Incidence of perforation per 1000 insertions for the entire study cohort observed over 1 year, stratified by breastfeeding and time since delivery at insertion (parous women)
Breastfeedingat time of insertion
Not breastfeedingat time of insertion
Insertion ≤ 36 weeks after delivery
5.695% CI: 3.9-7.9,n=6047 insertions)
1.795% CI: 0.8-3.1,n=5927 insertions)
Insertion > 36 weeks after delivery
1.6(95% CI: 0.0-9.1,n=608 insertions)
0.7(95% CI: 0.5-1.1,n=41910 insertions)
Extending the observational period to 5 years in a subgroup of this study (N=39009 women inserted with another levonorgestrel-IUS or copper IUD, 73% of these women had information available over the complete 5 years of follow-up), the incidence of perforation detected at any time during the entire 5-year period was 2.0 (95% CI: 1.6 – 2.5) per 1000 insertions. Breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were confirmed as risk factors also in the subgroup that were followed up for 5 years.
The risk of perforations may be increased in women with fixed retroverted uterus.
Re-examination after insertion should follow the guidance given under the heading "Medical examination/consultation" which may be adapted as clinically indicated in women with risk factors for perforation.
Lost threads
If the removal threads are not visible at the cervix on follow-up examinations, unnoticed expulsion and pregnancy must be excluded. The threads may have been drawn up into the uterus or cervical canal and may reappear during the next menstrual period. If pregnancy has been excluded, the threads may usually be located by gently probing the cervical canal with a suitable instrument. If they cannot be found, the possibility of expulsion or perforation should be considered. Ultrasound examination may be used to ascertain the position of the system. If ultrasound is not available or is not successful, X-ray may be used to locate Kyleena.
Ovarian cysts/enlarged ovarian follicles
Since the contraceptive effect of Kyleena is mainly due to its local effects within the uterus, there is generally no change in ovulatory function, including regular follicular development, oocyte release and follicular atresia in women of fertile age. Sometimes atresia of the follicle is delayed and folliculogenesis may continue. These enlarged follicles cannot be distinguished clinically from ovarian cysts. Ovarian cysts (including haemorrhagic ovarian cysts and ruptured ovarian cysts) have been reported over the course of the clinical trials as adverse event at least once in approximately 22.2% of women using Kyleena. Most of these cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.
In most cases, the enlarged follicles resolve spontaneously over two to three months observation. Should an enlarged follicle fail to resolve spontaneously, continued ultrasound monitoring and other diagnostic/ therapeutic measures may be appropriate. Rarely, surgical intervention may be required.
Psychiatric disorders
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their healthcare professional in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
4.5 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Fertility, pregnancy and lactation | Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Effects of other medicinal products on Kyleena
Interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones.
Substances increasing the clearance of levonorgestrel, e.g.:
Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John's wort.
The influence of these medicinal products on the contraceptive efficacy of Kyleena is not known, but it is not believed to be of major importance due to the local mechanism of action.
Substances with variable effects on the clearance of levonorgestrel, e.g.:
When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin.
Substances decreasing the clearance of levonorgestrel (enzyme inhibitors):
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.
Magnetic resonance imaging (MRI)
Non-clinical testing of another levonorgestrel-IUS with the same size silver ring and T-body has demonstrated that a patient can be scanned safely after placement of Kyleena (MR conditional) under the following conditions:
• Static magnetic field of 3-Tesla or less,
• Spatial gradient field of 36000 Gauss/cm (360 T/m) or less
• Maximum whole body averaged specific absorption rate (SAR) of 4 W/kg in the First Level Controlled mode for 15 minutes of continuous scanning
In non-clinical testing, the aforementioned levonorgestrel-IUS produced a temperature rise of equal to or less than 1.8°C at a maximum whole body averaged specific absorption rate (SAR) of 2.9 W/kg, for 15 minutes of MR scanning at 3 T using a transit/receive body coil.
A small amount of imaging artifact may occur if the area of interest is in the same area or relatively close to the position of Kyleena.
4.6 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Effects on ability to drive and use machines | Fertility, pregnancy and lactation
Fertility
The use of a levonorgestrel-releasing intrauterine system does not alter the course of future fertility. Upon removal of the intrauterine system, women return to their normal fertility (see section 5.1).
Pregnancy
The use of Kyleena during an existing or suspected pregnancy is contraindicated, see section 4.3 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Undesirable effects | Contraindications. If the woman becomes pregnant while using Kyleena the system should be removed as soon as possible, since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour. Removal of Kyleena or probing of the uterus may also result in spontaneous abortion. Ectopic pregnancy should be excluded.
If the woman wishes to continue the pregnancy and the system cannot be withdrawn, she should be informed about the risks and the possible consequences of premature birth to the infant. The course of such a pregnancy should be closely monitored. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.
In addition, an increased risk of virilising effects in a female foetus because of the intrauterine exposure to levonorgestrel cannot be excluded. There have been isolated cases of masculinisation of the external genitalia of the female foetus following local exposure to levonorgestrel during pregnancy with an LNG-IUS in place.
Breast-feeding
In general, there appears to be no deleterious effect on infant growth or development when using any progestogen-only method after 6 weeks postpartum. A levonorgestrel-releasing intrauterine system does not affect the quantity or quality of breast milk. Small amounts of progestogen (about 0.1% of the levonorgestrel dose) pass into the breast milk in nursing mothers.
4.7 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Overdose | Effects on ability to drive and use machines
Kyleena has no known influence on the ability to drive or use machines.
4.8 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Subsection 10 | Undesirable effects
Summary of the safety profile
The majority of women experience changes in menstrual bleeding pattern after insertion of Kyleena. Over time, the frequency of amenorrhoea and infrequent bleeding increases, and the frequency of prolonged, irregular and frequent bleeding decreases. The following bleeding patterns were observed in clinical trials:
Table 3: Bleeding patterns reported with Kyleena in clinical trials
Kyleena
First 90 days
Second 90 days
End of year 1
End of year 3
End of year 5
Amenorrhoea
< 1%
5%
12%
20%
23%
Infrequent bleeding
10%
20%
26%
26%
26%
Frequent bleeding
25%
10%
4%
2%
2%
Prolonged bleeding*
57%
14%
6%
2%
1%
Irregular bleeding
43%
25%
17%
10%
9%
*Subjects with prolonged bleeding may also be included in one of the other categories (excluding amenorrhoea)
Tabulated summary of adverse events
The frequencies of Adverse Drug Reactions (ADRs) reported with Kyleena are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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).
System Organ Class
Very Common
Common
Uncommon
Psychiatric disorders
Depressed mood/Depression
Decreased libido
Nervous system disorders
Headache
Migraine
Vascular disorders
Dizziness
Gastrointestinal disorders
Abdominal/pelvic pain
Nausea
Skin and subcutaneous tissue disorders
Acne/Seborrhoea
Alopecia
Hirsutism
Reproductive system and breast disorders
Bleeding changes including increased and decreased menstrual bleeding, spotting, infrequent bleeding and amenorrhoea
Ovarian cyst*
Vulvovaginitis
Upper genital tract infection
Dysmenorrhoea
Breast pain/discomfort
Device expulsion (complete and partial)
Genital discharge
Uterine perforation**
Investigations
Increased weight
* In clinical trials ovarian cysts had to be reported as AEs if they were abnormal, non-functional cysts and/or had a diameter > 3 cm on ultrasound examination.** This frequency is based on a large prospective comparative non-interventional cohort study with women using another levonorgestrel-IUS and copper IUDs which showed that breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth are independent risk factors for perforation (see section 4.4 under Perforation). In clinical trials with Kyleena that excluded breastfeeding women the frequency of perforation was "rare".
Description of selected adverse reactions
With the use of levonorgestrel-IUS, cases of hypersensitivity including rash, urticaria and angioedema have been reported.
If a woman becomes pregnant while using Kyleena, the relative likelihood of this pregnancy being ectopic is increased (see section 4.4 under Ectopic Pregnancy).
The removal threads may be felt by the partner during intercourse.
The following ADRs have been reported in connection with the insertion or removal procedure of Kyleena:
Procedural pain, procedural bleeding, insertion-related vasovagal reaction with dizziness or syncope. The procedure may precipitate a seizure in an epileptic patient.
Cases of sepsis (including group A streptococcal sepsis) have been reported following IUD insertion (see section 4.4 under Pelvic Infection).
Paediatric population
The safety profile of Kyleena is expected to be the same for adolescents under the age of 18 as for users 18 years and older. For data on safety in adolescents, see section 5.1.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google Play or Apple App Store.
4.9 |
Kyleena 19.5 mg intrauterine delivery system | Clinical particulars - Subsection 11 | Overdose
Not relevant.
5. Pharmacological properties
5.1 |
Kyleena 19.5 mg intrauterine delivery system | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Levonorgestrel is released locally into the uterine cavity. The in vivo release curve is characterized by an initial steep decline that slows down progressively resulting in little change after 1 year until the end of the intended 5-year period of use. Estimated in vivo delivery rates for different time points are provided in Table 4.
Table 4: Estimated in vivo release rates based on observed ex vivo residual content data
Time
Estimated in vivo release rate
[micrograms/24 hours]
24 days after insertion
17.5
60 days after insertion
15.3
1 year after insertion
9.8
3 years after insertion
7.9
5 years after insertion
7.4
Average over 1st year
12.6
Average over 5 years
9.0
Absorption
Following insertion, levonorgestrel is released from the IUS into the uterine cavity without delay. More than 90% of the released levonorgestrel is systemically available. Maximum serum concentrations of levonorgestrel are reached within the first two weeks after insertion of Kyleena. Seven days after insertion, a mean levonorgestrel concentration of 162 pg/ml (5th percentile: 81 pg/ml – 95th percentile: 308 pg/ml was determined. Thereafter serum concentrations of levonorgestrel decline over time to reach mean concentrations of 91 pg/ml (5th percentile: 47 pg/ml – 95th percentile: 170 pg/ml) after 3 years and 83 pg/ml (5th percentile: 45 pg/ml – 95th percentile: 153 pg/ml) after 5 years. With the use of a levonorgestrel-releasing intrauterine system, the high local drug exposure in the uterine cavity leads to a strong concentration gradient from the endometrium to the myometrium (gradient endometrium to myometrium > 100-fold), and to low concentrations of levonorgestrel in serum (gradient endometrium to serum > 1000-fold).
Distribution
Levonorgestrel is bound non-specifically to serum albumin and specifically to SHBG. Less than 2% of the circulating levonorgestrel is present as free steroid. Levonorgestrel binds with high affinity to SHBG. Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentrations) or in a decrease (at lower SHBG concentrations) of the total levonorgestrel concentration in serum. The concentration of SHBG declined on average by about 30% during the first 3 months after insertion of Kyleena and remained relatively stable over the 5 year period of use. The mean apparent volume of distribution of levonorgestrel is about 106 L.
Biotransformation
Levonorgestrel is extensively metabolized. The most important metabolic pathways are the reduction of the Δ4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of levonorgestrel. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for levonorgestrel compared to reduction and conjugation.
Elimination
The total clearance of levonorgestrel from plasma is approximately 1.0 ml/min/kg. Only trace amounts of levonorgestrel are excreted in unchanged form. The metabolites are excreted in feces and urine at an excretion ratio of about 1. The excretion half-life is about 1 day.
Linearity/non-linearity
The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG which itself is influenced by estrogens and androgens. A decrease of SHBG concentration leads to a decrease of total levonorgestrel concentration in serum indicating non-linear pharmacokinetics of levonorgestrel with regard to time. Based on the mainly local action of Kyleena, no impact on the efficacy of Kyleena is expected.
Paediatric population
In a one-year phase III study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) using another lower-dose levonorgestrel-IUS the pharmacokinetic analysis of 283 adolescents showed estimated levonorgestrel serum concentrations slightly higher (approximately 10%) in adolescents compared to adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie, however, within the ranges estimated for adults, showing high similarity.
No differences in the pharmacokinetics of adolescents and adults are expected with Kyleena.
Ethnic differences
A three-year phase III study in the Asian-Pacific region (93% Asian women, 7% other ethnicities) using another lower-dose levonorgestrel-IUS has been performed. A comparison of pharmacokinetic characteristics of levonorgestrel of the Asian population in this study with the Caucasian population from another phase III study showed no clinically relevant difference in systemic exposure and other pharmacokinetic parameters. In addition, the daily release rate of the levonorgestrel containing IUS was the same in both populations.
No pharmacokinetic differences in women of different ethnicities are expected with Kyleena.
5.3 |
Kyleena 19.5 mg intrauterine delivery system | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Nonclinical data revealed no special hazard for humans based on studies of safety pharmacology, pharmacokinetics and toxicity, including genotoxicity and carcinogenic potential of levonorgestrel. Studies in monkeys with intrauterine delivery of levonorgestrel for 9 to 12 months confirmed local pharmacological activity with good local tolerance and no signs of systemic toxicity. No embryotoxicity was seen in rabbits following intrauterine administration of levonorgestrel.
The safety evaluation of the elastomer components of the hormone reservoir, polyethylene and polypropylene materials as well as the silver ring of the product, and combination of elastomer and levonorgestrel, based on both the assessment of genetic toxicology in standard in vitro and in vivo test systems and on biocompatibility tests in mice, rats, guinea pigs, rabbits and in vitro test systems have not revealed bio-incompatibility.
Environmental risk assessment (ERA)
Environmental risk assessment studies have shown that levonorgestrel may pose a risk to the aquatic environment (see section 6.6).
6. |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical particulars - List of excipients | List of excipients
Polydimethylsiloxane elastomer
Silica, colloidal anhydrous
Polyethylene
Barium sulfate
Polypropylene
Copper phthalocyanine
Silver
6.2 |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
The product is individually packed into a thermoformed blister package (PETG) with a peelable lid (PE).
Pack sizes: 1x1 and 5x1.
Not all pack sizes may be marketed.
6.6 |
Kyleena 19.5 mg intrauterine delivery system | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
The product is supplied in a sterile package which should not be opened until required for insertion. Each system should be handled with aseptic precautions. If the seal of the sterile envelope is broken, the system inside should be disposed of in accordance with local guidelines for the handling of biohazardous waste. Likewise, a removed Kyleena and inserter should be disposed of in this manner.
To be inserted by a healthcare professional using aseptic technique (see section 4.2).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements. This medicinal product may pose a risk to the environment (see section 5.3).
7. |
Kyleena 19.5 mg intrauterine delivery system | Marketing authorisation holder | Bayer plc
400 South Oak Way
Reading
RG2 6AD
8. Marketing authorisation number(s)
PL 00010/0664
9. |
Kyleena 19.5 mg intrauterine delivery system | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 23 December 2016
Date of latest renewal: 23 September 2022
10. |
Kyleena 19.5 mg intrauterine delivery system | Date of revision of the text | 6 October 2022
Detailed information on this medicinal product is available on the website of the MHRA (https://www.gov.uk/pil-spc). |
Kymriah cells dispersion for infusion | Introduction | 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. |
Kymriah cells dispersion for infusion | Name of the medicinal product | Kymriah 1.2 x 106 – 6 x 108 cells dispersion for infusion
2. |
Kymriah cells dispersion for infusion | Qualitative and quantitative composition | 2.1 General description
Kymriah is an immunocellular therapy containing tisagenlecleucel, autologous T cells genetically modified ex vivo using a lentiviral vector encoding an anti-CD19 chimeric antigen receptor (CAR).
2.2 |
Kymriah cells dispersion for infusion | Qualitative and quantitative composition | Each ethylene vinyl acetate (EVA) infusion bag of Kymriah contains tisagenlecleucel cell dispersion at a batch-dependent concentration of autologous T cells genetically modified to express an anti-CD19 chimeric antigen receptor (CAR-positive viable T cells) (see section 4.2).
The concentration of CAR-positive viable T cells is dependent on indication and patient body weight (for B-cell acute lymphoblastic leukaemia [ALL]). The cellular composition and the final cell number varies between individual patient batches. In addition to T cells, NK cells may be present. The quantitative information regarding CAR-positive viable T cells/mL and total cells in the product is presented in the batch-specific documentation accompanying Kymriah.
1 or more infusion bags containing a total of 1.2 x 106 to 6 x 108 CAR-positive viable T cells.
Excipient with known effect
This medicinal product contains 2.43 mg sodium per mL and 24.3 to 121.5 mg sodium per dose.
For the full list of excipients, see section 6.1.
3. |
Kymriah cells dispersion for infusion | Pharmaceutical form | Dispersion for infusion
A colourless to slightly yellow dispersion.
4. |
Kymriah cells dispersion for infusion | Clinical particulars - Therapeutic indications | Therapeutic indications
Kymriah is indicated for the treatment of:
• Paediatric and young adult patients up to and including 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse.
• Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.
• Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.
4.2 |
Kymriah cells dispersion for infusion | Clinical particulars - Posology and method of administration | Posology and method of administration
Kymriah must be administered in a qualified treatment centre. Therapy should be initiated under the direction of and supervised by a healthcare professional experienced in the treatment of haematological malignancies and trained for administration and management of patients treated with Kymriah. Tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available per patient prior to infusion. The treatment centre must have access to additional doses of tocilizumab within 8 hours.
Kymriah is intended for autologous use only (see section 4.4). Manufacture and release of Kymriah usually takes about 3-4 weeks.
Posology
Dosage in paediatric and young adult B-cell ALL patients
- For patients 50 kg and below: 0.2 to 5 x 106 CAR-positive viable T cells/kg body weight.
- For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells (non-weight based).
Dosage in adult DLBCL and FL patients
- 0.6 to 6 x 108 CAR-positive viable T cells (non-weight based).
Pre-treatment conditioning (lymphodepleting chemotherapy)
The availability of Kymriah must be confirmed prior to starting the lymphodepleting regimen. For B-cell ALL and DLBCL indications,
Kymriah is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy. For FL, Kymriah is recommended to be infused 2 to 6 days after completion of the lymphodepleting chemotherapy.
Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count ≤1,000 cells/µL within one week prior to infusion.
If there is a delay of more than 4 weeks between completing lymphodepleting chemotherapy and the infusion and the WBC count is >1,000 cells/μL, then the patient should be re-treated with lymphodepleting chemotherapy prior to receiving Kymriah.
B-cell ALL
The recommended lymphodepleting chemotherapy regimen is:
- Fludarabine (30 mg/m2 intravenous daily for 4 days) and cyclophosphamide (500 mg/m2 intravenous daily for 2 days starting with the first dose of fludarabine).
If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortly before lymphodepleting chemotherapy, then the following should be used:
- Cytarabine (500 mg/m2 intravenous daily for 2 days) and etoposide (150 mg/m2 intravenous daily for 3 days starting with the first dose of cytarabine).
DLBCL and FL
The recommended lymphodepleting chemotherapy regimen is:
- Fludarabine (25 mg/m2 intravenous daily for 3 days) and cyclophosphamide (250 mg/m2 intravenous daily for 3 days starting with the first dose of fludarabine).
If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortly before lymphodepleting chemotherapy, then the following should be used:
- Bendamustine (90 mg/m2 intravenous daily for 2 days).
Pre-medication
To minimise potential acute infusion reactions, it is recommended that patients be pre-medicated with paracetamol and diphenhydramine or another H1 antihistamine within approximately 30 to 60 minutes prior to Kymriah infusion. Corticosteroids should not be used at any time except in the case of a life-threatening emergency (see section 4.4).
Clinical assessment prior to infusion
Kymriah treatment should be delayed in some patient groups at risk (see section 4.4).
Monitoring after infusion
- Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential cytokine release syndrome, neurological events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of cytokine release syndrome and/or neurological events.
- After the first 10 days following the infusion, the patient should be monitored at the physician's discretion.
- Patients should be instructed to remain within proximity (within 2 hours of travel) of a qualified clinical facility for at least 4 weeks following infusion.
Special populations
Paediatric population
B-cell ALL: There is limited experience with Kymriah in paediatric patients below the age of 3 years.
Currently available data in this age group are described in sections 4.8 and 5.1.
DLBCL: The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.
FL: The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established. No data are available.
Elderly
B-cell ALL: The safety and efficacy of Kymriah in this population have not been established.
DLBCL and FL: No dose adjustment is required in patients over 65 years of age.
Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
There is no experience with manufacturing Kymriah for patients with a positive test for HIV, active HBV, or active HCV infection. Leukapheresis material from these patients will not be accepted for Kymriah manufacturing. Screening for HBV, HCV, and HIV must be performed in accordance with clinical guidelines before collection of cells for manufacturing.
Method of administration
Kymriah is for intravenous use only.
Precautions to be taken before handling or administering the medicinal product
This medicinal product contains genetically modified human blood cells. Healthcare professionals handling Kymriah should take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases as for any human-derived material.
Preparation for infusion
Prior to Kymriah infusion, it must be confirmed that the patient's identity matches the essential unique patient information on the infusion bag(s).
The timing of thaw of Kymriah and infusion should be coordinated. Please refer to section 6.6 for details on inspection and thawing of the infusion bag. The infusion start time should be confirmed in advance and adjusted for thaw so that Kymriah is available for infusion when the recipient is ready. Once Kymriah has been thawed and is at room temperature (20°C -25°C), it should be infused within 30 minutes to maintain maximum product viability, including any interruption during the infusion.
Administration
Kymriah should be administered as an intravenous infusion through latex-free intravenous tubing without a leukocyte depleting filter, at approximately 10 to 20 mL per minute by gravity flow. All contents of the infusion bag(s) should be infused. Sodium chloride 9 mg/mL (0.9%) solution for injection should be used to prime the tubing prior to infusion and to rinse it after infusion. When the full volume of Kymriah has been infused, the infusion bag should be rinsed with 10 to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection by back priming to ensure as many cells as possible are infused into the patient.
If the volume of Kymriah to be administered is ≤20 mL, intravenous push may be used as an alternative method of administration.
For special precautions for disposal see section 6.6.
4.3 |
Kymriah cells dispersion for infusion | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. |
Kymriah cells dispersion for infusion | Clinical particulars - Special warnings and precautions for use | Contraindications of the lymphodepleting chemotherapy must be considered.
4.4 |
Kymriah cells dispersion for infusion | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Special warnings and precautions for use
Traceability
To ensure traceability the name of the product, the batch number and the name of the treated patient should be kept for a period of 30 years.
Reasons to delay treatment
Due to the risks associated with Kymriah treatment, infusion should be delayed if a patient has any of the following conditions:
- Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies.
- Active uncontrolled infection.
- Active graft-versus-host disease (GVHD).
- Significant clinical worsening of leukaemia burden or rapid progression of lymphoma following lymphodepleting chemotherapy.
Blood, organ, tissue and cell donation
Patients treated with Kymriah should not donate blood, organs, tissues or cells.
Active central nervous system (CNS) leukaemia or lymphoma
There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore, the risk/benefit of Kymriah has not been established in these populations.
Cytokine release syndrome
Cytokine release syndrome, including fatal or life-threatening events, has been frequently observed after Kymriah infusion (see section 4.8). In almost all cases, development of cytokine release syndrome occurred between 1 to 10 days (median onset 3 days) after Kymriah infusion in paediatric and young adult B-cell ALL patients, between 1 and 9 days (median onset 3 days) after Kymriah infusion in adult DLBCL patients and between 1 to 14 days (median onset 4 days) after Kymriah infusion in adult FL patients. The median time to resolution of cytokine release syndrome was 8 days in B-cell ALL patients, 7 days in DLBCL patients and 4 days in FL patients.
Symptoms of cytokine release syndrome may include high fever, rigors, myalgia, arthralgia, nausea, vomiting, diarrhoea, diaphoresis, rash, anorexia, fatigue, headache, hypotension, dyspnoea, tachypnoea, hypoxia, and tachycardia. Organ dysfunction, including cardiac insufficiency, renal insufficiency and liver injury with accompanying elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) or elevated total bilirubin may also be observed. In some cases, disseminated intravascular coagulation (DIC) with low fibrinogen levels, capillary leak syndrome (CLS), macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis(HLH) may occur in the setting of cytokine release syndrome. Patients should be closely monitored for signs or symptoms of these events, including fever.
Risk factors for severe cytokine release syndrome in paediatric and young adult B-cell ALL patients are: high pre-infusion tumour burden, uncontrolled or accelerating tumour burden following lymphodepleting chemotherapy, active infection and early onset of fever or cytokine release syndrome following Kymriah infusion. High tumour burden prior to Kymriah infusion was identified as a risk factor for developing severe cytokine release syndrome in adult DLBCL patients.
Prior to administration of Kymriah in paediatric and young adult B-cell ALL patients, efforts should be made to lower and control the patient's tumour burden.
In all indications, appropriate prophylactic and therapeutic treatment for infections should be provided, and complete resolution of any existing infections should be ensured. Infections may also occur during cytokine release syndrome and may increase the risk of a fatal event.
Management of cytokine release syndrome associated with Kymriah
Cytokine release syndrome should be managed solely based on the patient's clinical presentation and according to the cytokine release syndrome management algorithm provided in Table 1. Anti-IL-6 based therapy such as tocilizumab has been administered for moderate or severe cytokine release syndrome associated with Kymriah. One dose of tocilizumab per patient must be on site and available for administration prior to Kymriah infusion. The treatment centre should have access to additional doses of tocilizumab within 8 hours. Corticosteroids may be administered in cases of life-threatening emergencies. Tisagenlecleucel continues to expand and persist following administration of tocilizumab and corticosteroids. Patients with medically significant cardiac dysfunction should be managed by standards of critical care and measures such as echocardiography should be considered. Tumour necrosis factor (TNF) antagonists are not recommended for management of Kymriah-associated cytokine release syndrome.
Table 1 Cytokine release syndrome management algorithm
Cytokine release syndrome severity
Symptomatic treatment
Tocilizumab
Corticosteroids
Mild symptoms requiring symptomatic treatment only, e.g.
- low fever
- fatigue
- anorexia
Exclude other causes (e.g. infection) and treat specific symptoms with, for example, antipyretics, anti-emetics, analgesics, etc.
If neutropenic, administer antibiotics per local guidelines
Not applicable
Not applicable
Symptoms requiring moderate intervention:
- high fever
- hypoxia
- mild hypotension
Antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors as needed
Treat other organ toxicities as per local guidance
If no improvement after symptomatic treatment administer tocilizumab intravenously over 1 hour:
- 8 mg/kg (max. 800 mg) if body weight ≥30 kg
- 12 mg/kg if body weight <30 kg
If no improvement, repeat every 8 hours (max total of 4 doses)*
If no improvement within 12-18 hours of tocilizumab, administer a daily dose of 2 mg/kg intravenously methylprednisolone (or equivalent) until vasopressor and oxygen no longer needed, then taper*
Symptom requiring aggressive intervention:
- hypoxia requiring high-flow oxygen supplementation or
- hypotension requiring high-dose or multiple vasopressors
High-flow oxygen
Intravenous fluids and high-dose vasopressor(s)
Treat other organ toxicities as per local guidelines
Life-threatening symptoms:
- haemodynamic instability despite intravenous fluids and vasopressors
- worsening respiratory distress
- rapid clinical deterioration
Mechanical ventilation Intravenous fluids and high-dose vasopressor(s)
Treat other organ toxicities as per local guidelines
* If no improvement after tocilizumab and steroids, consider other anti-cytokine and anti-T-cell therapies following institutional policy and published guidelines.
Alternative cytokine release syndrome management strategies may be implemented based on appropriate institutional or academic guidelines.
Neurological adverse reactions
Neurological events, in particular encephalopathy, confusional state or delirium, occur frequently with Kymriah and can be severe or life-threatening (see section 4.8). Other manifestations included depressed level of consciousness, seizures, aphasia and speech disorder. The majority of neurological events occurred within 8 weeks following Kymriah infusion and were transient. The median time to onset of the first neurological events occurring at any time following Kymriah infusion was 9 days in B-cell ALL, 6 days in DLBCL, and 9 days in FL. The median time to resolution was 7 days for B-cell ALL, 13 days for DLBCL, and 2 days for FL. Neurological events can be concurrent with cytokine release syndrome, following resolution of cytokine release syndrome or in the absence of cytokine release syndrome.
Patients should be monitored for neurological events. In case of neurological events, patients should be diagnostically worked up and managed depending on the underlying pathophysiology and in accordance with local standard of care.
Infections and febrile neutropenia
Patients with active, uncontrolled infection should not start Kymriah treatment until the infection is resolved. Prior to Kymriah infusion, infection prophylaxis should follow standard guidelines based on the degree of preceding immunosuppression.
Serious infections, including life-threatening or fatal infections, in some cases with late onset, occurred frequently in patients after Kymriah infusion (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated appropriately. As appropriate, prophylactic antibiotics should be administered and surveillance testing should be employed prior to and during treatment with Kymriah. Infections are known to complicate the course and management of concurrent cytokine release syndrome. The possibility of opportunistic infections of the central nervous system should be considered in patients with neurological adverse events and appropriate diagnostic evaluations should be performed.
Febrile neutropenia was frequently observed in patients after Kymriah infusion (see section 4.8) and may be concurrent with cytokine release syndrome. In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.
In patients achieving complete remission following Kymriah, resulting low immunoglobulin levels can increase the risk for infections. Attention to signs and symptoms of infection should be implemented according to age and standard specific guidelines.
Prolonged cytopenias
Patients may continue to exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Kymriah infusion and should be managed according to standard guidelines. The majority of patients who had cytopenias at day 28 following Kymriah treatment resolved to Grade 2 or below within three months after treatment for paediatric ALL and DLBCL patients, and within six months for FL patients. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), have the potential to worsen cytokine release syndrome symptoms and are not recommended during the first 3 weeks after Kymriah infusion or until cytokine release syndrome has resolved.
Secondary malignancies
Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. They should be monitored life-long for secondary malignancies. In the event that a secondary malignancy occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.
Hypogammaglobulinaemia
Hypogammaglobulinaemia and agammaglobulinaemia can occur in patients after Kymriah infusion. Immunoglobulin levels should be monitored after treatment with Kymriah. In patients with low immunoglobulin levels pre-emptive measures such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be taken according to age and standard guidelines.
Tumour lysis syndrome (TLS)
TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to Kymriah infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.
Concomitant disease
Patients with a history of active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function were excluded from the studies. These patient are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.
Prior stem cell transplantation
It is not recommended that patients receive Kymriah within 4 months of undergoing an allogeneic stem cell transplant (SCT) because of the potential risk of Kymriah worsening GVHD. Leukapheresis for Kymriah manufacturing should be performed at least 12 weeks after allogeneic SCT.
Serological testing
There is currently no experience with manufacturing Kymriah for patients testing positive for HBV, HCV and HIV.
Screening for HBV, HCV and HIV must be performed in accordance with clinical guidelines before collection of cells for manufacturing. Hepatitis B virus (HBV) reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure and death.
Prior treatment with anti-CD19 therapy
There is limited experience with Kymriah in patients exposed to prior CD19-directed therapy. While activity of tisagenlecleucel has been observed, data are currently too limited to make an adequate assessment of the benefit-risk profile in these patients. Kymriah is not recommended if the patient has relapsed with CD19-negative leukaemia after prior anti-CD19 therapy.
Interference with serological testing
Due to limited and short spans of identical genetic information between the lentiviral vector used to create Kymriah and HIV, some commercial HIV nucleic acid tests (NAT) may give a false positive result.
Sodium and potassium content
This medicinal product contains 24.3 to 121.5 mg sodium per dose, equivalent to 1 to 6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially “potassium-free”.
Content of dextran 40 and dimethyl sulfoxide (DMSO)
This medicinal product contains 11 mg dextran 40 and 82.5 mg dimethyl sulfoxide (DMSO) per mL. Each of these excipients are known to possibly cause anaphylactic reaction following parenteral administration. All patients should be observed closely during the infusion period.
4.5 |
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