medication_name stringlengths 6 170 | section_title stringclasses 42 values | text stringlengths 0 47.1k |
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Gaviscon Peppermint Liquid Relief | Date of first authorisation/renewal of the authorisation | 03/02/2003 / 27/02/2009
10. |
Gaviscon Peppermint Liquid Relief | Date of revision of the text | 09/07/2019 |
Gaviscon Strawberry Flavour Tablets | Name of the medicinal product | Gaviscon Strawberry Flavour Tablets.
2. |
Gaviscon Strawberry Flavour Tablets | Qualitative and quantitative composition | Each tablet contains sodium alginate 250 mg, sodium hydrogen carbonate 133.5 mg, calcium carbonate 80 mg.
Excipient(s) with known effect:
Aspartame (E951)
Sodium
For excipients, see Section 6.1.
3. |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical form | Chewable tablet. (Tablet)
Pale pink, circular, flat with bevelled edges with the odour and flavour of strawberry.
4. |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment of symptoms of gastro-oesophageal reflux such as acid regurgitation, heartburn and indigestion, for example, following meals or during pregnancy.
4.2 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
For oral administration, after being thoroughly chewed.
Adults and children 12 years and over: Two to four tablets after meals and at bedtime. Children under 12 years: Should be given only on medical advice. Elderly: No dose modifications necessary for this age group. Hepatic Impairment: No dose modification necessary.
Renal Insufficiency: Caution if highly restricted salt diet is necessary (see section 4.4).
4.3 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Contraindications | Contraindications
This medicinal product is contraindicated in patients with known or suspected hypersensitivity to the active substances or to any of the excipients.
4.4 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
If symptoms do not improve after 7 days, the clinical situation should be reviewed.
This medicinal product contains 254.84 mg (11.08 mmol) of sodium per four-tablet dose, equivalent to 12.74% of the WHO recommended maximum daily intake for sodium. The maximum daily dose of this product is equivalent to 50.96 % of the WHO adult recommended maximum daily intake for sodium. This product is considered high in sodium. This should be particularly taken into account for those on a low salt diet (e.g. in some cases of congestive heart failure and renal impairment).
Each four-tablet dose contains 320 mg (3.2 mmol) of calcium carbonate. Care needs to be taken in treating patients with hypercalcaemia, nephrocalcinosis and recurrent calcium containing renal calculi.
Due to its aspartame content this product should not be given to patients with phenylketonuria.
4.5 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
A time-interval of 2 hours should be considered between Gaviscon intake and the administration of other medicinal products, especially tetracyclines, digoxine, fluoroquinolone, iron salt, ketoconazole, neuroleptics, thyroid hormones, penicillamine, beta-blockers (atenolol, metoprolol, propanolol), glucocorticoid, chloroquine, biphosphonates (diphosphonates) and estramustine. See also 4.4.
4.6 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy:
Clinical studies in more than 500 pregnant women as well as a large amount of data from post-marketing experience indicate no malformative nor feto/ neonatal toxicity of the active substances.
Gaviscon can be used during pregnancy, if clinically needed.
Breast feeding:
No effects of the active substances have been shown in breastfed newborns/infants of treated mothers. Gaviscon can be used during breast-feeding.
Fertility:
Pre-clinical investigations have revealed alginate has no negative effect on parental or offspring fertility or reproduction.
Clinical data do not suggest that Gaviscon has an effect on human fertility.
4.7 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
None.
4.8 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Adverse reactions have been ranked under headings of frequency using the following convention: very common (1/10), common (1/100 and <1/10), uncommon (1/1000 and <1/100), rare (1/10,000 and <1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
System Organ Class
Frequency
Adverse Event
Immune System Disorders
Very rare
Anaphylactic and anaphylactoid reactions. Hypersensitivity reactions such as urticaria.
Respiratory, Thoracic and Mediastinal Disorders
Very rare
Respiratory effects such as bronchospasm.
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 |
Gaviscon Strawberry Flavour Tablets | Clinical particulars - Overdose | Overdose
Symptoms
Symptoms are likely to be minor; some abdominal discomfort may be experienced.
Management
In the event of overdose symptomatic treatment should be given.
5. Pharmacological properties
5.1 |
Gaviscon Strawberry Flavour Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The mode of action of Gaviscon Strawberry Flavour Tablets is physical and does not depend on absorption into the systemic circulation.
5.3 |
Gaviscon Strawberry Flavour Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
No pre-clinical findings of any relevance to the prescriber have been reported.
6. |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Mannitol
Macrogol 20,000
Aspartame
Magnesium stearate
Xylitol and Carmellose sodium
Red iron oxide
Strawberry cream flavour (Strawberry cream PHS-048481)
Ingredients of the strawberry cream flavour:
Maltodextrin
Modified starch E1450
Vegetable oil
Propylene glycol E1520
6.2 |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical particulars - Shelf life | Shelf life
Two years.
6.4 |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
6.5 |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Unprinted, glass-clear, thermoformable laminate of uPVC/PE/PVdC with aluminium foil lidding blisters packed into cartons.
Pack sizes: 2, 4, 6, 8,16, 24, 32, 48, 60, 64, 72, 80.
Polypropylene container.
Pack sizes 8, 12, 16, 32.
Not all pack sizes may be marketed.
6.6 |
Gaviscon Strawberry Flavour Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special instructions.
7. |
Gaviscon Strawberry Flavour Tablets | Marketing authorisation holder | Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS, United Kingdom.
8. Marketing authorisation number(s)
PL 00063/0155.
9. |
Gaviscon Strawberry Flavour Tablets | Date of first authorisation/renewal of the authorisation | 17/12/2009
10. |
Gaviscon Strawberry Flavour Tablets | Date of revision of the text | 19/06/2019 |
Gavreto 100 mg hard capsules | 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. |
Gavreto 100 mg hard capsules | Name of the medicinal product | GAVRETO 100 mg hard capsules
2. |
Gavreto 100 mg hard capsules | Qualitative and quantitative composition | Each hard capsule contains 100 mg of pralsetinib.
For the full list of excipients, see section 6.1.
3. |
Gavreto 100 mg hard capsules | Pharmaceutical form | Hard capsule.
Light blue, opaque hard capsule, size 0 (22 mm long x 7 mm wide) with “BLU-667” printed on the capsule shell body and “100 mg” on the capsule shell cap in white ink.
4. |
Gavreto 100 mg hard capsules | Clinical particulars - Therapeutic indications | Therapeutic indications
Gavreto is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor.
4.2 |
Gavreto 100 mg hard capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a physician experienced in the administration of anticancer medicinal products.
Patient selection for treatment of RET fusion-positive advanced NSCLC should be based on a validated test method.
Posology
The recommended dose is 400 mg pralsetinib once daily on an empty stomach (see method of administration). Treatment should be continued until disease progression or unacceptable toxicity.
If vomiting occurs after taking a dose of pralsetinib, the patient should not take an additional dose but continue with the next scheduled dose.
Missed doses
If a dose of pralsetinib is missed, the patient should make up for the missed dose as soon as possible on the same day. The regular daily dose schedule for pralsetinib should be resumed the next day.
Dose modifications for adverse reactions
Interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.
Patients may have their dose reduced by 100 mg decrements to a minimum dose of 100 mg once daily. Gavreto should be permanently discontinued in patients who are unable to tolerate 100 mg orally once daily.
Recommended dose modifications for adverse reactions are indicated in Table 1.
Table 1. Recommended dose modifications for Gavreto for adverse reactions
Adverse reaction
Severitya
Dose modification
Pneumonitis/Interstitial lung disease (ILD)
(see section 4.4)
Grade 1 or 2
Interrupt treatment with Gavreto until resolution. Resume at a reduced dose.
Permanently discontinue Gavreto for recurrent pneumonitis/ILD.
Grade 3 or 4
Permanently discontinue for pneumonitis/ILD.
Hypertension
Grade 3
Interrupt treatment with Gavreto for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled.
Grade 4
Permanently discontinue Gavreto.
Transaminase elevations
Grade 3 or 4
Interrupt treatment with Gavreto and monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) once weekly until resolution to Grade 1 or baseline.
Resume at a reduced dose.
If the transaminase elevation recurs at Grade 3 or higher, permanently discontinue treatment with Gavreto.
Haemorrhagic events
Grade 3 or 4
Interrupt treatment with Gavreto until resolution to Grade 1.
Resume at a reduced dose.
Permanently discontinue Gavreto for life-threatening or recurrent severe haemorrhagic events.
QT prolongation
Grade 3
Interrupt treatment with Gavreto for QTc intervals >500 ms until QTc interval returns to <470 ms.
Resume at the same dose if risk factors that cause QT prolongation are identified and corrected.
Resume treatment at a reduced dose if other risk factors that cause QT prolongation are not identified.
Grade 4
Permanently discontinue Gavreto if the patient has life-threatening arrhythmia.
Other clinically significant adverse reactions (see section 4.8)
Grade 3 or 4
Interrupt treatment with Gavreto until improvement to ≤Grade 2. Resume at a reduced dose.
Permanently discontinue for recurrent Grade 4 adverse reactions.
a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
Dose modification for use with strong cytochrome P-450 (CYP)3A4 inhibitors or combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors
Concomitant use of pralsetinib with known strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors should be avoided (see section 4.4 and section 4.5). If co-administration with a strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor cannot be avoided, the current dose of pralsetinib should be reduced as recommended in Table 2. After the strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor have been discontinued for 3 to 5 elimination half-lives, the pralsetinib dose that was taken prior to the use of the inhibitor should be resumed.
Table 2. Recommended dose modifications for Gavreto for co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors
Current Gavreto dose
Recommended Gavreto dose
400 mg orally once daily
200 mg orally once daily
300 mg orally once daily
200 mg orally once daily
200 mg orally once daily
100 mg orally once daily
Dose modification for use with strong CYP3A4 inducers
Concomitant use of pralsetinib with strong CYP3A4 inducers should be avoided (see section 4.4 and section 4.5). If concomitant use with a strong CYP3A4 inducer cannot be avoided, the dose of pralsetinib should be increased to double the current pralsetinib dose starting on Day 7 of co-administration of pralsetinib with the strong CYP3A4 inducer. After the strong CYP3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose that was taken prior to the use of the inducer should be resumed.
Special populations
Renal impairment
No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLCR] 30 to 89 mL/min estimated by Cockcroft-Gault). Pralsetinib has not been studied in patients with severe renal impairment (CLCR 15 to 29 mL/min) or end-stage renal disease (CLCR <15 mL/min). Since pralsetinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment or end-stage renal disease (see section 5.2).
Hepatic impairment
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). Pralsetinib has not been studied in patients with moderate or severe hepatic impairment, therefore its use in patients with moderate or severe hepatic impairment is not recommended (see section 5.2).
Elderly
No dose adjustment is recommended for patients aged 65 years and above (see section 5.1).
Paediatric population
The safety and efficacy of pralsetinib in paediatric patients below 18 years of age with RET fusion-positive advanced NSCLC have not been established. No data are available.
Method of administration
Gavreto is for oral use. Patients should swallow the hard capsules whole with a glass of water, on an empty stomach. They should not eat for at least two hours before and at least one hour after taking pralsetinib (see section 5.2).
4.3 |
Gavreto 100 mg hard capsules | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Gavreto 100 mg hard capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Pneumonitis/ILD
Severe, life-threatening or fatal cases of pneumonitis/ILD have been reported in patients who received pralsetinib in clinical trials (see section 4.8). Patients who present with clinically symptomatic pneumonitis or ILD were excluded from clinical trials.
Patients should be advised to contact their healthcare provider immediately to report new or worsening respiratory symptoms.
Patients who present with acute or worsening of respiratory symptoms indicative of pneumonitis/ILD (e.g., dyspnoea, cough, and fever) should be investigated to exclude other potential causes. If pneumonitis/ILD is considered to be related to pralsetinib, the dose of Gavreto should be interrupted, reduced or permanently discontinued based on severity of confirmed pneumonitis/ILD (see section 4.2).
Hypertension
Hypertension was observed in pralsetinib-treated patients in clinical trials (see section 4.8). Treatment-related hypertension was most commonly managed with anti-hypertensive medicinal products.
Treatment with Gavreto should not be initiated in patients with uncontrolled hypertension. Pre-existing hypertension should be adequately controlled before starting Gavreto treatment. Monitoring of blood pressure is recommended after 1 week, at least monthly thereafter and as clinically indicated. Anti-hypertensive therapy should be initiated or adjusted as appropriate. The dose should be interrupted, reduced, or permanently discontinued based on the severity of hypertension observed during treatment with Gavreto (see section 4.2).
Transaminase elevations
Severe cases of transaminase elevations have been reported in patients who received pralsetinib in clinical trials (see section 4.8).
ALT and AST should be monitored prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Treatment with Gavreto should be interrupted, reduced or permanently discontinued based on severity of the transaminase elevation observed during treatment with Gavreto (see section 4.2).
Haemorrhagic events
Severe, including fatal, haemorrhagic events can occur with Gavreto. In patients with life-threatening or recurrent severe haemorrhage, Gavreto should be permanently discontinued (see section 4.2).
QT prolongation
Prolongation of the QT interval has been observed in patients who received Gavreto in clinical trials (see section 4.8). Therefore, before starting Gavreto treatment, patients should have a QTc interval ≤470 ms and serum electrolytes within normal range. Hypokalaemia, hypomagnesaemia, and hypocalcaemia should be corrected both prior and during Gavreto treatment. Electrocardiograms (ECGs) and serum electrolytes should be monitored at the end of the first week and of the first month of Gavreto treatment, then periodically, as clinically indicated, depending also on presence of other risk factors (e.g. intercurrent diarrhoea, vomiting, nausea, concomitant medications).
Pralsetinib should be used with caution in patients with medical history of cardiac arrhythmias or QT interval prolongation, as well as in patients on strong CYP 3A4 inhibitors or on medicinal products known to be associated with QT/QTc prolongation.
Gavreto may require interruption, dose modification, or discontinuation (see section 4.2).
Drug interactions
Co-administration of Gavreto with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors should be avoided because they may increase the plasma concentration of pralsetinib (see sections 4.2 and 4.5).
Co-administration of Gavreto with strong CYP3A4 inducers should be avoided because they may decrease the plasma concentration of pralsetinib (see section 4.2 and section 4.5).
Fertility and pregnancy
During treatment with Gavreto and for at least 1 week after the final dose, male patients with female partners of childbearing potential must use effective contraception (see section 4.6).
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Gavreto. A highly effective non-hormonal method of contraception is required for female patients during treatment with pralsetinib, because pralsetinib can render hormonal contraceptives ineffective. If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 2 weeks after the final dose (see section 4.6).
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially “sodium-free”.
4.5 |
Gavreto 100 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
Pharmacokinetic interactions
In vitro data indicate that pralsetinib is primarily metabolised by CYP3A4 and transported by P-gp. Therefore, inducers and inhibitors of CYP3A4 and P-gp may alter the plasma concentrations of pralsetinib.
Active substances that may have an effect on pralsetinib
Strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors
Co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors can increase pralsetinib plasma concentrations, which may increase the incidence and severity of adverse reactions of pralsetinib. Co-administration of 200 mg pralsetinib once daily with itraconazole 200 mg once daily (a strong CYP3A4 and P-gp inhibitor) increased pralsetinib Cmax by 84% and AUC0-∞ by 251%, compared to pralsetinib administered alone.
Therefore, co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges) should be avoided (see section 4.4). If co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors cannot be avoided, reduce the current dose of pralsetinib (section 4.2).
Strong CYP3A4 inducers
Co-administration of pralsetinib with strong CYP3A4 inducers can decrease pralsetinib plasma concentrations, which may decrease the efficacy of pralsetinib. Co-administration of 400 mg pralsetinib as a single dose with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased pralsetinib Cmax by 30% and AUC0-∞ by 68%. Based on a population PK analysis, CYP3A4 weak inducers decreased pralsetinib exposures, but were not clinically significant in patients with NSCLC.
Therefore, co-administration of pralsetinib with strong CYP3A4 inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort [Hypericum perforatum]) should be avoided (see section 4.4). If co-administration cannot be avoided, increase the pralsetinib dose (see section 4.2).
Sensitive substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1 and MATE2-K with narrow therapeutic index
Co-administration of pralsetinib can alter the exposure of sensitive substrates of CYP enzymes (CYP3A4, CYP2C9 and CYP2C8) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1 and MATE2-K). Substrate drugs of these CYP enzymes and transporters with narrow therapeutic index (including, but not limited to cyclosporine, paclitaxel and warfarin) should be avoided.
4.6 |
Gavreto 100 mg hard capsules | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in females and males
Women of childbearing potential should be informed that pralsetinib may cause foetal harm (see section 5.3).
The pregnancy status of women of childbearing potential should be verified prior to initiating Gavreto treatment.
Women of childbearing potential have to use highly effective non-hormonal contraception during treatment and for at least 2 weeks following the last dose of Gavreto (see section 4.4).
Males with female partners of childbearing potential have to use effective contraception during treatment with Gavreto and for at least 1 week following the last dose of Gavreto.
Patients should be advised to contact their healthcare provider immediately if they become pregnant, or if pregnancy is suspected, while taking Gavreto.
Pregnancy
There are no data from the use of pralsetinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Based on its mechanism of action and findings in animals, pralsetinib may cause foetal harm when administered to pregnant women.
Gavreto should not be used during pregnancy unless the clinical condition of the woman requires treatment with pralsetinib.
Breast-feeding
It is unknown whether pralsetinib or its metabolites are excreted in human milk.
A risk to the breast-fed child cannot be excluded.
Breast-feeding should be discontinued during treatment with Gavreto and for 1 week following the final dose.
Fertility
There is no clinical data on the effects of pralsetinib on fertility.
Based on non-clinical safety findings, fertility may be compromised during treatment with pralsetinib (see section 5.3). Men and women should seek advice on effective fertility preservation before treatment.
4.7 |
Gavreto 100 mg hard capsules | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Gavreto has minor influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience fatigue while taking Gavreto (see section 4.8).
4.8 |
Gavreto 100 mg hard capsules | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most common adverse reactions were anaemia (47.2%), aspartate aminotransferase increased (46.0%), neutropenia (43.9%), constipation (41.9%), musculoskeletal pain (39.8%), fatigue (37.3%), leukopenia (35.4%), alanine aminotransferase increased (33.9%), and hypertension (33.0%). The most common serious adverse reactions were pneumonia (11.7%), pneumonitis (5.3%) and anaemia (3.8%).
Based on the data from clinical trials, exposure-response relationships for any Grade 3 or 4 adverse reaction were observed at higher exposures, with a faster time to onset for adverse reactions with increasing pralsetinib exposure.
Dose reductions due to adverse reactions occurred in 41.5% of patients treated with a starting doe of 400mg. The most common adverse reactions resulting in dose reductions were neutropenia (14.0%), anaemia (8.5%), lymphopenia (5.3%), pneumonitis (5.3%), leukopenia (4.2%), blood creatine phosphokinase increased (4.0%), hypertension (4.0%), and fatigue (3.8%).
Permanent discontinuation due to adverse reactions occurred in 8.1% of patients treated with Gavreto. The most common adverse reactions that led to permanent discontinuation of Gavreto were pneumonia and pneumonitis (1.9% for each).
Tabulated list of adverse reactions
The safety population includes a total of 528 patients, including 281 patients with advanced NCSLC, as well as patients with other solid tumours (including RET fusion thyroid cancer and RET mutation medullary thyroid cancer), who received pralsetinib at a starting dose of 400 mg, see section 5.1. No clinically relevant differences in the safety profile across indications have been observed.
Adverse reactions reported in patients treated with a starting dose of 400mg in the ARROW trial are listed below (Table 3), according to the MedDRA System Organ Class and frequency.
Frequencies are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).
Within each system organ class, adverse reactions are presented in order of decreasing frequency and severity.
Table 3. Adverse reactions reported in all patients treated with 400 mg Gavreto in the ARROW trial (N=528)
System organ class / Adverse reactions
Frequency category
All grades
%
Grades 3-4
%
Infections and infestations
Pneumonia1
Urinary tract infection
Very common
17.4
12.7
10.2
3.8
Blood and lymphatic system disorders
Anaemia2
Neutropenia3
Leukopenia4
Lymphopenia5
Thrombocytopenia6
Very common
47.2
43.9
35.4
22.3
18.8
17.6
20.1
8.3
14.2
4.7
Metabolism and nutrition disorders
Hypocalcaemia
Hyperphosphataemia
Hypoalbuminaemia
Hypophosphataemia
Hyponatraemia
Very common
20.6
17.8
11.6
10.4
10.2
3.6
0.2
-
5.5
4.2
Nervous system disorders
Taste disorder7
Headache8
Very common
15.9
15.7
-
0.4
Vascular disorders
Hypertension9
Haemorrhage10
Very common
33.0
18.8
16.1
3.0
Respiratory, thoracic and mediastinal disorders
Cough11
Dyspnoea
Pneumonitis12
Very common
23.7
16.9
11.6
0.6
2.1
3.0
Gastrointestinal disorders
Constipation
Diarrhoea
Dry mouth
Nausea
Abdominal pain13
Vomiting
Very common
41.9
29.4
15.9
15.9
15.3
12.3
0.6
2.8
-
0.2
1.3
1.1
Stomatitis14
Common
6.8
1.3
Hepatobiliary disorders
Aspartate aminotransferase increased*
Alanine aminotransferase increased*
Hyperbilirubinaemia15
Very common
46.0
33.9
13.4
5.7
4.2
1.3
Skin and subcutaneous tissue disorders
Rash16
Very common
17.2
-
Musculoskeletal and connective tissue disorders
Musculoskeletal pain17
Blood creatine phosphokinase increased
Very common
39.8
16.3
2.1
6.4
General disorders and administration site conditions
Fatigue18
Oedema19
Pyrexia
Very common
37.3
28.2
25.2
4.0
0.2
1.1
Cardiac disorders
QT prolongation20
Common
5.1
0.4
Renal and urinary disorders
Blood creatinine increased
Very common
22.3
0.4
Investigations
Blood alkaline phosphatase increased
Very common
10.4
1.1
1 includes pneumonia, pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, atypical pneumonia, lung infection, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, pneumonia streptococcal, pneumonia moraxella, pneumonia staphylococcal, pneumonia pseudomonal, atypical mycobacterial pneumonia, pneumonia legionella
2 includes anaemia, haematocrit decreased, red blood cell count decreased, haemoglobin decreased, aplastic anaemia
3 includes neutrophil count decreased, neutropenia
4 includes white blood cell count decreased, leukopenia
5 includes lymphopenia, lymphocyte count decreased
6 includes thrombocytopenia, platelet count decreased
7 includes ageusia, dysgeusia
8 includes headache, tension headache
9 includes hypertension, blood pressure increased
10 includes 39 preferred terms from the SMQ Haemorrhage (excl laboratory terms) narrow, with the exclusion of terms related to invasive drug administration, terms related to rupture, disseminated intravascular coagulopathy, terms related to traumatic haemorrhages, and haemorrhagic terms related to pregnancy, birth or neonatal
11 includes cough, productive cough
12 includes pneumonitis, interstitial lung disease
13 includes abdominal pain, abdominal pain upper
14 includes stomatitis, aphthous ulcer
15 includes blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased, blood bilirubin unconjugated increased
16 includes rash, rash maculo-papular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pustular, rash macular, rash erythematous
17 includes musculoskeletal chest pain, myalgia, arthralgia, pain in extremity, neck pain, musculoskeletal pain, back pain, bone pain, spinal pain, musculoskeletal stiffness
18 includes asthenia, fatigue
19 includes oedema, swelling face, peripheral swelling, oedema peripheral, face oedema, periorbital oedema, eyelid oedema, generalised oedema, swelling, localised oedema
20 includes electrocardiogram QT prolonged, long QT syndrome
* additionally, 3.0% transaminases increased were reported (0.6% Grades 3-4)
Description of selected adverse reactions
Pneumonitis/ILD
Pneumonitis and ILD occurred in 11.6% of 528 patients with NSCLC or other solid tumours, enrolled in the ARROW Study who received Gavreto at a starting dose of 400mg (see section 4.4). Among the patients who had pneumonitis/ILD, the median time to onset was 15.6 weeks.
Serious adverse reactions of pneumonitis/ILD were reported for 5.3% of patients, including Grade 3 events (2.5%), Grade 4 (0.6%) and one fatal (Grade 5) event (0.2%).
In clinical trials, the majority of the patients with Grade 1 or Grade 2 pneumonitis were able to continue treatment without recurrent pneumonitis/ILD following dose interruption and dose reduction. Dose interruption occurred in 8.9%, dose reduction in 5.3% and permanent dose discontinuation in 1.9% of patients due to ILD/pneumonitis. The median time to resolution was 3.7 weeks.
Hypertension
Hypertension (including blood pressure increased) occurred in 33.0% of 528 patients with NSCLC or other solid tumours, including Grade ≤2 events in 16.9% and Grade 3 in 16.1% of patients. No Grade 4 or Grade 5 events were reported. Among the patients who had hypertension, the median time to onset was 2.1 weeks.
Serious adverse reactions of hypertension were reported in 1.3% of all patients (all Grade 3 events).
Dose interruption occurred in 7.4% of patients, dose reduction in 4.0% and one patient (0.2%) required permanent dose discontinuation. The median time to resolution was 3.1 weeks.
Transaminase elevations
Increased AST occurred in 46.0% of 528 patients, including Grade 3 or 4 in 5.7% of patients. Increased ALT occurred in 33.9% of patients, including Grade 3 or 4 events in 4.2% of patients. The median time to first onset for increased AST was 2.1 weeks and increased ALT was 3.1 weeks.
Serious adverse reactions of increased AST and ALT were each reported for 0.6% of all patients.
Dose interruption due to increased AST or ALT occurred in 4.4% and 3.4% of patients, respectively and dose reduction in 1.3% for both events. No patients required permanent dose discontinuation. The median time to resolution was 5.3 and 4.1 weeks for increased AST and ALT, respectively.
Haemorrhagic events
Haemorrhagic events occurred in 18.8% of the 528 patients, including Grade 3 events in 2.8% of patients and a Grade 4 or fatal (Grade 5) event each occurred in one patient (0.2%).
Serious adverse reactions of haemorrhage were reported for 3.2% of patients.
Fourteen patients (2.7%) required dose interruption and dose reduction or permanent dose discontinuation due to haemorrhage each occurred in one patient.
QT prolongation
QT prolongation occurred in 5.1% of 528 patients with NSCLC or other solid tumours. In 2 patients (0.4%) the event was assessed as serious. The majority of patients experienced non-severe events – i.e. Grade 1, in 21 (4.0%) and Grade 2, in 4 patients (0.8%). Two patients (0.4%) experienced Grade 3 events of Electrocardiogram QT prolonged, which both resolved. There was no life-threatening or fatal QT prolongation. Three patients (0.6%) had an event that remained unresolved by time of data cut-off. Dose reductions or interruptions were required by two Electrocardiogram QT prolonged patients, each. No QT prolongation event led to permanent discontinuation of pralsetinib.
Infections
Infections were commonly experienced by 57.2% of 528 patients during the median treatment time of 9.5 months. Most frequently (>10%), the preferred terms of pneumonia and urinary tract infection were reported (14.2% and 12.7%, respectively). The majority of infections were mild (Grade 1 or 2) and resolved; severe infection (Grade ≥3) occurred in 23.5% patients (with fatal events reported for 1.9%).
Infections reported as serious occurred for 24.2% of patients. The most common (>2%) serious infection preferred term was pneumonia (9.8%), followed by urinary tract infection (3.4%) and sepsis (2.8%). The majority of patients experiencing sepsis had concurrent pneumonia or urinary tract infection reported.
Dose interruption due to infection occurred for 19.5% of patients (mainly due to the preferred terms of pneumonia [6.8%] and urinary tract infection [2.7%]). Dose was reduced due to infections in 3.2% of patients (mainly due to the preferred term of pneumonia [1.9%]). Permanent treatment discontinuation was required by 3.4% of patients due to infections (mainly due to the preferred term of pneumonia [1.7%]).
Elderly
In ARROW (N=528), 37.8% of patients were 65 years of age and older. Compared with younger patients (<65), more patients of ≥65 years old reported adverse reactions that led to permanent dose discontinuation (25.8% versus 13.4%). Of the commonly reported events with higher incidence in elderly patients (≥65), hypertension has the greatest difference in comparison with patients <65 years of age. However, hypertension is also expected to occur more frequently in the elderly population. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (87.1% versus 72.3%).
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 (see details below).
United Kingdom
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 |
Gavreto 100 mg hard capsules | Clinical particulars - Overdose | Overdose
Symptoms
No cases of overdose have been reported in clinical trials with pralsetinib. The maximum dose of pralsetinib studied clinically is 600 mg orally once daily. Adverse reactions observed at this dose were consistent with the safety profile at 400 mg once daily (see section 4.8).
Management
There is no known antidote for Gavreto overdose. In the event of suspected overdose, Gavreto should be interrupted and supportive care instituted. Based on the large volume of distribution of pralsetinib and extensive protein binding, dialysis is unlikely to result in significant removal of pralsetinib.
5. Pharmacological properties
5.1 |
Gavreto 100 mg hard capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Pralsetinib Cmax and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose); pharmacokinetics was linear in the dose range of 200 and 400 mg in healthy volunteers. Pralsetinib plasma concentrations reached steady state by 3 to 5 days.
At the recommended dose of 400 mg once daily under fasting conditions, the mean steady state Cmax of pralsetinib was 2830 ng/mL and the mean steady state area under the concentration-time curve (AUC0-24h) was 43900 h•ng/mL. The mean accumulation ratio was ~2-fold after repeated dosing.
Absorption
The median time to peak concentration (Tmax) ranged from 2.0 to 4.0 hours following single doses of pralsetinib 60 mg to 600 mg (0.15 to 1.5 times the approved recommended dose). The absolute bioavailability of pralsetinib has not been determined.
Effect of food
Following administration of a single dose of 200 mg Gavreto with a high-fat meal (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) Cmax of pralsetinib was increased by 104% (65%, 153%), the mean (90% CI) AUC0-∞ was increased by 122% (96%, 152%), and the median Tmax was delayed from 4 to 8.5 hours, compared to the fasted state.
Distribution
The mean apparent volume of distribution of pralsetinib is 3.8 L/kg (268 L). Plasma protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.
Biotransformation
Pralsetinib is primarily metabolised by CYP3A4 and UGT1A4, and to a lesser extent by CYP2D6 and CYP1A2 in vitro.
Following a single oral dose of approximately 310 mg of radiolabelled pralsetinib to healthy subjects, pralsetinib metabolites from oxidation (M531, M453, M549b) and glucuronidation (M709) were detected in small to trace amounts (~ 5%).
Elimination
The mean plasma elimination half-life of pralsetinib was 14.7 hours following a single dose of 400 mg (the recommended dose) pralsetinib and 22.2 hours following multiple doses of 400 mg pralsetinib.
The steady state mean apparent oral clearance of pralsetinib (CL/F) is 9.1 L/h.
Following a single oral dose of radiolabelled pralsetinib to healthy subjects, 72.5% of the radioactive dose was recovered in faeces (66% as unchanged) and 6.1% in urine (4.8% as unchanged).
Interactions with CYP substrates
In vitro studies indicate that pralsetinib is a time-dependent inhibitor of CYP3A4/5 at clinically relevant concentrations. Pralsetinib may have the potential to inhibit or induce CYP2C8, CYP2C9, and CYP3A4/5 at clinically relevant concentrations.
Interactions with transport proteins
In vitro studies indicate that pralsetinib may have the potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K at clinically relevant concentrations. Pralsetinib is a substrate of P-gp. (see section 4.5).
In vitro studies with drug transporters
In vitro studies indicate that pralsetinib may be a potential substrate of P-glycoprotein (P-gp) and BCRP at clinically relevant concentrations.
Special populations
No clinically relevant differences in the pharmacokinetics of pralsetinib were observed based on age (19 to 87 years), sex, race (White, Black, or Asian), body weight (34.9 to 128 kg), mild to moderate (CLCR 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). The effect of severe renal impairment (CLCR 15 to 29 mL/min), end-stage renal disease (CLCR < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) on the pharmacokinetics of pralsetinib is unknown (see section 4.2). Hence, no dose modifications are needed in the above mentioned special populations.
5.3 |
Gavreto 100 mg hard capsules | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Repeat-dose toxicity studies
In studies of up to 13 weeks duration in rats and cynomolgus monkeys, the primary findings at exposures similar to steady state human exposures (AUC) at 400 mg once daily in patients with advanced NSCLC included physeal dysplasia in the rat (2 times margin) and haematological effects (1 times margin) in both species. Additional adverse findings at higher exposures include degenerative changes in male and female reproductive organs (2 times margin) and increases in blood phosphorus with corresponding mineralization in soft tissues in rats (≥2 times margin), and myocardial haemorrhage in rats (4.4 times margin). Increased blood pressure was observed in rats after a single dose of 25 mg/kg (2 times). The No-Observed-Adverse-Effect-Level (NOAEL) of pralsetinib in the 13-week studies was 10 mg/kg/day in both species, corresponding to exposure (AUC) margins of 1 times relative to the human exposures.
Regarding local exposure and toxicity, there was no evidence of gastrointestinal disturbance in either species up to the NOAEL dose of 10 mg/kg (0.9 times human margin). At higher doses in monkeys, gastrointestinal ulcerations and haemorrhage were observed.
Embryotoxicity / Teratogenicity
In an embryo-fetal development study, administration of pralsetinib to rats during the period of organogenesis was teratogenic and embryotoxic at exposures below the steady-state human clinical exposure (AUC) at 400 mg once daily dose. Malformations, including visceral (primarily kidney and ureter) and skeletal (vertebral, rib, costal cartilage, and vertebral central anomalies) were observed at approximately 0.2-fold of the human exposure. Postimplantation loss occurred at 0.5-fold of the human exposure, and increased to 100% incidence at 1.5-fold of human exposure.
Reproductive toxicity
In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats pralsetinib did not have an effect on male or female mating performance or ability to become pregnant. However, consistent with the findings of the embryofetal development toxicology study there was post-implantation loss at doses as low as 5 mg/kg (approximately 0.3 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study). At the 20 mg/kg dose level (approximately 2.5-3.6 times the human exposure) 82% of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions).
In a 13-week repeat-dose toxicology study, male rats exhibited microscopic evidence of tubular degeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses ≥10 mg/kg/day, approximately 0.9 times the human exposure based on AUC at the clinical dose of 400 mg.
No findings were noted in the reproductive organs in a 13-week repeated-dose toxicology study in monkeys at dose levels up to 10 mg/kg/day (approximately 1 times the human exposure at the 400 mg once daily dose).
Genotoxicity and carcinogenicity
Pralsetinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was negative in both in vitro human lymphocyte chromosome aberration assay and in vivo rat bone marrow micronucleus tests.
Carcinogenicity studies with pralsetinib have not been conducted.
6. |
Gavreto 100 mg hard capsules | Pharmaceutical particulars - List of excipients | List of excipients
Capsule content
Hypromellose
Cellulose microcrystalline
Starch, pregelatinised
Sodium hydrogen carbonate
Citric acid
Magnesium stearate
Capsule shell
Brilliant blue FCF (E133)
Hypromellose
Titanium dioxide (E171)
Printing ink
Shellac
Propylene glycol (E1520)
Potassium hydroxide
Titanium dioxide (E171)
6.2 |
Gavreto 100 mg hard capsules | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Gavreto 100 mg hard capsules | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Gavreto 100 mg hard capsules | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
6.5 |
Gavreto 100 mg hard capsules | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
High density polyethylene (HDPE) bottle with child-resistant cap (polypropylene) and foiled induction seal liner and desiccant sachet (silica gel)
Pack sizes: 60, 90 or 120 capsules.
Not all pack sizes may be marketed.
6.6 |
Gavreto 100 mg hard capsules | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Gavreto 100 mg hard capsules | Marketing authorisation holder | Roche Products Limited
6 Falcon Way, Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing authorisation number(s)
PLGB 00031/0929
9. |
Gavreto 100 mg hard capsules | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 14 January 2022
Date of latest renewal: 01 March 2023
10. |
Gavreto 100 mg hard capsules | Date of revision of the text | 01 March 2023 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Name of the medicinal product | Gazyvaro 1,000 mg concentrate for solution for infusion.
2. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Qualitative and quantitative composition | One vial of 40 mL concentrate contains 1,000 mg obinutuzumab, corresponding to a concentration before dilution of 25 mg/mL.
Obinutuzumab is a Type II humanised anti-CD20 monoclonal antibody of the IgG1 subclass derived by humanisation of the parental B-Ly1 mouse antibody and produced in the Chinese Hamster Ovary cell line by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical form | Concentrate for solution for infusion.
Clear, colourless to slightly brownish liquid.
4. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Therapeutic indications | Therapeutic indications
Chronic lymphocytic leukaemia (CLL)
Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy (see section 5.1).
Follicular lymphoma (FL)
Gazyvaro in combination with chemotherapy, followed by Gazyvaro maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced FL (see section 5.1)
Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.
4.2 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Posology and method of administration | Posology and method of administration
Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available.
Posology
Prophylaxis and premedication for tumour lysis syndrome (TLS)
Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12-24 hours prior to start of Gazyvaro infusion as per standard practice (see section 4.4). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.
Prophylaxis and premedication for infusion related reactions (IRRs)
Premedication to reduce the risk of IRRs is outlined in Table 1 (see also section 4.4). Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.
Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration (see section 4.4).
Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of IRRs in patients with CLL and FL (see section 4.4)
Day of treatment cycle
Patients requiring premedication
Premedication
Administration
Cycle 1:
Day 1 for CLL and FL
All patients
Intravenous corticosteroid1,4
(mandatory for CLL, recommended for FL)
Completed at least 1 hour prior to Gazyvaro infusion
Oral analgesic/anti-pyretic2
At least 30 minutes before Gazyvaro infusion
Anti-histaminic medicine3
Cycle 1:
Day 2 for CLL only
All patients
Intravenous corticosteroid1
(mandatory)
Completed at least 1 hour prior to Gazyvaro infusion
Oral analgesic/anti-pyretic2
At least 30 minutes before Gazyvaro infusion
Anti-histaminic medicine3
All subsequent infusions for CLL and FL
Patients with no IRR during the previous infusion
Oral analgesic/anti-pyretic2
At least 30 minutes before Gazyvaro infusion
Patients with an IRR (Grade 1 or 2) with the previous infusion
Oral analgesic/anti-pyretic2
Anti-histaminic medicine3
Patients with a Grade 3 IRR with the previous infusion OR Patients with lymphocyte counts >25 x 109/L prior to next treatment
Intravenous corticosteroid1,4
Completed at least 1 hour prior to Gazyvaro infusion
Oral analgesic/anti-pyretic2
Anti-histaminic medicine3
At least 30 minutes before Gazyvaro infusion
1
100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be used as it has not been effective in reducing rates of IRR.
2 e.g. 1,000 mg acetaminophen/paracetamol
3
e.g. 50 mg diphenhydramine
4.
If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medicinal product if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required.
Dose
Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil1)
For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 2.
Cycle 1
The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered over Day 1 and Day 2, (or Day 1 continued), and on Day 8 and Day 15 of the first 28 day treatment cycle.
Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day.
Cycles 2 – 6
The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered on Day 1 of each cycle.
Table 2 Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days duration for patients with CLL
Cycle
Day of treatment
Dose of Gazyvaro
Cycle 1
Day 1
100 mg
Day 2
(or Day 1 continued)
900 mg
Day 8
1,000 mg
Day 15
1,000 mg
Cycles 2-6
Day 1
1,000 mg
1See section 5.1 for information on chlorambucil dose
Duration of treatment
Six treatment cycles, each of 28 day duration.
Delayed or missed doses
If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyvaro should be maintained between doses.
Follicular lymphoma
For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shown in Table 3.
Patients with previously untreated follicular lymphoma
Induction (in combination with chemotherapy2)
Gazyvaro should be administered with chemotherapy as follows:
• Six 28-day cycles in combination with bendamustine2 or,
• Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro alone or,
• Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone(CVP).
Maintenance
Patients who achieve a complete or partial response to induction treatment with Gazyvaro in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).
Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen
Induction (in combination with bendamustine2)
Gazyvaro should be administered in six 28-day cycles in combination with bendamustine2.
Maintenance
Patients who achieved a complete or partial response to induction treatment (i.e. the initial 6 treatment cycles) with Gazyvaro in combination with bendamustine or have stable disease should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).
Table 3 Follicular lymphoma: Dose of Gazyvaro to be administered during induction treatment, followed by maintenance treatment
Cycle
Day of treatment
Dose of Gazyvaro
Cycle 1
Day 1
1,000 mg
Day 8
1,000 mg
Day 15
1,000 mg
Cycles 2–6or 2–8
Day 1
1,000 mg
Maintenance
Every 2 months for 2 years or until disease progression (whichever occurs first)
1,000 mg
2See section 5.1 for information on bendamustine dose
Duration of treatment
Induction treatment of approximately six months (six treatment cycles of Gazyvaro, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyvaro, each of 21 day duration when combined with CHOP or CVP) followed by maintenance once every 2 months for 2 years or until disease progression (whichever occurs first).
Delayed or missed doses
If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose.
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.
During maintenance, maintain the original dosing schedule for subsequent doses.
Dose modifications during treatment (all indications)
No dose reductions of Gazyvaro are recommended.
For management of symptomatic adverse events (including IRRs), see paragraph below (Management of IRRs or section 4.4).
Special populations
Elderly
No dose adjustment is required in elderly patients (see section 5.2).
Renal impairment
No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30-89 mL/min) (see section 5.2). The safety and efficacy of Gazyvaro has not been established in patients with severe renal impairment (CrCl < 30 mL/min) (see sections 4.8 and 5.2).
Hepatic impairment
The safety and efficacy of Gazyvaro in patients with impaired hepatic function has not been established. No specific dose recommendations can be made.
Paediatric population
The safety and efficacy of Gazyvaro in children and adolescents aged below 18 years has not been established. No data are available.
Method of administration
Gazyvaro is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution (see section 6.6). Gazyvaro infusions should not be administered as an intravenous push or bolus.
For instructions on dilution of Gazyvaro before administration, see section 6.6.
Instructions on the rate of infusion are shown in Tables 4-6.
Chronic lymphocytic leukaemia (CLL)
Table 4 Chronic lymphocytic leukaemia: Standard infusion rate in the absence of IRRs/hypersensitivity and recommendations in case an IRR occurred with previous infusion
Cycle
Day of treatment
Rate of infusion
The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to “Management of IRRs”.
Cycle 1
Day 1
(100 mg)
Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate.
Day 2
(or Day 1 continued)
(900 mg)
If no IRR occurred during the previous infusion, administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
If the patient experienced an IRR during the previous infusion, start with administration at 25 mg/hr. The rate of infusion can be escalated in increments up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
Day 8
(1,000 mg)
If no IRR occurred during the previous infusion, when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
If the patient experienced an IRR during the previous infusion administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
Day 15
(1,000 mg)
Cycles 2-6
Day 1
(1,000 mg)
Follicular lymphoma (FL)
Gazyvaro should be administered at the standard infusion rate in Cycle 1 (see Table 5). In patients who do not experience Grade ≥3 infusion related reactions (IRRs) during Cycle 1, Gazyvaro may be administered as a short (approximately 90 minutes) duration infusion (SDI) from Cycle 2 onwards (see Table 6).
Table 5 Follicular lymphoma: Standard infusion rate and recommendations in case an IRR occurred with previous infusion
Cycle
Day of treatment
Rate of infusion
The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to “Management of IRRs”.
Cycle 1
Day 1
(1,000 mg)
Administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
Day 8
(1,000 mg)
If no IRR or if an IRR Grade 1 occurred during the previous infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
If the patient experienced an IRR of Grade 2 or higher during the previous infusion administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
Day 15
(1,000 mg)
Cycles 2–6 or 2–8
Day 1
(1,000 mg)
Maintenance
Every 2 months for 2 years or until disease progression (whichever occurs first)
Table 6 Follicular lymphoma: Short duration infusion rate and recommendations in case an IRR occurred with previous infusion
Cycle
Day of treatment
Rate of infusion
For management of IRRs that occur during the infusion, refer to “Management of IRRs”.
Cycles 2–6 or 2–8
Day 1
(1,000 mg)
If no IRR of Grade ≥3 occurred during
Cycle 1:
100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes.
If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 IRR occurred during the previous SDI infusion, administer the next obinutuzumab infusion at the standard rate (see Table 5).
Maintenance
Every 2 months for 2 years or until disease progression (whichever occurs first)
Management of IRRs (all indications)
Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below (see also section 4.4).
• Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.
• Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 -6). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.
The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.
• Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 -6). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.
Management of IRRs occurring during SDI
• Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.
• Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and not greater than 400 mg/hr.
If the patient experiences a second Grade 3 IRR after resuming the infusion, the infusion must be stopped and therapy must be permanently discontinued. If the patient is able to complete the infusion without further Grade 3 IRRs, the next infusion should be given at a rate not higher than the standard rate.
• Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 5-6).
4.3 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Based on a subgroup analysis in previously untreated follicular lymphoma, the efficacy in FLIPI low risk (0-1) patients is currently inconclusive (see section 5.1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyvaro plus chemotherapy and the patient-specific situation.
Infusion related reactions
The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1,000 mg. IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti-histamine, omission of antihypertensive medicine in the morning of the first infusion, and the Cycle 1 Day 1 dose administered over 2 days) as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidence and severity of infusion related symptoms decreased substantially after the first 1,000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyvaro (see section 4.8).
In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable from immunoglobulin E (IgE) mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumour burden and/or high circulating lymphocyte count in CLL [> 25 x 109/L] may be at increased risk of severe IRRs. Patients with renal impairment (CrCl < 50 mL/min) and patients with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including severe IRRs (see section 4.8). For management of IRRs see section 4.2 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Posology and method of administration.
Patients must not receive further Gazyvaro infusions if they experience:
• acute life-threatening respiratory symptoms,
• a Grade 4 (i.e. life threatening) IRR or,
• a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion).
Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine.
Hypersensitivity reactions
Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to clinically distinguish from IRRs. Hypersensitivity symptoms can occur after previous exposure and very rarely with the first infusion. If a hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity to obinutuzumab must not be treated (see section 4.3).
Tumour lysis syndrome (TLS)
TLS has been reported with Gazyvaro. Patients who are considered to be at risk of TLS (e.g. patients with a high tumour burden and/or a high circulating lymphocyte count [> 25 x 109/L] and/or renal impairment [CrCl < 70 mL/min]) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidate (e.g. rasburicase) starting 12-24 hours prior to the infusion of Gazyvaro as per standard practice (see section 4.2). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.
Neutropenia
Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyvaro. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life-threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should also be considered (see section 4.2). Late onset neutropenia (occurring >28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped) may occur. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia (see section 4.8).
Thrombocytopenia
Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyvaro. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of thrombocytopenia (see section 4.8). Fatal haemorrhagic events have also been reported in Cycle 1 in patients treated with Gazyvaro. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician. Use of any concomitant therapies which could possibly worsen thrombocytopenia-related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle.
Coagulation abnormalities including disseminated intravascular coagulation (DIC)
DIC including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving Gazyvaro. The majority of cases involved non-overt DIC, with subclinical (asymptomatic) changes in platelets and laboratory coagulation parameters occurring within 1-2 days after the first infusion with spontaneous resolution usually occurring within one to two weeks, not requiring drug discontinuation or specific intervention. In some cases, the events were associated with IRRs and/or TLS. No specific baseline risk factors for DIC were identified. Patients suspected to have non-overt DIC should be monitored closely with coagulation parameters including platelets and clinical observation for signs or symptoms of overt DIC. Gazyvaro should be discontinued at first onset of suspected overt DIC and appropriate treatment initiated.
Worsening of pre-existing cardiac conditions
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.8). These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload.
Infections
Gazyvaro should not be administered in the presence of an active infection and caution should be exercised when considering the use of Gazyvaro in patients with a history of recurring or chronic infections. Serious bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Gazyvaro therapy. Fatal infections have been reported.
Patients (CLL) with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections (see section 4.8). In the follicular lymphoma studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in the maintenance phase. During the follow-up phase, Grade 3-5 infections are observed more in patients who received Gazyvaro plus bendamustine in the induction phase.
Hepatitis B reactivation
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro (see section 4.8). HBV screening should be performed in all patients before initiation of treatment with Gazyvaro. At a minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B core antibody (HBcAb) status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation.
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with Gazyvaro (see section 4.8). The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA). Therapy with Gazyvaro should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML.
Immunisation
The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery.
Exposure in utero to obinutuzumab and vaccination of infants with live virus vaccines
Due to the potential depletion of B-cells in infants of mothers who have been exposed to Gazyvaro during pregnancy, infants should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B-cell count has recovered. The safety and timing of vaccination should be discussed with the infant's physician (see section 4.6).
4.5 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Fertility, pregnancy and lactation | Interaction with other medicinal products and other forms of interaction
No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP, fludarabine and cyclophosphamide (FC), and chlorambucil.
A risk for interactions with other concomitantly used medicinal products cannot be excluded.
Pharmacokinetic interactions
Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with medicinal products known to be metabolised by these enzyme systems.
Co-administration with Gazyvaro had no effect on the pharmacokinetics of bendamustine, FC, chlorambucil or the individual components of CHOP. In addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyvaro.
Pharmacodynamic interactions
Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery because of the immunosuppressive effect of obinutuzumab (see section 4.4).
The combination of obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia (see section 4.4).
4.6 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Effects on ability to drive and use machines | Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must use effective contraception during and for 18 months after treatment with Gazyvaro.
Pregnancy
A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B-lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta (see section 5.3). There are no data from the use of obinutuzumab in pregnant women. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
In case of exposure during pregnancy, depletion of B-cells may be expected in infants due to the pharmacological properties of the product. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyvaro during pregnancy until the infant's B-cell levels are within normal ranges (see section 4.4).
Breast-feeding
Animal studies have shown secretion of obinutuzumab in breast milk (see section 5.3).
Since human immunoglobulin G (IgG) is secreted in human milk and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breast-feeding during Gazyvaro therapy and for 18 months after the last dose of Gazyvaro.
Fertility
No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies in cynomolgus monkeys (see section 5.3).
4.7 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Undesirable effects | Effects on ability to drive and use machines
Gazyvaro has no or negligible influence on the ability to drive and use machines. IRRs are very common during the first infusion of Gazyvaro, and patients experiencing infusion related symptoms should be advised not to drive or use machines until symptoms abate.
4.8 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Clinical particulars - Overdose | Undesirable effects
Summary of the safety profile
The adverse drug reactions (ADRs) from clinical trials were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the three pivotal clinical studies:
• BO21004/CLL11 (N=781): Patients with previously untreated CLL
• BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL)
• GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.
These trials investigated Gazyvaro in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by Gazyvaro maintenance therapy for iNHL. The studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolled patients with iNHL including FL. Therefore, in order to provide the most comprehensive safety information, the analysis of ADRs presented in the following has been performed on the entire study population (i.e. iNHL).
Table 7 summarises all ADRs including those of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of ≥ 2%) compared to the relevant comparator arm in at least one pivotal study in:
• Patients with CLL receiving Gazyvaro plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11)
• Patients with previously untreated iNHL receiving Gazyvaro plus chemotherapy (bendamustine, CHOP, CVP) followed by Gazyvaro maintenance in patients achieving a response, compared to rituximab plus chemotherapy followed by rituximab maintenance in patients achieving a response (study BO21223/GALLIUM)
• Patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen receiving Gazyvaro plus bendamustine, followed by Gazyvaro maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN)
The incidences presented in Table 7 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.
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) and very rare (< 1/10,000). not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Tabulated list of adverse reactions
Table 7 Summary of ADRs reported in patients# receiving Gazyvaro + chemotherapy*
System organ class
Frequency
All Grades
Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL)
Grades 3-5†
Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL)
Infections and infestations
Very common
Upper respiratory tract infection, sinusitis§,urinary tract infection, pneumonia§ ,herpes zoster§, nasopharyngitis
Common
Oral herpes, rhinitis, pharyngitis, lung infection, influenza
Urinary tract infection, pneumonia, lung infection, upper respiratory tract infection, sinusitis, herpes zoster
Uncommon
Hepatitis B reactivation
Nasopharyngitis, rhinitis, influenza, oral herpes
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Common
Squamous cell carcinoma of skin, Basal cell carcinoma
Squamous cell carcinoma of skin, Basal cell carcinoma
Blood and lymphatic system disorders
Very common
Neutropenia§, thrombocytopenia, anaemia, leukopenia
Neutropenia, thrombocytopenia
Common
Febrile neutropenia
Anaemia, leukopenia, febrile neutropenia
Uncommon
Disseminated intravascular coagulation##
Metabolism and nutrition disorders
Common
Tumour lysis syndrome, hyperuricaemia, hypokalaemia
Tumour lysis syndrome, hypokalaemia
Uncommon
Hyperuricaemia
Psychiatric disorders
Very common
Insomnia
Common
Depression, anxiety
Uncommon
Insomnia, depression, anxiety
Nervous system disorders
Very common
Headache
Uncommon
Headache
Not known
Progressive multifocal leukoencephalopathy
Cardiac disorders
Common
Atrial fibrillation
Atrial fibrillation
Vascular disorders
Common
Hypertension
Hypertension
Respiratory, thoracic and mediastinal disorders
Very common
Cough§
Common
Nasal congestion, rhinorrhoea, oropharyngeal pain
Uncommon
Cough, oropharyngeal pain
Gastrointestinal disorders
Very common
Diarrhoea, constipation§
Common
Dyspepsia, haemorrhoids
gastrointestinal perforation
Diarrhoea
Uncommon
Constipation, haemorrhoids
Skin and subcutaneous tissue disorders
Very common
Alopecia, pruritus
Common
Eczema
Uncommon
Pruritus
Musculoskeletal and connective tissue disorders
Very common
Arthralgia§, back pain, pain in extremity
Common
Musculoskeletal chest pain, bone pain
Pain in extremity
Uncommon
Arthralgia, back pain, musculoskeletal chest pain, bone pain
Renal and Urinary Disorders
Common
Dysuria, urinary incontinence
Uncommon
Dysuria, urinary incontinence
General disorders and administration site conditions
Very common
Pyrexia, Asthenia, fatigue
Common
Chest pain
Pyrexia, asthenia, fatigue
Uncommon
Chest pain
Investigations
Common
White blood cell count decreased, neutrophil count decreased, weight increased
White blood cell count decreased, neutrophil count decreased
Injury, poisoning and procedural complications
Very common
IRRs
IRRs
# Only the highest frequency observed in the trials is reported (based on studies BO21004/previously untreated CLL, BO21223/previously untreated advanced iNHL and GAO4753g/rituximab refractory iNHL)
## Disseminated intravascular coagulation (DIC) including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving Gazyvaro (see section 4.4)
† No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms
* Chemotherapy: Chlorambucil in CLL; bendamustine, CHOP, CVP in iNHL including FL
§
observed also during maintenance treatment with at least 2% higher incidence in Gazyvaro arm (BO21223)
The profile of adverse reactions in patients with FL was consistent with the overall iNHL population in both studies.
Description of selected adverse reactions
The incidences presented in the following sections if referring to iNHL are the highest incidence of that ADR reported from either pivotal study (BO21223/GALLIUM, GAO4753g/GADOLIN).
The study MO40597 was designed to characterize the safety profile of short duration infusions (approximately 90 minutes) from Cycle 2, in patients with previously untreated FL (see section 5.1 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmacodynamic properties). | Infusion related reactions
Most frequently reported (≥ 5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, flushing, hypertension, tachycardia, dyspnoea, and chest discomfort. Respiratory symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported (see section 4.4).
Chronic Lymphocytic Leukaemia
The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 66% with the infusion of the first 1,000 mg of Gazyvaro (20% of patients experiencing a Grade 3-4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3-5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1.
In patients who received the recommended measures for prevention of IRRs as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which occurred in relatively few patients) were similar before and after mitigation measures were implemented.
Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma
Grade 3-4 IRRs occurred in 12% of patients. In Cycle 1, the overall incidence of IRRs was higher in patients receiving Gazyvaro plus chemotherapy compared to patients in the comparator arm. In patients receiving Gazyvaro plus chemotherapy, the incidence of IRRs was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyvaro alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions was comparable between the Gazyvaro and the relevant comparator arms. Overall, 4% of patients experienced an infusion related reaction leading to discontinuation of Gazyvaro.
Short Duration Infusion in patients with Follicular Lymphoma
In study MO40597 assessing the safety of SDI, a greater proportion of patients experienced any grade IRRs at Cycle 2 compared to the proportion who experienced IRRs after standard infusion at Cycle 2 in study BO21223 (10/99 [10.1%] vs. 23/529 [4.3%] respectively; IRRs attributed by the investigator to any component of study therapy). No patients experienced Grade ≥3 IRRs after SDI at Cycle 2 in MO40597; 3/529 (0.6%) experienced Grade ≥3 IRRs at Cycle 2 in study BO21223. IRR symptoms and signs were similar in both studies.
Infusion related reactions observed in Study MO40597/GAZELLE are summarized in Table 8.
Table 8 Study MO40597/GAZELLE Short-Duration Infusion: Infusion Related Reactionsa by Cycle (Safety-Evaluable Population)
CTCAE Grade
C1 Overall
(standard infusion)
C1b by day
C2C
C3
C4
C5
C6
C7
Over all induction cycles
Day 1
Day 2d
Day 8
Day 15
All Grade
65/113 (57.5%)
57/113 (50.4%)
4/51 (7.8%)
6/112 (5.4%)
5/111 (4.5%)
13/110 (11.8%)
9/108 (8.3%)
7/108 (6.5%)
6/107 (5.6%)
5/105 (4.8%)
2/55 (3.6%)
71/113 (62.8%)
Grade ≥3
6/113 (5.3%)
5/113 (4.4%)
1/51 (2.0%)
0
0
0
0
0
1/107 (0.9%)
0
0
7/113 (6.2%)
C=cycle; CTCAE = Common Terminology Criteria for Adverse Events; IRR=infusion related reaction
a Infusion related reaction defined as any event that occurred during or within 24 hours from the end of study treatment infusion that were judged by the investigator to be related to any components of therapy.
b C1 comprised three infusions at the standard infusion rate, administered at weekly intervals
c Patients received short-duration infusion from C2 onward. The denominator at C2 and subsequent cycles represents the number of patients who received SDI at that cycle.
d Patients treated with bendamustine on Cycle 1 Day 2.
Neutropenia and infections
Chronic Lymphocytic Leukaemia
The incidence of neutropenia was higher in the Gazyvaro plus chlorambucil arm (41%) compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3-5 events reported in 12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of prolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyvaro plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see section 4.4).
Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma
In the Gazyvaro plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 8%, respectively. The incidence of infection was 81% in the Gazyvaro plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections (see section 4.4).
Short Duration Infusion in patients with Follicular Lymphoma
In study MO40597, assessing the safety of SDI, neutropenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients receiving standard duration infusion 69/113 [61.1%] vs 247/595 [41.5%], respectively, throughout induction). The median and range of neutrophil count values were similar in both studies at each time point. Febrile neutropenia was reported in a similar proportion of patients in MO40597 and BO21223 (6/113 [5.3%] vs 31/595 [5.2%], respectively). Infection was reported less frequently in MO40597 than in BO21223 (45/113 [39.8%] vs 284/595 [47.7%], respectively).
Thrombocytopenia and haemorrhagic events
Chronic Lymphocytic Leukaemia
The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm (16% vs. 7%) especially during the first cycle. Four percent of patients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyvaro infusion) (see section 4.4). The overall incidence of haemorrhagic events was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however, all of the events in patients treated with Gazyvaro were reported in Cycle 1. No Grade 5 events of thrombocytopenia were reported. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.
Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma
The incidence of thrombocytopenia was 15%. Thrombocytopenia occurred more frequently in Cycle 1 in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 4% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients; none of the fatal adverse events occurred in Cycle 1.
Short Duration Infusion in patients with Follicular Lymphoma
In study MO40597, assessing the safety of SDI, thrombocytopenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients received standard duration infusion (21/113 [28.6%] vs 63/595 [10.6%], respectively, throughout induction). The median and range of platelet count values were similar in both studies at each time point. No thrombocytopenia events reported in MO40597 were associated with bleeding.
Special populations
Elderly
Chronic Lymphocytic Leukaemia
In the pivotal BO21004/CLL11 study, 46% (156 out of 336) of patients with CLL treated with Gazyvaro plus chlorambucil were 75 years or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than those patients < 75 years of age.
Indolent Non Hodgkin Lymphoma including Follicular Lymphoma
In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, patients 65 years or older experienced more serious adverse events and adverse events leading to withdrawal or death than patients < 65 years of age.
Renal impairment
Chronic Lymphocytic Leukaemia
In the pivotal BO21004/CLL11 study, 27% (90 out of 336) of patients treated with Gazyvaro plus chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than patients with a CrCl ≥ 50 mL/min (see section 4.2, 4.4 and 5.2). Patients with a CrCl < 30 mL/min were excluded from the study (see section 5.1).
Indolent Non Hodgkin Lymphoma including Follicular Lymphoma
In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and 7% (14 out of 204) of patients treated with Gazyvaro, respectively, had moderate renal impairment (CrCL < 50 mL/min). These patients experienced more serious adverse events, G rade 3 to 5 adverse events and adverse events leading to treatment withdrawal (patients in BO21223 only) than patients with a CrCl ≥ 50 mL/min (see section 4.2 and 5.2). Patients with a CrCl < 40 mL/min were excluded from the studies (see section 5.1).
Additional safety information from clinical studies experience
Worsening of pre-existing cardiac conditions
Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.4). These events may occur as part of an IRR and can be fatal.
Laboratory abnormalities
Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyvaro.
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 (see details below).
United Kingdom
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Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 Overdose
No experience with overdose is available from human clinical studies. In clinical studies with Gazyvaro, doses ranging from 50 mg up to and including 2,000 mg per infusion have been administered. The incidence and intensity of adverse reactions reported in these studies did not appear to be dose dependent.
Patients who experience overdose should have immediate interruption or reduction of their infusion and be closely supervised. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B-cell depleted.
5. Pharmacological properties
5.1 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
A population pharmacokinetic (PK) model was developed to analyse the PK data in 469 iNHL, 342 CLL and 130 diffuse large B-cell lymphoma (DLBCL) patients from Phase I, Phase II and Phase III studies who received obinutuzumab alone or in combination with chemotherapy.
Absorption
Obinutuzumab is administered intravenously, therefore absorption is not applicable. There have been no studies performed with other routes of administration. From the population PK model, after the Cycle 6 Day 1 infusion in CLL patients, the estimated median Cmax value was 465.7 μg/mL and AUC() value was 8961 μg•d/mL and in iNHL patients the estimated median Cmax value was 539.3 μg/mL and AUC() value was 10956 μg•day/mL.
Distribution
Following intravenous administration, the volume of distribution of the central compartment (2.98 L in patients with CLL and 2.97 in patients with iNHL), approximates serum volume, which indicates distribution is largely restricted to plasma and interstitial fluid.
Biotransformation
The metabolism of obinutuzumab has not been directly studied. Antibodies are mostly cleared by catabolism.
Elimination
The clearance of obinutuzumab was approximately 0.11 L/day in CLL patients and 0.08 L/day in iNHL patients with a median elimination t½ of 26.4 days in CLL patients and 36.8 days in iNHL patients. Obinutuzumab elimination comprises two parallel pathways which describe clearance, a linear clearance pathway and a non-linear clearance pathway which changes as a function of time. During the initial treatment, the non-linear time-varying clearance pathway is dominant and is consequently the major clearance pathway. As treatment continues, the impact of this pathway diminishes and the linear clearance pathway predominates. This is indicative of target mediated drug disposition (TMDD), where the initial abundance of CD20 cells causes a rapid removal of obinutuzumab from the circulation. However, once the majority of CD20 cells are bound with obinutuzumab, the impact of TMDD on PK is minimised.
Pharmacokinetic/pharmacodynamic relationship(s)
In the population pharmacokinetic analysis, gender was found to be a covariate which explains some of the inter-patient variability, with a 22% greater steady state clearance (CLss) and a 19% greater volume of distribution (V) in males. However, results from the population analysis have shown that the differences in exposure are not significant (with an estimated median AUC and Cmax in CLL patients of 11282 µg•d/mL and 578.9 µg/mL in females and 8451 µg•d/mL and 432.5 µg/mL in males, respectively at Cycle 6 and AUC and Cmax in iNHL of 13172 µg•d/mL and 635.7 µg/mL in females and 9769 µg•d/mL and 481.3 µg/mL in males, respectively), indicating that there is no need to dose adjust based on gender.
Elderly
The population pharmacokinetic analysis of obinutuzumab showed that age did not affect the pharmacokinetics of obinutuzumab. No significant difference was observed in the pharmacokinetics of obinutuzumab among patients < 65 years (n=375), patients between 65-75 years (n=265) and patients > 75 years (n=171).
Paediatric population
No studies have been conducted to investigate the pharmacokinetics of obinutuzumab in paediatric patients.
Renal impairment
The population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does not affect pharmacokinetics of obinutuzumab. Pharmacokinetics of obinutuzumab in patients with mild creatinine clearance (CrCl 50-89 mL/min, n=464) or moderate (CrCl 30 to 49 mL/min, n=106) renal impairment were similar to those in patients with normal renal function (CrCl ≥ 90 mL/min, n=383). Pharmacokinetic data in patients with severe renal impairment (CrCl 15-29 mL/min) is limited (n=8), therefore no dose recommendations can be made.
Hepatic impairment
No formal pharmacokinetic study has been conducted in patients with hepatic impairment.
5.3 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
No studies have been performed to establish the carcinogenic potential of obinutuzumab.
No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility. In repeat-dose toxicity studies in cynomolgus monkeys obinutuzumab had no adverse effects on male and female reproductive organs.
An enhanced pre and postnatal development (ePPND) toxicity study in pregnant cynomolgus monkeys showed no evidence of teratogenic effects. However, weekly obinutuzumab dosing from post-coitum day 20 to delivery resulted in complete depletion of B-cells in infant monkeys at weekly intravenous obinutuzumab doses of 25 and 50 mg/kg (2-5 times the clinical exposure based on Cmax and AUC). Offspring exposure on day 28 post-partum suggests that obinutuzumab can cross the blood-placenta barrier. Concentrations in infant serum on day 28 post-partum were in the range of concentrations in maternal serum, whereas concentrations in milk on the same day were very low (less than 0.5% of the corresponding maternal serum levels) suggesting that exposure of infants must have occurred in utero. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months post-partum.
In a 26-week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinical exposure based on Cmax and AUC at steady state after weekly administration of 5, 25, and 50 mg/kg). Findings included acute anaphylactic or anaphylactoid reactions and an increased prevalence of systemic inflammation and infiltrates consistent with immune-complex mediated hypersensitivity reactions, such as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation. These reactions led to unscheduled termination of 6/36 animals treated with obinutuzumab during dosing and recovery phases; these changes were partially reversible. No renal toxicity with a causal relationship to obinutuzumab has been observed in humans.
6. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical particulars - List of excipients | List of excipients
Histidine
Histidine hydrochloride monohydrate
Trehalose dihydrate
Poloxamer 188
Water for injections
6.2 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical particulars - Incompatibilities | Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical particulars - Shelf life | Shelf life
Unopened vial
3 years.
After dilution
After dilution, chemical and physical stability have been demonstrated in sodium chloride 9 mg/mL (0.9%) solution for injection at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C followed by 48 hours (including infusion time) at ≤ 30°C.
From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
40 mL concentrate in a 50 mL vial (clear Type I glass) with stopper (butyl rubber). Pack size of 1 vial.
6.6 |
Gazyvaro 1,000 mg concentrate for solution for infusion | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Instructions for dilution
Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake the vial. Use a sterile needle and syringe to prepare Gazyvaro.
For CLL cycles 2 – 6 and all FL cycles
Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC polyolefin infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for injection.
CLL only – Cycle 1
To ensure differentiation of the two infusion bags for the initial 1,000 mg dose, it is recommended to utilise bags of different sizes to distinguish between the 100 mg dose for Cycle 1 Day 1 and the 900 mg dose for Cycle 1 Day 1 (continued) or Day 2. To prepare the 2 infusion bags, withdraw 40 mL of concentrate from the vial and dilute 4 mL into a 100 mL PVC or non-PVC polyolefin infusion bag and the remaining 36 mL in a 250 mL PVC or non-PVC polyolefin infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection. Clearly label each infusion bag. For storage conditions of the infusion bags see section 6.3.
Dose of Gazyvaro to be administered
Required amount of Gazyvaro concentrate
Size of PVC or non-PVC polyolefin infusion bag
100 mg
4 mL
100 mL
900 mg
36 mL
250 mL
1000 mg
40 mL
250 mL
Do not use other diluents such as glucose (5%) solution (see section 6.2).
The bag should be gently inverted to mix the solution in order to avoid excessive foaming. The diluted solution should not be shaken or frozen.
Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration.
No incompatibilities have been observed between Gazyvaro, in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Gazyvaro with sodium chloride 9 mg/mL (0.9%) solution for injection, and:
• PVC, polyethylene (PE), polypropylene or polyolefin bags
• PVC, polyurethane (PUR) or PE infusion sets
• optional inline filters with product contact surfaces of polyethersulfone (PES), a 3-way stopcock infusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU).
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Marketing authorisation holder | Roche Products Limited
6 Falcon Way, Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing authorisation number(s)
PLGB 00031/0856
9. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 01 January 2021
Date of latest renewal:
10. |
Gazyvaro 1,000 mg concentrate for solution for infusion | Date of revision of the text | 13 April 2023 |
Gefitinib 250 mg film-coated tablets | Name of the medicinal product | Gefitinib 250 mg film-coated tablets
2. |
Gefitinib 250 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 250 mg of gefitinib.
Excipient(s) with known effect
Each film-coated tablet contains 163.50 mg of lactose (as monohydrate).
Each film-coated tablet contains 3.869 mg of sodium.
For the full list of excipients, see section 6.1.
3. |
Gefitinib 250 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Tablets are round, biconvex, brown film coated tablets debossed with 'C' on one side and plain on the other side. Diameter: 11.00 mm ± 0.20 mm.
4. |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Gefitinib is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (see section 4.4).
4.2 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Treatment with gefitinib should be initiated and supervised by a physician experienced in the use of anticancer therapies.
Posology
The recommended posology of gefitinib is one 250 mg tablet once a day. If a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose.
Paediatric population
The safety and efficacy of gefitinib in children and adolescents aged less than 18 years have not been established. There is no relevant use of gefitinib in the paediatric population in the indication of NSCLC.
Hepatic impairment
Patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to cirrhosis have increased plasma concentrations of gefitinib. These patients should be closely monitored for adverse events. Plasma concentrations were not increased in patients with elevated aspartate transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases (see section 5.2).
Renal impairment
No dose adjustment is required in patients with impaired renal function at creatinine clearance >20 ml/min. Only limited data are available in patients with creatinine clearance ≤ 20 ml/min and caution is advised in these patients (see section 5.2).
Elderly
No dose adjustment is required on the basis of patient age (see section 5.2).
CYP2D6 poor metabolisers
No specific dose adjustment is recommended in patients with known CYP2D6 poor metaboliser genotype, but these patients should be closely monitored for adverse events (see section 5.2).
Dose adjustment due to toxicity
Patients with poorly tolerated diarrhoea or skin adverse reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg dose (see section 4.8). For patients unable to tolerate treatment after a therapy interruption, gefitinib should be discontinued and an alternative treatment should be considered.
Method of administration
The tablet may be taken orally with or without food, at about the same time each day. The tablet can be swallowed whole with some water or if dosing of whole tablets is not possible, tablets may be administered as a dispersion in water (non-carbonated). No other liquids should be used. Without crushing it, the tablet should be dropped in half a glass of drinking water. The glass should be swirled occasionally, until the tablet is dispersed (this may take up to 20 minutes). The dispersion should be drunk immediately after dispersion is complete (i.e. within 60 minutes). The glass should be rinsed with half a glass of water, which should also be drunk. The dispersion can also be administered through a naso-gastric or gastrostomy tube.
4.3 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Breast-feeding (see section 4.6).
4.4 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
When considering the use of gefitinib as a treatment for locally advanced or metastatic NSCLC, it is important that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumour sample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used.
Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status of tumours or ctDNA should be used to avoid false negative or false positive determinations (see section 5.1).
Interstitial lung disease (ILD)
Interstitial lung disease (ILD), which may be acute in onset, has been observed in 1.3 % of patients receiving gefitinib, and some cases have been fatal (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, gefitinib should be interrupted and the patient should be promptly investigated. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately.
In a Japanese pharmacoepidemiological case control study in 3159 patients with NSCLC receiving gefitinib or chemotherapy who were followed up for 12 weeks, the following risk factors for developing ILD (irrespective of whether the patient received gefitinib or chemotherapy) were identified: smoking, poor performance status (PS≥ 2), CT scan evidence of reduced normal lung (≤ 50 %), recent diagnosis of NSCLC (< 6 months), pre-existing ILD, older age (≥ 55 years old) and concurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95 % CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95 % CI 1.1 to 5.8). Risk of mortality among patients who developed ILD on gefitinib or chemotherapy was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤ 50 %), pre-existing ILD, older age (≥ 65 years old), and extensive areas adherent to pleura (≥ 50 %).
Hepatotoxicity and liver impairment
Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis (see section 4.8). There have been isolated reports of hepatic failure which in some cases led to fatal outcomes. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in liver function. Discontinuation should be considered if changes are severe.
Impaired liver function due to cirrhosis has been shown to lead to increased plasma concentrations of gefitinib (see section 5.2).
Interactions with other medicinal products
CYP3A4 inducers may increase metabolism of gefitinib and decrease gefitinib plasma concentrations. Therefore, concomitant administration of CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or herbal preparations containing St John's wort/Hypericum perforatum) may reduce efficacy of the treatment and should be avoided (see section 4.5).
In individual patients with CYP2D6 poor metaboliser genotype, treatment with a potent CYP3A4 inhibitor might lead to increased plasma levels of gefitinib. At initiation of treatment with a CYP3A4 inhibitor, patients should be closely monitored for gefitinib adverse reactions (see section 4.5).
International normalised ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin together with gefitinib (see section 4.5). Patients taking warfarin and gefitinib concomitantly should be monitored regularly for changes in prothrombin time (PT) or INR.
Medicinal products that cause significant sustained elevation in gastric pH, such as proton-pump inhibitors and h2-antagonists may reduce bioavailability and plasma concentrations of gefitinib and, therefore, may reduce efficacy. Antacids if taken regularly close in time to administration of gefitinib may have a similar effect (see sections 4.5 and 5.2).
Data from phase II clinical trials, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine.
Lactose
Gefitinib contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Further precautions for use
Patients should be advised to seek medical advice immediately if they experience severe or persistent diarrhoea, nausea, vomiting or anorexia as these may indirectly lead to dehydration. These symptoms should be managed as clinically indicated (see section 4.8).
Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.
If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and if symptoms do not resolve, or if symptoms recur on reintroduction of gefitinib, permanent discontinuation should be considered.
In a phase I/II trial studying the use of gefitinib and radiation in paediatric patients, with newly diagnosed brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of Central Nervous System (CNS) haemorrhages were reported from 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with gefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving gefitinib has not been established.
Gastrointestinal perforation has been reported in patients taking gefitinib. In most cases this is associated with other known risk factors, including concomitant medications such as steroids or NSAIDs, underlying history of GI ulceration, age, smoking or bowel metastases at sites of perforation.
4.5 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6.
Active substances that may increase gefitinib plasma concentrations
In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do not suggest any clinical consequences to this in vitro finding.
Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administration with potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increase may be clinically relevant since adverse reactions are related to dose and exposure. The increase might be higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80 % increase in the mean AUC of gefitinib in healthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for gefitinib adverse reactions.
There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of this enzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisers by about 2-fold (see section 5.2). If concomitant treatment with a potent CYP2D6 inhibitor is initiated, the patient should be closely monitored for adverse reactions.
Active substances that may reduce gefitinib plasma concentrations
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John's wort (Hypericum perforatum)), should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83 % (see section 4.4).
Substances that cause significant sustained elevation in gastric pH may reduce gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of gefitinib. Concomitant administration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥5 resulted in a reduced mean gefitinib AUC by 47 % in healthy volunteers (see sections 4.4 and 5.2).
Active substances that may have their plasma concentrations altered by gefitinib
In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. In a clinical trial in patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35 % increase in exposure to metoprolol. Such an increase might potentially be relevant for CYP2D6 substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered in combination with gefitinib, a dose modification of the CYP2D6 substrate should be considered especially for products with a narrow therapeutic window.
Gefitinib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding is unknown.
Other potential interactions
INR elevations and/or bleeding events have been reported in some patients concomitantly taking warfarin (see section 4.4).
4.6 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must be advised not to get pregnant during therapy.
Pregnancy
There are no data from the use of gefitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Gefitinib should not be used during pregnancy unless clearly necessary.
Breastfeeding
It is not known whether gefitinib is secreted in human milk. Gefitinib and metabolites of gefitinib accumulated in milk of lactating rats (see section 5.3). Gefitinib is contraindicated during breastfeeding and therefore breastfeeding must be discontinued while receiving gefitinib therapy (see section 4.3).
4.7 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
During treatment with gefitinib, asthenia has been reported. Therefore, patients who experience this symptom should be cautious when driving or using machines.
4.8 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 gefitinib-treated patients), the most frequently reported adverse drug reactions (ADRs), occurring in more than 20 % of the patients, are diarrhoea and skin reactions (including rash, acne, dry skin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible. Approximately 8 % of patients had a severe ADR (common toxicity criteria, (CTC) grade 3 or 4). Approximately 3 % of patients stopped therapy due to an ADR.
Interstitial lung disease (ILD) has occurred in 1.3 % of patients, often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.
Tabulated list of adverse reactions
The safety profile presented in Table 1 is based on the gefitinib clinical development programme and post-marketed experience. Adverse reactions have been assigned to the frequency categories in Table 1 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 gefitinib-treated patients).
Frequencies of occurrence of undesirable effects 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), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Adverse reactions
Adverse reactions by system organ class and frequency
Metabolism and nutrition disorders
Very common
Anorexia mild or moderate (CTC grade 1 or 2).
Eye disorders
Common
Conjunctivitis, blepharitis, and dry eye*, mainly mild (CTC grade 1).
Uncommon
Corneal erosion, reversible and sometimes in association with aberrant eyelash growth.
Keratitis (0.12%)
Vascular disorders
Common
Haemorrhage, such as epistaxis and haematuria.
Respiratory, thoracic and mediastinal disorders
Common
Interstitial lung disease (1.3 %), often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.
Gastrointestinal disorders
Very common
Diarrhoea, mainly mild or moderate (CTC grade 1 or 2).
Vomiting, mainly mild or moderate (CTC grade 1 or 2).
Nausea, mainly mild (CTC grade 1).
Stomatitis, predominantly mild in nature (CTC grade 1).
Common
Dehydration, secondary to diarrhoea, nausea, vomiting or anorexia.
Dry mouth*, predominantly mild (CTC grade 1).
Uncommon
Pancreatitis.
Gastrointestinal perforation.
Hepatobiliary disorders
Very common
Elevations in alanine aminotransferase, mainly mild to moderate.
Common
Elevations in aspartate aminotransferase, mainly mild to moderate.
Elevations in total bilirubin, mainly mild to moderate.
Uncommon
Hepatitis**
Skin and subcutaneous tissue disorders
Very common
Skin reactions, mainly a mild or moderate (CTC grade 1 or 2) pustular rash, sometimes itchy with dry skin, including skin fissures, on an erythematous base.
Common
Nail disorder
Alopecia
Allergic reactions (1.1%), including angioedema and urticaria
Uncommon
Palmar-plantar erythrodysaesthesia syndrome
Rare
Bullous conditions including Toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme
Cutaneous vasculitis
Renal and urinary disorders
Common
Asymptomatic laboratory elevations in blood creatinine
Proteinuria
Cystitis
Rare
Haemorrhagic cystitis
General disorders and administration site conditions
Very common
Asthenia, predominantly mild (CTC grade 1).
Common
Pyrexia
The frequency of adverse drug reactions relating to abnormal laboratory values is based on patients with a change from baseline of 2 or more CTC grades in the relevant laboratory parameters.
* This adverse reaction can occur in association with other dry conditions (mainly skin reactions) seen with gefitinib.
** This includes isolated reports of hepatic failure which in some cases led to fatal outcomes.
Interstitial lung disease (ILD)
In the INTEREST trial, the incidence of ILD type events was 1.4 % (10) patients in the gefitinib group versus 1.1 % (8) patients in the docetaxel group. One ILD-type event was fatal, and this occurred in a patient receiving gefitinib.
In the ISEL trial, the incidence of ILD-type events in the overall population was approximately 1 % in both treatment arms. The majority of ILD-type events reported was from patients of Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving gefitinib therapy and placebo was approximately 3 % and 4 % respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.
In a post-marketing surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8 %. The proportion of ILD-type events with a fatal outcome was 38.6 %.
In a phase III open-label clinical trial (IPASS) in 1217 patients comparing gefitinib to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6 % on the gefitinib treatment arm versus 1.4 % on the carboplatin/paclitaxel treatment arm.
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 |
Gefitinib 250 mg film-coated tablets | Clinical particulars - Overdose | Overdose
There is no specific treatment in the event of overdose of gefitinib. However, in phase I clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase of frequency and severity of some adverse reactions was observed, mainly diarrhoea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular severe diarrhoea should be managed as clinically indicated. In one study a limited number of patients were treated weekly with doses from 1500 mg to 3500 mg. In this study gefitinib exposure did not increase with increasing dose, adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of gefitinib.
5. Pharmacological properties
5.1 |
Gefitinib 250 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Following oral administration of gefitinib, absorption is moderately slow and peak plasma concentrations of gefitinib typically occur at 3 to 7 hours after administration. Mean absolute bioavailability is 59 % in cancer patients. Exposure to gefitinib is not significantly altered by food. In a trial in healthy volunteers where gastric pH was maintained above pH 5, gefitinib exposure was reduced by 47 %, likely due to impaired solubility of gefitinib in the stomach (see sections 4.4 and 4.5).
Distribution
Gefitinib has a mean steady-state volume of distribution of 1400 l indicating extensive distribution into tissue. Plasma protein binding is approximately 90 %. Gefitinib binds to serum albumin and alpha 1-acid glycoprotein.
In vitro data indicate that gefitinib is a substrate for the membrane transport protein Pg-p.
Biotransformation
In vitro data indicate that CYP3A4 and CYP2D6 are the major P450 isozyme involved in the oxidative metabolism of gefitinib.
In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. Gefitinib shows no enzyme induction effects in animal studies and no significant inhibition (in vitro) of any other cytochrome P450 enzyme.
Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in excreta and 8 metabolites in plasma. The major metabolite identified was O-desmethyl gefitinib, which is 14-fold less potent than gefitinib at inhibiting EGFR stimulated cell growth and has no inhibitory effect on tumour cell growth in mice. It is therefore considered unlikely that it contributes to the clinical activity of gefitinib.
The formation of O-desmethyl gefitinib has been shown, in vitro, to be via CYP2D6. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthy volunteers genotyped for CYP2D6 status. In poor metabolisers no measurable levels of O-desmethyl gefitinib were produced. The levels of exposure to gefitinib achieved in both the extensive and the poor metaboliser groups were wide and overlapping but the mean exposure to gefitinib was 2-fold higher in the poor metaboliser group. The higher average exposures that could be achieved by individuals with no active CYP2D6 may be clinically relevant since adverse effects are related to dose and exposure.
Elimination
Gefitinib is excreted mainly as metabolites via the faeces, with renal elimination of gefitinib and metabolites accounting for less than 4 % of the administered dose.
Gefitinib total plasma clearance is approximately 500 ml/min and the mean terminal half-life is 41 hours in cancer patients. Administration of gefitinib once daily results in 2- to 8-fold accumulation, with steady-state exposures achieved after 7 to 10 doses. At steady-state, circulating plasma concentrations are typically maintained within a 2- to 3-fold range over the 24-hour dosing interval.
Special populations
From analyses of population pharmacokinetic data in cancer patients, no relationships were identified between predicted steady-state trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance (above 20 ml/min).
Hepatic impairment
In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase in exposure in all groups compared with healthy controls. An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib.
Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normal hepatic function, or moderate or severe hepatic impairment (classified according to baseline Common Toxicity Criteria grades for AST, alkaline phosphatase and bilirubin) due to liver metastases. It was shown that following daily administration of 250 mg gefitinib, time to steady-state, total plasma clearance (CmaxSS) and steady-state exposure (AUC24SS) were similar for the groups with normal and moderately impaired hepatic function. Data from 4 patients with severe hepatic impairment due to liver metastases suggested that steady-state exposures in these patients are also similar to those in patients with normal hepatic function.
5.3 |
Gefitinib 250 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to the clinical exposure levels and with possible relevance to clinical use were as follows:
- Corneal epithelia atrophy and corneal translucencies
- Renal papillary necrosis
- Hepatocellular necrosis and eosinophilic sinusoidal macrophage infiltration
Data from non-clinical (in vitro) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarization process (e.g. QT interval). Clinical experience has not shown a causal association between QT prolongation and gefitinib.
A reduction in female fertility was observed in the rat at a dose of 20 mg/kg/day.
Published studies have shown that genetically modified mice, lacking expression of EGFR, exhibit developmental defects, related to epithelial immaturity in a variety of organs including the skin, gastrointestinal tract and lung. When gefitinib was administered to rats during organogenesis, there were no effects on embryofoetal development at the highest dose (30 mg/kg/day). However, in the rabbit, there were reduced foetal weights at 20 mg/kg/day and above.
There were no compound-induced malformations in either species. When administered to the rat throughout gestation and parturition, there was a reduction in pup survival at a dose of 20 mg/kg/day.
Following oral administration of C-14 labelled gefitinib to lactating rats 14 days post-partum, concentrations of radioactivity in milk were 11-19 fold higher than in blood.
Gefitinib showed no genotoxic potential.
A 2-year carcinogenicity study in rats resulted in a small but statistically significant increased incidence of hepatocellular adenomas in both male and female rats and mesenteric lymph node haemangiosarcomas in female rats at the highest dose (10 mg/kg/day) only. The hepatocellular adenomas were also seen in a 2-year carcinogenicity study in mice, which demonstrated a small increased incidence of this finding in male mice at the mid dose, and in both male and female mice at the highest dose. The effects reached statistical significance for the female mice, but not for the males. At no-effect levels in both mice and rats there was no margin in clinical exposure. The clinical relevance of these findings is unknown.
The results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential.
6. |
Gefitinib 250 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Lactose monohydrate,
Croscarmellose sodium,
Microcrystalline cellulose,
Povidone (E1201),
Sodium lauryl sulfate,
Magnesium stearate (E572).
Tablet coating
Polyvinyl alcohol-part hydrolysed (E1203),
Macrogol (E1521),
Talc,
Titanium dioxide (E171),
Red iron oxide (E172),
Yellow iron oxide (E172).
6.2 |
Gefitinib 250 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Gefitinib 250 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
2 years.
6.4 |
Gefitinib 250 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage condition.
6.5 |
Gefitinib 250 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
PVC/Aluminium in perforated unidose blister containing 10 tablets or PVC/Aluminium non-perforated blister containing 10 tablets.
Three blisters are combined with an aluminium foil laminate over-wrap in a carton.
Pack size of 30 film-coated tablets. Not all pack sizes may be marketed.
6.6 |
Gefitinib 250 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Gefitinib 250 mg film-coated tablets | Marketing authorisation holder | Cipla (EU) Limited
Dixcart House,Addlestone Road,
Bourne Business Park Addlestone
KT15 2LE
United Kingdom.
8. Marketing authorisation number(s)
PL 36390/0244
9. |
Gefitinib 250 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 20/03/2019
10. |
Gefitinib 250 mg film-coated tablets | Date of revision of the text | 26/05/2022 |
Gefitinib 250 mg Film-Coated Tablets | Name of the medicinal product | Gefitinib 250 mg film-coated tablets
2. |
Gefitinib 250 mg Film-Coated Tablets | Qualitative and quantitative composition | Each tablet contains 250 mg of gefitinib.
Excipient with known effect:
Each tablet contains 163.5 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
3. |
Gefitinib 250 mg Film-Coated Tablets | Pharmaceutical form | Film-coated tablet.
Brown coloured, round biconvex coated tablets (with a diameter of approximately 11 mm), debossed with G9FB 250 on one side.
4. |
Gefitinib 250 mg Film-Coated Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Gefitinib is indicated as monotherapy for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK (see section 4.4).
4.2 |
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