ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Tyverb 250 mg film-coated tablets
2.
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Oval, biconvex, yellow film-coated tablets, with “GS XJG” debossed on one side.
4.
Tyverb is indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2
(ErbB2);
•
in combination with capecitabine for patients with advanced or metastatic disease with
progression following prior therapy, which must have included anthracyclines and taxanes and
therapy with trastuzumab in the metastatic setting (see section 5.1).
•
in combination with an aromatase inhibitor for postmenopausal women with hormone receptor
positive metastatic disease, not currently intended for chemotherapy. The patients in the
registration study were not previously treated with trastuzumab or an aromatase inhibitor (See
section 5.1).
Tyverb treatment should only be initiated by a physician experienced in the administration of
anti-cancer agents.
HER2 (ErbB2) overexpressing tumours are defined by IHC3+, or IHC2+ with gene amplification or
gene amplification alone. HER2 status should be determined using accurate and validated methods.
The daily dose of Tyverb should not be divided. Tyverb should be taken either at least one hour
before, or at least one hour after food. To minimise variability in the individual patient, administration
of Tyverb should be standardised in relation to food intake, for example always to be taken one hour
before a meal (see sections 4.5 and 5.2 for information on absorption).
Missed doses should not be replaced and the dosing should resume with the next scheduled daily dose
(see section 4.9).
Consult the full prescribing information of the co-administered medicinal product for relevant details
of their posology including any dose reductions, contraindications and safety information.
2
Tyverb / capecitabine combination posology
The recommended dose of Tyverb is 1250 mg (i.e. five tablets) once daily continuously.
The recommended dose of capecitabine is 2000 mg/m
2
/day taken in 2 doses 12 hours apart on days
1-14 in a 21 day cycle (see section 5.1). Capecitabine should be taken with food or within 30 minutes
after food. Please refer to the full prescribing information of capecitabine.
Tyverb / aromatase inhibitor combination posology
The recommended dose of Tyverb is 1500 mg (i.e. six tablets) once daily continuously.
Please refer to the full prescribing information of the co-administered aromatase inhibitor for dosing
details.
Dose delay and dose reduction
Cardiac events
Tyverb should be discontinued in patients with symptoms associated with decreased left ventricular
ejection fraction (LVEF) that are National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI CTCAE) grade 3 or greater or if their LVEF drops below the institutions lower limit of
normal (see section 4.4). Tyverb may be restarted at a reduced dose (1000 mg/day when administered
with capecitabine or 1250 mg/day when administered with an aromatase inhibitor) after a minimum of
2 weeks and if the LVEF recovers to normal and the patient is asymptomatic.
Interstitial lung disease / pneumonitis
Tyverb should be discontinued in patients who experience pulmonary symptoms which are NCI
CTCAE grade 3 or greater (see section 4.4).
Other toxicities
Discontinuation or interruption of dosing with Tyverb may be considered when a patient develops
toxicity greater than or equal to grade 2 on the NCI CTCAE. Dosing can be restarted, when the
toxicity improves to grade 1 or less, at either 1250 mg/day when administered with capecitabine or
1500 mg/day when administered with an aromatase inhibitor. If the toxicity recurs, then Tyverb
should be restarted at a lower dose (1000 mg/day when administered with capecitabine or
1250 mg/day when administered with an aromatase inhibitor).
Renal impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment. Caution is
advised in patients with severe renal impairment as there is no experience of Tyverb in this population
(see section 5.2).
Hepatic impairment
Tyverb should be discontinued if changes in liver function are severe and patients should not be
retreated (see section 4.4).
Administration of Tyverb to patients with moderate to severe hepatic impairment should be
undertaken with caution due to increased exposure to the medicinal product. Insufficient data are
available in patients with hepatic impairment to provide a dose adjustment recommendation (see
section 5.2).
Paediatric Population
3
Tyverb is not recommended for use in the paediatric population due to insufficient data on safety and
efficacy.
Elderly
There are limited data of the use of Tyverb and capecitabine in patients aged ≥65 years.
In the phase III clinical study of Tyverb in combination with letrozole, of the total number of hormone
receptor positive metastatic breast cancer patients (Intent to treat population N=642), 44 % were
≥65 years of age. No overall differences in efficacy and safety of the combination of Tyverb and
letrozole were observed between these subjects and subjects <65 years of age.
Hypersensitivity to the active substance or to any of the excipients.
Lapatinib has been associated with reports of decreases in left ventricular ejection fraction (LVEF)
(see section 4.8). Lapatinib has not been evaluated in patients with symptomatic cardiac failure
.
Caution should be taken if Tyverb is to be administered to patients with conditions that could impair
left ventricular function (including coadministration with potentially cardiotoxic agents). Evaluation of
cardiac function, including LVEF determination, should be conducted for all patients prior to initiation
of treatment with Tyverb to ensure that the patient has a baseline LVEF that is within the institutions
normal limits. LVEF should continue to be evaluated during treatment with Tyverb to ensure that
LVEF does not decline to an unacceptable level (see section 4.2). In some cases, LVEF decrease may
be severe and lead to cardiac failure. Fatal cases have been reported, causality of the deaths is
uncertain.
There has been no dedicated study to assess the potential for lapatinib to prolong the QT interval. A
small, concentration dependent increase in QTc interval was observed in an uncontrolled, open-label
dose-escalation study of lapatinib in advanced cancer patients, such that an effect on QT interval
cannot be ruled out. Caution should be taken if Tyverb is administered to patients with conditions that
could result in prolongation of QTc (including hypokalemia, hypomagnesemia, congenital long QT
syndrome, or coadministration of other medicines known to cause QT prolongation). Hypokalemia or
hypomagnesemia should be corrected prior to treatment. Electrocardiograms with QT measurement
should be considered prior to administration of Tyverb and throughout treatment.
Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and
pneumonitis (see section 4.8). Patients should be monitored for symptoms of pulmonary toxicity
(dyspnoea, cough, fever) and treatment discontinued in patients who experience symptoms which are
NCI CTCAE grade 3 or greater. Pulmonary toxicity may be severe and lead to respiratory failure.
Fatal cases have been reported, causality of the deaths is uncertain.
Hepatotoxicity has occurred with Tyverb use and may in rare cases be fatal. At the initiation of
treatment patients should be advised of the potential for hepatotoxicity. Liver function (transaminases,
bilirubin and alkaline phosphatase) should be monitored before the initiation of treatment and monthly
thereafter, or as clinically indicated. Tyverb dosing should be discontinued if changes in liver function
are severe and patients should not be retreated.
Caution is warranted if Tyverb is prescribed to patients with moderate or severe hepatic impairment
(see sections 4.2 and 5.2).
Caution is advised if Tyverb is prescribed to patients with severe renal impairment (see sections 4.2
and 5.2).
4
Diarrhoea, including severe diarrhoea, has been reported with Tyverb treatment (see section 4.8). At
the start of therapy, the patients bowel pattern and any other symptoms (e.g. fever, cramping pain,
nausea, vomiting, dizziness and thirst) should be determined, to allow identification of changes during
treatment and to help identify patients at greater risk of diarrhoea. Patients should be instructed to
promptly report any change in bowel patterns. Proactive management of diarrhoea with anti-diarrhoeal
agents is important. Severe cases of diarrhoea may require administration of oral or intravenous
electrolytes and fluids, and interruption or discontinuation of Tyverb therapy (see section 4.2 – dose
delay and dose reduction – other toxicities).
Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposure
to lapatinib (see section 4.5).
Concomitant treatment with strong inhibitors of CYP3A4 should be avoided due to risk of increased
exposure to lapatinib (see section 4.5).
Grapefruit juice should be avoided during treatment with Tyverb (see section 4.5).
Coadministration of Tyverb with orally administered medicinal products with narrow therapeutic
windows that are substrates of CYP3A4 should be avoided (see section 4.5).
Coadministration of Tyverb with medicinal products with narrow therapeutic windows that are
substrates of CYP2C8 should be avoided (see section 4.5).
Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib
solubility and absorption may decrease (see section 4.5).
Effects of other medicinal products on lapatinib
Lapatinib is predominantly metabolised by CYP3A (see section 5.2).
In healthy volunteers receiving ketoconazole, a strong CYP3A4 inhibitor, at 200 mg twice daily for 7
days, systemic exposure to lapatinib (100 mg daily) was increased approximately 3.6–fold, and half-
life increased 1.7–fold. Coadministration of Tyverb with strong inhibitors of CYP3A4 (e.g. ritonavir,
saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should
be avoided. Coadministration of Tyverb with moderate inhibitors of CYP3A4 should proceed with
caution and clinical adverse reactions should be carefully monitored.
In healthy volunteers receiving carbamazepine, a CYP3A4 inducer, at 100 mg twice daily for 3 days
and 200 mg twice daily for 17 days, systemic exposure to lapatinib was decreased approximately 72%.
Coadministration of Tyverb with known inducers of CYP3A4 (e.g. rifampicin, rifabutin,
carbamazepine, phenytoin or Hypericum perforatum [St John’s Wort]) should be avoided.
Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors (ketoconazole,
itraconazole, quinidine, verapamil, cyclosporine, erythromycin) and inducers (rifampicin, St John’s
Wort) of these proteins may alter the exposure and/or distribution of lapatinib (see section 5.2).
The solubility of lapatinib is pH-dependent. Concomitant treatment with substances that increase
gastric pH should be avoided, as lapatinib solubility and absorption may decrease.
Effects of lapatinib on other medicinal products
Lapatinib inhibits CYP3A4
in vitro
at clinically relevant concentrations. Coadministration of Tyverb
with orally administered midazolam resulted in an approximate 45% increase in the AUC of
midazolam. There was no clinically meaningful increase in AUC when midazolam was dosed
intravenously. Coadministration of Tyverb with orally administered medicines with narrow
5
therapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) should be
avoided (see sections 4.4 and 5.2).
Lapatinib inhibits CYP2C8
in vitro
at clinically relevant concentrations. Coadministration of Tyverb
with medicines with narrow therapeutic windows that are substrates of CYP2C8 (e.g. repaglinide)
should be avoided (see sections 4.4 and 5.2).
Coadministration of lapatinib with intravenous paclitaxel increased the exposure of paclitaxel by 23%,
due to lapatinib inhibition of CYP2C8 and/or Pgp. An increase in the incidence and severity of
diarrhoea and neutropenia has been observed with this combination in clinical trials. Caution is
advised if lapatinib is coadministered with paclitaxel.
Coadministration of lapatinib with intravenously administered docetaxel did not significantly affect
the AUC or Cmax of either active substance. However, the occurrence of docetaxel-induced
neutropenia was increased.
Coadministration of Tyverb with irinotecan (when administered as part of the FOLFIRI regimen)
resulted in an approximate 40% increase in the AUC of SN-38, the active metabolite of irinotecan.
The precise mechanism of this interaction is unknown, but it is assumed to be due to inhibition of one
or more transport proteins by lapatinib. Adverse reactions should be carefully monitored if Tyverb is
coadministered with irinotecan, and a reduction in the dose of irinotecan should be considered.
Lapatinib inhibits the transport protein Pgp
in vitro
at clinically relevant concentrations.
Coadministration of lapatinib with orally administered digoxin resulted in an approximate 80%
increase in the AUC of digoxin. Caution should be exercised when dosing lapatinib concurrently with
medications with narrow therapeutic windows that are substrates of Pgp, and a reduction in the dose of
the Pgp substrate should be considered.
Lapatinib inhibits the transport proteins BCRP and OATP1B1
in vitro
. The clinical relevance of this
effect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics of
substrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin) (see section 5.2).
Concomitant administration of Tyverb with capecitabine, letrozole or trastuzumab did not
meaningfully alter the pharmacokinetics of these agents (or the metabolites of capecitabine) or
lapatinib.
Interactions with food and drink
The bioavailability of lapatinib is increased up to about 4 times by food, depending on e.g. the fat
content in the meal (see sections 4.2 and 5.2).
Grapefruit juice may inhibit CYP3A4 in the gut wall and increase the bioavailability of lapatinib and
should therefore be avoided during treatment with Tyverb.
There are no adequate data from the use of Tyverb in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). The potential risk for humans is not known.
Tyverb should not be used during pregnancy unless clearly necessary. Women of childbearing
potential should be advised to use adequate contraception and avoid becoming pregnant while
receiving treatment with Tyverb.
The safe use of Tyverb during breast-feeding has not been established. It is not known whether
lapatinib is excreted in human milk. In rats, growth retardation was observed in pups which were
exposed to lapatinib via breast milk. Breast-feeding must be discontinued in women who are
receiving therapy with Tyverb.
6
No studies on the effects of lapatinib on the ability to drive and use machines have been performed. A
detrimental effect on such activities cannot be predicted from the pharmacology of lapatinib. The
clinical status of the patient and the adverse event profile of lapatinib should be borne in mind when
considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.
The safety of lapatinib has been evaluated as monotherapy or in combination with other
chemotherapies for various cancers in more than 11,000 patients, including 198 patients who received
lapatinib in combination with capecitabine and 654 patients who received lapatinib in combination
with letrozole (see section 5.1).
The most common adverse reactions (>25%) during therapy with lapatinib were gastrointestinal events
(such as diarrhoea, nausea, and vomiting) and rash. Palmar-plantar erythrodysesthesia [PPE] was also
common (>25%) when lapatinib was administered in combination with capecitabine. The incidence of
PPE was similar in the lapatinib plus capecitabine and capecitabine alone treatment arms. Diarrhoea
was the most common adverse reaction resulting in discontinuation of treatment when lapatinib was
administered in combination with capecitabine, or with letrozole.
The following convention has been utilised for the classification of frequency: 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, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions have been reported to have a causal association with lapatinib alone
or lapatinib in combination with capecitabine or letrozole.
Immune system disorders
Rare Hypersensitivity reactions including anaphylaxis (see section 4.3)
Metabolism and nutrition disorders
Very common Anorexia
Psychiatric disorders
Very common Insomnia*
Nervous system disorders
Very common
Headache
†
Common
Headache*
Cardiac disorders
Common
Decreased left ventricular ejection fraction (see section 4.2 - dose reduction –
cardiac events and section 4.4).
Vascular disorders
Very common Hot flush
†
Respiratory, thoracic and mediastinal disorders
Very common
Epistaxis
†
, cough
†
, dyspnoea
†
.
7
Uncommon Interstitial lung disease/pneumonitis.
Gastrointestinal disorders
Very common Diarrhoea, which may lead to dehydration (see section 4.2 - dose delay and
dose reduction – other toxicities and section 4.4), nausea, vomiting,
dyspepsia*, stomatitis*, constipation*, abdominal pain*.
Common Constipation
†
Hepatobiliary disorders
Common Hyperbilirubinaemia, hepatotoxicity (see section 4.4).
Skin and subcutaneous tissue disorders
Very common Rash (including dermatitis acneiform) (see section 4.2 - dose delay and dose
reduction – other toxicities), dry skin*
†
, palmar-plantar erythrodysaesthesia*,
alopecia
†
, pruritus
†
.
Common Nail disorders including paronychia.
Musculoskeletal and connective tissue disorders
Very common Pain in extremity*
†
, back pain*
†
, arthralgia
†
.
General disorders and administration site conditions
Very common Fatigue, mucosal inflammation*, asthenia
†
.
*These adverse reactions were observed when lapatinib was administered in combination with
capecitabine.
†
These adverse reactions were observed when lapatinib was administered in combination with
letrozole.
Decreased left ventricular ejection fraction and QT interval prolongation
Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% of
patients receiving lapatinib and were asymptomatic in more than 90% of cases. LVEF decreases
resolved or improved in more than 70 % of cases, in 60 % of these on discontinuation of treatment
with lapatinib, and in 40 % of cases lapatinib was continued. Symptomatic LVEF decreases were
observed in approximately 0.2% of patients who received lapatinib monotherapy or in combination
with other anti-cancer agents. Observed symptoms included dyspnoea, cardiac failure and palpitations.
Overall 58 % of these symptomatic subjects recovered. LVEF decreases were reported in 2.5 % of
patients who received lapatinib in combination with capecitabine, as compared to 1.0 % with
capecitabine alone. LVEF decreases were reported in 3.1 % of patients who received lapatinib in
combination with letrozole as compared to 1.3 % of patients receiving letrozole plus placebo.
A small, concentration dependent increase in QTc interval was observed in a phase I uncontrolled
study. The potential for lapatinib to prolong the QTc interval has not been ruled out (see section 4.4).
Diarrhoea
Diarrhoea occurred in approximately 65 % of patients who received lapatinib in combination with
capecitabine and in 64 % of patients who received lapatinib in combination with letrozole. Most cases
of diarrhoea were grade 1 or 2 and did not result in discontinuation of treatment with lapatinib.
Diarrhoea responds well to proactive management (see section 4.4). However, a few cases of acute
renal failure have been reported secondary to severe dehydration due to diarrhoea.
Rash
Rash occurred in approximately 28 % of patients who received lapatinib in combination with
capecitabine and in 45 % of patients who received lapatinib in combination with letrozole. Rash was
generally low grade and did not result in discontinuation of treatment with lapatinib. Prescribing
8
physicians are advised to perform a skin examination prior to treatment and regularly during
treatment. Patients experiencing skin reactions should be encouraged to avoid exposure to sunlight and
apply broad spectrum sunscreens with a Sun Protection Factor (SPF) ≥ 30. If a skin reaction occurs a
full body examination should be performed at every visit until one month after resolution. Patients
with extensive or persistent skin reactions should be referred to a dermatologist.
There is no specific antidote for the inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosine
phosphorylation. The maximum oral dose of lapatinib that has been administered in clinical trials is
1800 mg once daily.
Asymptomatic and symptomatic cases of overdose have been reported in patients being treated with
Tyverb. In patients who took up to 5000 mg of lapatinib, symptoms observed include known lapatinib
associated events (
see Section 4.8
) and in some cases sore scalp and/or mucosal inflammation. In a
single case of a patient who took 9000 mg of Tyverb, sinus tachycardia (with otherwise normal ECG)
was also observed.
Lapatinib is not significantly renally excreted and is highly bound to plasma proteins, therefore
haemodialysis would not be expected to be an effective method to enhance the elimination of
lapatinib.
Further management should be as clinically indicated or as recommended by the national poisons
centre, where available.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protein kinase inhibitor, ATC code: L01XE07
This medicinal product has been authorised under a so-called “conditional approval” scheme.
This means that further evidence on this medicinal product is awaited.
The European Medicines Agency (EMA) will review new information on the product every year and
this SPC will be updated as necessary.
The European Medicines Agency has waived the obligation to submit the results of studies with
Tyverb in all subsets of the paediatric population in the treatment of breast carcinoma (see section 4.2
for information on paediatric use).
Mechanism of action
Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both
EGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Ki
app
values of 3nM and 13nM,
respectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes).
Lapatinib inhibits ErbB-driven tumour cell growth
in vitro
and in various animal models.
The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines.
Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in
trastuzumab-containing medium
in vitro
.
Clinical studies
Combination treatment with Tyverb and capecitabine
9
The efficacy and safety of Tyverb in combination with capecitabine in breast cancer patients with
good performance status was evaluated in a randomised, phase III trial. Patients eligible for enrolment
had HER2-overexpressing, locally advanced or metastatic breast cancer, progressing after prior
treatment that included taxanes, anthracyclines and trastuzumab. LVEF was evaluated in all patients
(using echocardiogram or MUGA) prior to initiation of treatment with Tyverb to ensure baseline
LVEF was within the institutions normal limits. In the clinical trial LVEF was monitored at
approximately eight week intervals during treatment with Tyverb to ensure it did not decline to below
the institutions lower limit of normal. The majority of LVEF decreases (greater than 60 %) were
observed during the first nine weeks of treatment, however limited data was available for long term
exposure.
Patients were randomised to receive either Tyverb 1250 mg once daily (continuously) plus
capecitabine (2000 mg/m
2
/day on days 1-14 every 21 days), or to receive capecitabine alone
(2500 mg/m
2
/day on days 1-14 every 21 days). The primary endpoint was time to progression (TTP).
Assessments were undertaken by the study investigators and by an independent review panel, blinded
to treatment. The study was halted based on the results of a pre-specified interim analysis that showed
an improvement in TTP for patients receiving Tyverb plus capecitabine. An additional 75 patients
were enrolled in the study between the time of the interim analysis and the end of the enrolment.
Investigator analysis on data at the end of enrolment is presented in Table 1.
Table 1 Time to Progression data from Study EGF100151 (Tyverb / capecitabine)
Investigator assessment
Tyverb (1,250 mg/day)+
capecitabine (2,000 mg/m
2
/day)
Capecitabine (2,500 mg/m
2
/day)
(N = 198)
(N = 201)
Number of TTP events
121
126
Median TTP, weeks
23.9
18.3
Hazard Ratio
0.72
(95%CI)
(0.56,0.92)
pvalue
0.008
The independent assessment of the data also demonstrated that Tyverb when given in combination
with capecitabine significantly increased time to progression (Hazard Ratio 0.57 [95 % Cl 0.43, 0.77]
p=0.0001) compared to capecitabine alone.
Results of an updated analysis of the overall survival data to 28 September 2007 are presented in
Table 2.
Table 2 Overall survival data from Study EGF100151 (Tyverb / capecitabine)
Tyverb (1,250 mg/day)+
capecitabine (2,000 mg/m
2
/day)
Capecitabine (2,500 mg/m
2
/day)
(N = 207)
(N = 201)
Number of subjects who
died
148
154
Median overall survival,
weeks
74.0
65.9
Hazard Ratio
0.9
(95% CI)
(0.71, 1.12)
pvalue
0.3
On the combination arm, there were 4 (2%) progressions in the central nervous system as compared
with the 13 (6%) progressions on the capecitabine alone arm.
10
Combination treatment with Tyverb and letrozole
Tyverb has been studied in combination with letrozole for the treatment of postmenopausal women
with hormone receptor-positive (oestrogen receptor [ER] positive and / or progesterone receptor [PgR]
positive) advanced or metastatic breast cancer.
The Phase III study (EGF30008) was randomised, double-blind, and placebo controlled. The study
enrolled patients who had not received prior therapy for their metastatic disease. The period of
enrolment to the trial (December 2003 – December 2006) preceded the adoption of trastuzumab in
combination with an aromatase inhibitor. A comparative study between lapatinib and trastuzumab in
this patient population has not been conducted.
In the HER2-overexpressing population, only 2 patients were enrolled who had received prior
trastuzumab, 2 patients had received prior aromatase inhibitor therapy, and approximately half had
received tamoxifen.
Patients were randomised to letrozole 2.5 mg once daily plus Tyverb 1500 mg once daily or letrozole
with placebo. Randomisation was stratified by sites of disease and by time from discontinuation of
prior adjuvant anti-oestrogen therapy. HER2 receptor status was retrospectively determined by central
laboratory testing. Of all patients randomised to treatment, 219 patients had tumours overexpressing
the HER2 receptor, and this was the pre-specified primary population for the analysis of efficacy.
There were 952 patients with HER2-negative tumours, and a total of 115 patients whose tumour HER2
status was unconfirmed (no tumour sample, no assay result, or other reason).
In patients with HER2-overexpressing MBC, investigator-determined progression-free survival (PFS)
was significantly greater with letrozole plus Tyverb compared with letrozole plus placebo. In the
HER2-negative population, there was no benefit in PFS when letrozole plus Tyverb was compared
with letrozole plus placebo (see Table 3).
Table 3 Progression Free Survival data from Study EGF30008 (Tyverb / letrozole)
HER2-Overexpressing Population HER2-NegativePopulation
N = 111
N = 108
N = 478
N = 474
Tyverb 1500 mg
/ day
+ Letrozole 2.5
mg /day
Letrozole 2.5
mg /day
+ placebo
Tyverb 1500 mg
/ day
+ Letrozole 2.5
mg /day
Letrozole 2.5
mg /day
+ placebo
Median PFS, weeks
(95% CI)
35.4
(24.1, 39.4)
13.0
(12.0, 23.7)
59.7
(48.6, 69.7)
58.3
(47.9, 62.0)
Hazard Ratio
0.71 (0.53, 0.96)
0.90 (0.77, 1.05)
P-value
0.019
0.188
Objective Response
Rate (ORR)
27.9%
14.8%
32.6%
31.6%
Odds Ratio
0.4 (0.2, 0.9)
0.9 (0.7, 1.3)
P-value
0.021
0.26
Clinical Benefit Rate
(CBR)
47.7%
28.7%
58.2%
31.6%
Odds Ratio
0.4 (0.2, 0.8)
1.0 (0.7, 1.2)
P-value
0.003
0.199
CI= confidence interval
HER2 overexpression = IHC 3+ and/or FISH positive; HER2 negative = IHC 0, 1+ or 2+ and/or
FISH negative
Clinical Benefit Rate was defined as complete plus partial response plus stable disease for
≥
6 months.
11
At the time of analysis, the overall survival data were not mature and there was no significant
difference between treatment groups (Tyverb + letrozole combination HR= 0.77 [95 %CI 0.52-1.14]
p=0.185). However, no negative effect on overall survival was apparent.
5.2 Pharmacokinetic properties
The absolute bioavailability following oral administration of lapatinib is unknown, but it is incomplete
and variable (approximately 70% coefficient of variation in AUC). Serum concentrations appear after
a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (C
max
) of lapatinib
are achieved approximately 4 hours after administration. Daily dosing of 1250 mg produces steady
state geometric mean (coefficient of variation) C
max
values of 2.43 (76%) µg/ml and AUC values of
36.2 (79%) µg*hr/ml.
Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were
approximately 3- and 4-fold higher (C
max
approximately 2.5 and 3–fold higher) when administered
with a low fat (5% fat [500 calories]) or with a high fat (50% fat [1,000 calories]) meal, respectively.
Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein.
In vitro
studies indicate that lapatinib is a substrate for the transporters BCRP (ABCG1) and p-glycoprotein
(ABCB1). Lapatinib has also been shown
in vitro
to inhibit these efflux transporters, as well as the
hepatic uptake transporter OATP 1B1, at clinically relevant concentrations (IC
50
values were equal to
2.3 µg/ml). The clinical significance of these effects on the pharmacokinetics of other medicinal
products or the pharmacological activity of other anti-cancer agents is not known.
Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor
contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which
account for more than 14% of the dose recovered in the faeces or 10% of lapatinib concentration in
plasma.
Lapatinib inhibits CYP3A (Ki 0.6 to 2.3 µg/ml) and CYP2C8 (0.3 µg/ml)
in vitro
at clinically relevant
concentrations. Lapatinib did not significantly inhibit the following enzymes in human liver
microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes (
in vitro
IC
50
values were
greater than or equal to 6.9 µg/ml).
The half-life of lapatinib measured after single doses increases with increasing dose. However, daily
dosing of lapatinib results in achievement of steady state within 6 to 7 days, indicating an effective
half-life of 24 hours. Lapatinib is predominantly eliminated through metabolism by CYP3A4/5.
Biliary excretion may also contribute to the elimination.
The primary route of excretion for lapatinib
and its metabolites is in faeces. Recovery of unchanged lapatinib in faeces accounts for a median 27%
(range 3 to 67%) of an oral dose. Less than 2% of the administered oral dose (as lapatinib and
metabolites) excreted in urine.
Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in
patients undergoing haemodialysis. Available data suggest that no dose adjustment is necessary in
patients with mild to moderate renal impairment.
The pharmacokinetics of lapatinib were examined in subjects with moderate (n = 8) or severe (n = 4)
hepatic impairment (Child-Pugh scores of 7-9, or greater than 9, respectively) and in 8 healthy control
subjects. Systemic exposure (AUC) to lapatinib after a single oral 100 mg dose increased
approximately 56% and 85% in subjects with moderate and severe hepatic impairment, respectively.
Administration of lapatinib in patients with hepatic impairment should be undertaken with caution (see
sections 4.2 and 4.4).
5.3 Preclinical safety data
Lapatinib was studied in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day.
There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib
12
and precocious ossification) occurred in rats at ≥60 mg/kg/day (4 times the expected human clinical
exposure). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (8%
and 23% of the expected human clinical exposure, respectively) and abortions at 120 mg/kg/day. At
≥60 mg/kg/day there were decreased foetal body weights, and minor skeletal variations. In the rat pre-
and postnatal development study, a decrease in pup survival occurred between birth and postnatal day
21 at doses of 60 mg/kg/day or higher (5 times the expected human clinical exposure). The highest no-
effect dose for this study was 20 mg/kg/day.
In oral carcinogenicity studies with lapatinib, severe skin lesions were seen at the highest doses tested
which produced exposures based on AUC up to 2-fold in mice and male rats, and up to 15-fold in
female rats, compared to humans given 1250 mg of lapatinib once daily. There was no evidence of
carcinogenicity in mice. In rats, the incidence of benign haemangioma of the mesenteric lymph nodes
was higher in some groups than in concurrent controls. There was also an increase in renal infarcts and
papillary necrosis in female rats at exposures 7 and 10-fold compared to humans given 1250 mg of
lapatinib once daily. The relevance of these findings for humans is uncertain.
There were no effects on male or female rat gonadal function, mating, or fertility at doses up to
120 mg/kg/day (females) and up to 180 mg/kg/day (males) (8 and 3 times the expected human clinical
exposure, respectively). The effect on human fertility is unknown.
Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster
chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay and
an
in vivo
rat bone marrow chromosome aberration assay.
6.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Povidone (K30)
Sodium starch glycolate (Type A)
Magnesium stearate
Tablet coating
Hypromellose
Titanium dioxide (E171)
Macrogol 400
Polysorbate 80
Iron oxide yellow (E172)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30ºC.
6.5
Nature and contents of container
Tyverb is supplied in either blister packs or bottles.
13
Blister packs
Tyverb / capecitabine combination posology
Each pack of Tyverb contains 70 film-coated tablets in foil blisters (polyamide / aluminium /
polyvinyl chloride / aluminium) of 10 tablets each. Each foil has a perforation down the middle to
allow the blisters to be separated into a daily dose of 5 tablets.
Multipacks contain 140 film-coated tablets consisting of 2 x 70 tablet packs in a large outer carton.
Tyverb / aromatase inhibitor combination posology
Each pack of Tyverb contains 84 film-coated tablets in foil blisters (polyamide / aluminium /
polyvinyl chloride / aluminium) of 12 tablets each. Each foil has a perforation down the middle to
allow the blisters to be separated into a daily dose of 6 tablets.
Bottles
Tyverb is also supplied in high density polyethylene bottles (HDPE) with a child resistant
polypropylene closure containing 70, 84 or 140 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.
8.
EU/1/07/440/001-006
9.
Date of first authorisation: 10/06/2008
Date of last renewal: 12/06/2009
{MMYYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu./
14
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
C.
SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
15
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Glaxo Operations UK Limited
Priory Street
Ware
Hertfordshire
SG12 0DG
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 8 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame. The results of which shall be taken into account in the risk benefit balance
during the assessment of the application for a renewal.
16
Clinical aspects
To conduct a Phase III randomised, controlled clinical study to evaluate the incidence of brain
metastases as the site of relapse with a lapatinib-containing therapy compared with an
appropriate, trastuzumab-containing control arm.
The final study report for the trial will by submitted by May 2013.
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A.LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (14 DAY, SINGLE PACK)
1.
Tyverb 250 mg film-coated tablets
lapatinib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.
3.
LIST OF EXCIPIENTS
4.
70 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC.
20
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/1/07/440/001
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
tyverb 250 mg
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (28-DAY, MULTIPACK)
1.
Tyverb 250 mg film-coated tablets
lapatinib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.
3.
LIST OF EXCIPIENTS
4.
140 film-coated tablets
Multipack comprising 2 packs, each containing 70 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC.
22
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/1/07/440/002
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
tyverb 250 mg
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (14 DAY PACK, PART OF 28 DAY MULTIPACK)
1.
Tyverb 250 mg film-coated tablets
lapatinib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.
3.
LIST OF EXCIPIENTS
4.
70 film-coated tablets
Component of the multipack, not to be sold separately
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC.
24
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/1/07/440/002
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
tyverb 250 mg
25
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Tyverb 250 mg tablets
lapatinib
2.
Glaxo Group Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (14 DAY, SINGLE PACK)
1.
Tyverb 250 mg film-coated tablets
lapatinib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.
3.
LIST OF EXCIPIENTS
4.
84 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC.
27
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/1/07/440/003
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
tyverb 250 mg
28
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Tyverb 250 mg tablets
lapatinib
2.
Glaxo Group Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON AND BOTTLE LABEL
1.
Tyverb 250 mg film-coated tablets
lapatinib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.
3.
LIST OF EXCIPIENTS
4.
70 film-coated tablets
84 film-coated tablets
140 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30ºC.
30
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/1/07/440/004 70 tablets
EU/1/07/440/005 140 tablets
EU/1/07/440/006 84 tablets
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
tyverb 250 mg
31
B. PACKAGE LEAFLET
32
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tyverb 250 mg film-coated tablets
Lapatinib
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Don’t pass it on to others. It may harm them, even if
their symptoms seem the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, tell
your doctor or pharmacist.
In this leaflet
:
1. What Tyverb is and what it is used for
2. Before you take Tyverb
3. How to take Tyverb
4. Possible side effects
5.
How to store Tyverb
6.
1.
WHAT TYVERB IS AND WHAT IT IS USED FOR
Tyverb is used to treat certain types of breast cancer
(HER2-overexpressing)
which have spread
beyond the original tumour (
advanced
or
metastatic
breast cancer). It may slow or stop cancer cells
from growing, or may kill them.
Tyverb is prescribed to be taken in combination with another anti-cancer medicine.
Tyverb is prescribed in
combination with capecitabine
, for patients who have had other treatment for
advanced or metastatic breast cancer
before.
Tyverb is prescribed in
combination with an aromatase inhibitor
, for patients with hormone
sensitive metastatic breast cancer (breast cancer that is more likely to grow in the presence of
hormones), who are not currently intended for chemotherapy.
Information about these medicines is described in separate patient information leaflets.
Ask your
doctor
to give you information about these other medicines.
2.
BEFORE YOU TAKE TYVERB
Do not take Tyverb
•
if you are allergic (
hypersensitive
) to lapatinib or any of the other ingredients of Tyverb.
Take special care with Tyverb
Your doctor will run tests to check that your heart is working properly
before and during your
treatment with Tyverb.
Tell your doctor if you have any heart problems
before you take Tyverb.
33
Further information
Your doctor also needs to know before you take Tyverb:
•
if you have any
liver problems
.
•
if you have any
kidney problems
.
Your doctor will run tests to check that your liver is working properly
before and during your
treatment with Tyverb.
Tell your doctor
if any of these apply to you.
Taking other medicines
Tell your doctor or pharmacist if you are taking, or have recently taken any other medicines.
This includes any medicines you bought without a prescription.
It is especially important to tell your doctor
if you are taking, or have recently taken any of the
following medicines. Some medicines may affect the way Tyverb works or Tyverb may affect how
other medicines work. These medicines include some medicines in the following groups:
•
St John’s Wort – a herb extract used to treat
depression
•
erythromycin, ketoconazole, itraconazole, posaconazole, voriconazole, rifabutin, rifampicin,
telithromycin
–
medicines
used to treat
infections
•
cyclosporine – a medicine used to
suppress the immune system
for example after organ
transplantations
•
ritonavir, saquinavir – medicines used to treat
HIV
•
phenytoin, carbamazepine – medicines used to treat
seizures
•
cisapride – a medicine used to treat certain
digestive system
problems
•
pimozide – a medicine used to treat certain
mental health problems
•
quinidine, digoxin – medicines used to treat certain
heart problems
•
repaglinide – a medicine used to treat
diabetes
•
verapamil – a medicine used to treat
high blood pressure
or
heart problems
(
angina
)
•
nefazodone – a medicine used to treat
depression
•
topotecan, paclitaxel, irinotecan, docetaxel – medicines used to treat certain types of
cancer
•
rosuvastatin – a medicine used to treat
high cholesterol
•
medicines that decrease stomach acidity - used to treat
stomach ulcers
or
indigestion
Tell your doctor
if you’re taking, or have recently taken, any of these.
Your doctor will review the medicines you are currently taking to make sure you are not taking
something that can’t be taken with the Tyverb. Your doctor will advise you whether an alternative is
available.
Taking Tyverb with food and drink
Take Tyverb either at least one hour before or at least one hour after food.
Tyverb is affected by food intake.
It is important that you take your tablets at the same time in
relation to food each day
- for example, you could always take your tablet one hour before breakfast.
Don’t drink grapefruit juice while you are being treated with Tyverb.
Pregnancy and breast-feeding
The effect of Tyverb during pregnancy is not known. You should not use Tyverb if you are
pregnant unless your doctor specifically recommends it.
.
•
If you are pregnant
or planning to become pregnant
tell your doctor.
34
•
Use a reliable method of contraception
to avoid becoming pregnant while you’re taking
Tyverb.
•
If you become pregnant
during treatment with Tyverb,
tell your doctor
.
It is not known whether Tyverb passes into breast-milk. Do not breast-feed while taking Tyverb.
•
If you are breast-feeding
or planning to breast-feed,
tell your doctor
.
Ask your doctor or pharmacist for advice
before taking Tyverb if you are unsure
.
Driving and using machines
No studies have been performed on the effects of Tyverb on your ability to drive or use machines.
You are responsible to decide if you are able to drive a motor vehicle or perform other tasks that
require increased concentration. Because of the possible side effects of Tyverb, your ability to drive or
operate machinery could be affected.
These effects are described in section 4, ‘Possible side effects’.
Read all the information in this leaflet for guidance. Discuss with your doctor, nurse or pharmacist if
you are unsure about anything.
3.
HOW TO TAKE TYVERB
Always take Tyverb exactly as your doctor has told you
. Check with your doctor or pharmacist if
you’re not sure.
Your doctor will decide on the correct dose of Tyverb depending on the type of breast cancer being
treated.
If you are prescribed Tyverb in
combination with capecitabine
, the usual dose is
5 Tyverb tablets a
day
, as a single dose.
If you are prescribed Tyverb in
combination with an aromatase inhibitor
, the usual dose is
6 Tyverb tablets a day
, as a single dose.
Take the prescribed dose every day for as long as your doctor tells you to.
Your doctor will advise you about the dose of your other anti-cancer medicine, and how to take it.
Taking your tablets
•
Swallow the tablets whole with water
, one after the other, at the same time each day.
•
Take Tyverb either at least one hour before or at least one hour after food
. Take Tyverb at
the same time in relation to food each day.
See ‘Taking Tyverb with food and drink’ in section 2
for more information
.
While you are taking Tyverb
•
Depending on your response to treatment, your doctor may recommend lowering your dose or
temporarily stopping your treatment.
•
Your doctor will also carry out tests to check your heart and liver function before and during
treatment with Tyverb.
35
If you take too much Tyverb
Contact a doctor or pharmacist immediately. If possible show them the pack.
If you forget to take Tyverb
Don’t take a double dose
to make up for a missed dose. Just take the next dose at the scheduled time.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tyverb can cause side effects, although not everybody gets them.
Severe allergic reaction
This rare side effect may affect up to 1 in 1000 people and develop rapidly.
Symptoms may include:
•
skin rash (including itchy, bumpy rash)
•
unusual wheezing, or difficulty in breathing
•
swollen eyelids, lips or tongue
•
pains in muscles or joints
•
collapse or blackout.
Tell your doctor immediately
if you get any of these symptoms. Don’t take any more tablets.
Very common side effects
These may affect more than 1 in 10 people:
•
diarrhoea (which may make you dehydrated and lead to more severe complications)
Tell your doctor if you get diarrhoea
. There is more advice on reducing the risk of diarrhoea at the
end of section 4.
•
rash, dry skin, itching
Tell your doctor if you get a skin rash
. There is more advice on reducing the risk of skin rash at the
end of section 4.
Other very common side effects
•
loss of appetite
•
feeling sick (nausea)
•
being sick (vomiting)
•
tiredness, feeling weak
•
indigestion
•
constipation
•
sore mouth/mouth ulcers
•
stomach pain
•
trouble sleeping
•
back pain
•
pain in hands and feet
•
joint or back pain
•
a skin reaction on the palms of the hands or soles of the feet (including tingling, numbness,
pain, swelling or reddening)
•
cough, shortness of breath
•
headache
36
•
nose bleed
•
hot flush
•
unusual hair loss or thinning
Tell your doctor
if any of these side effects get severe or troublesome.
Common side effects
These may affect up to 1 in 10 people:
•
an effect on how your heart works
In most cases, the effect on your heart will not have any symptoms. If you do experience symptoms
associated with this side effect, these are likely to include an irregular heartbeat and shortness of
breath.
•
liver problems, which may cause itching, yellow eyes or skin (
jaundice
), or dark urine or pain or
discomfort in the right upper area of the stomach.
Tell your doctor if you get any of these symptoms.
Other common side effects
•
nail disorders – such as a tender infection and swelling of the cuticles
Tell your doctor or pharmacist
if this side effect gets severe or troublesome.
Uncommon side effects
These may affect up to 1 in 100 people:
•
treatment-induced lung inflammation, which may cause shortness of breath or cough
Tell your doctor immediately if you get either of these symptoms
.
Other uncommon side effects include:
•
blood tests results that show changes in liver function (usually mild and temporary)
Rare side effects
This may affect up to 1 in 1000 people:
•
severe allergic reactions (
see the beginning of section 4
)
If you get other side effects
If you notice any side effects not listed in this leaflet:
Tell your doctor or pharmacist.
Reducing the risk of diarrhoea and skin rash
Tyverb can cause severe diarrhoea
If you suffer from diarrhoea while taking Tyverb:
•
drink plenty of fluids (8 to 10 glasses a day), such as water, sports drinks or other clear liquids
•
eat low-fat, high protein foods instead of fatty or spicy foods
37
•
eat cooked vegetables instead of raw vegetables and remove the skin from fruits before eating
•
avoid milk and milk products (including ice cream)
•
avoid herbal supplements (some may cause diarrhoea).
Tell your doctor
if your diarrhoea continues.
Tyverb can cause skin rash
Your doctor will check your skin before and during treatment.
To care for sensitive skin:
•
wash with a soap-free cleanser
•
use fragrance free, hypoallergenic beauty products
•
use sunscreen (Sun Protection Factor [SPF] 30 or higher).
Tell your doctor
if you get a skin rash.
5.
HOW TO STORE TYVERB
Keep out of the reach and sight of children.
Do not use Tyverb after the expiry date which is stated on the blister or bottle and the carton.
Do not store above 30ºC
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Tyverb contains
The active substance in Tyverb is
lapatinib.
Each film-coated tablet contains lapatinib ditosylate
monohydrate, equivalent to 250 mg lapatinib.
The other ingredients are
:
Microcrystalline cellulose, povidone (K30), sodium starch glycolate (Type A), magnesium stearate,
hypromellose, titanium dioxide (E171), macrogol 400, polysorbate 80, iron oxide yellow (E172), iron
oxide red (E172).
What Tyverb looks like and contents of the pack
Tyverb film-coated tablets are oval, biconvex, yellow film-coated, with ‘GS XJG’ marked on one side.
Tyverb is supplied in either blisters packs or bottles:
Blister packs
Each pack of Tyverb contains 70 or 84 tablets in aluminium foil blisters of 10 or 12 tablets each. Each
foil has a perforation down the middle and can be divided into two blisters with 5 or 6 tablets in each,
depending on the pack size. Always take the number of Tyverb tablets each day exactly as your doctor
has told you. Check with your doctor or pharmacist if you are not sure.
Tyverb is also available in multipacks containing 140 tablets that comprise 2 packs, each containing
70 tablets.
38
Bottles
Tyverb is also available in plastic bottles containing 70, 84 or 140 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.
Manufacturer
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations), Priory Street, Ware,
Hertfordshire, SG 12 0DJ, United Kingdom.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
39
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline (Cyprus) Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
{MM/YYYY}.
This medicine has been given “conditional approval”.
This means that there is more evidence to come about this medicine.
The European Medicines Agency (EMA) will review new information on the medicine every year and
this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu./
40
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/tyverb.html
Copyright © 1995-2021 ITA all rights reserved.