Stivarga 40mg film-coated tablets - Ireland[爱尔兰药品]

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Stivarga 40mg film-coated tablets

2014-01-07 01:25:49 来源: 作者: 【大中小】浏览:1014次评论:0条

Table of Contents
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipient(s)
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT

1. NAME OF THE MEDICINAL PRODUCT

Stivarga 40 mg film-coated tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 40 mg of regorafenib.

Excipients with known effect:

Each daily dose of 160 mg contains 2.427 mmol (or 55.8 mg) of sodium (see section 4.4).

Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya) (see section 4.4).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Light pink film-coated tablets, oval shaped with a length of 16 mm and a width of 7 mm embossed with 'BAYER' on one side and '40' on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Stivarga is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy (see section 5.1).

4.2 Posology and method of administration

Stivarga should be prescribed by physicians experienced in the administration of anticancer therapy.

Posology

The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy. This 4-week period is considered a treatment cycle.

If a dose is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose. In case of vomiting after regorafenib administration, the patient should not take additional tablets.

Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs (see section 4.4).

Patients with performance status (PS) 2 or higher were excluded from clinical studies. There is limited data in patients with PS ≥2.

Posology adjustments

Dose interruptions and/or dose reductions may be required based on individual safety and tolerability. Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg. The maximum daily dose is 160 mg.

For recommended dose modifications and measures in case of hand-foot skin reaction (HFSR) / palmar-plantar erythrodysesthesia syndrome see Table 1.

Table 1: Recommended dose modifications and measures for HFSR

Skin toxicity grade	Occurrence	Recommended dose modification and measures
Grade 1	Any	Maintain dose level and immediately institute supportive measures for symptomatic relief.
Grade 2	1st occurrence	Decrease dose by 40 mg (one tablet) and immediately institute supportive measures. If no improvement occurs despite dose reduction, interrupt therapy for a minimum of 7 days, until toxicity resolves to Grade 0-1. A dose re-escalation is permitted at the discretion of the physician.
	No improvement within 7 days or 2nd occurrence	Interrupt therapy until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician.
	3rd occurrence	Interrupt therapy until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician.
	4th occurrence	Discontinue treatment with Stivarga permanently.
Grade 3	1st occurrence	Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet). A dose re-escalation is permitted at the discretion of the physician.
	2nd occurrence	Institute supportive measures immediately. Interrupt therapy for a minimum of 7 days until toxicity resolves to Grade 0-1. When re-starting treatment, decrease dose by 40 mg (one tablet).
	3rd occurrence	Discontinue treatment with Stivarga permanently.

For recommended measures and dose modifications in case of worsening of liver function tests considered related to treatment with Stivarga see Table 2 (see also section 4.4).

Table 2: Recommended measures and dose modifications in case of drug-related liver function test abnormalities

Observed elevations of ALT and/or AST	Occurrence	Recommended measures and dose modification
≤5 times upper limit of normal (ULN) (maximum Grade 2)	Any occurrence	Continue Stivarga treatment. Monitor liver function weekly until transaminases return to <3 times ULN (Grade 1) or baseline.
>5 times ULN ≤20 times ULN (Grade 3)	1st occurrence	Interrupt Stivarga treatment. Monitor transaminases weekly until return to <3 times ULN or baseline. Restart: If the potential benefit outweighs the risk of hepatotoxicity, re-start Stivarga treatment, reduce dose by 40 mg (one tablet), and monitor liver function weekly for at least 4 weeks.
>5 times ULN ≤20 times ULN (Grade 3)	Re-occurrence	Discontinue treatment with Stivarga permanently.
>20 times ULN (Grade 4)	Any occurrence	Discontinue treatment with Stivarga permanently.
>3 times ULN (Grade 2 or higher) with concurrent bilirubin >2 times ULN	Any occurrence	Discontinue treatment with Stivarga permanently. Monitor liver function weekly until resolution or return to baseline. Exception : patients with Gilbert's syndrome who develop elevated transaminases should be managed as per the above outlined recommendations for the respective observed elevation of ALT and/or AST.

Hepatic impairment

Regorafenib is eliminated mainly via the hepatic route.

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose adjustment is required in patients with mild hepatic impairment. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B) and since regorafenib has not been studied in patients with severe hepatic impairment (Child Pugh C), no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2).

Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population.

Renal impairment

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild renal impairment (estimated Glomerular Filtration Rate [eGFR] 60-89 mL/min/1.73m²) and patients with normal renal function. Limited pharmacokinetic data indicate no difference in exposure in patients with moderate renal impairment (eGFR 30-59 mL/min/1.73m²). No dose adjustment is required in patients with mild or moderate renal impairment (see also section 5.2).No clinical data are available in patients with severe renal impairment (eGFR <30 mL/min/1.73m²).

Elderly population

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between elderly (aged 65 years and above) and younger patients. There is only limited information for patients older than 75 years (see also section 5.2).

Gender

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male and female patients. No dose adjustment is necessary based on gender (see also section 5.2).

Ethnic differences

In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients of different ethnic groups. No dose adjustment is necessary based on ethnicity (see section 5.2). There is limited data on regorafenib in patients of Black race.

Paediatric population

There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer.

Method of administration

Stivarga is for oral use.

Stivarga should be taken at the same time each day. The tablets should be swallowed whole with water after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Hepatic effects

Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations (including fatal outcomes) have been reported in a small proportion of patients (see section 4.8).

It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated.

Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor (see section 4.5). Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert's syndrome.

For patients with observed worsening of liver function tests considered related to treatment with Stivarga (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring advice in Table 2 should be followed (see section 4.2).

Regorafenib is eliminated mainly via the hepatic route.

Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population and exposure might be increased in these patients.

Patients with KRAS mutant tumours

In patients with KRAS mutant tumours, a significant improvement in PFS was observed and a numerically lower effect on OS was documented (refer to section 5.1). In view of the substantial toxicity related to treatment, physicians are recommended to carefully eva luate benefits and risks when prescribing regorafenib in patients with KRAS mutant tumours.

Haemorrhage

Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were fatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. In the event of severe