4.1. Therapeutic indications

Stivarga is indicated as monotherapy 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)

- unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib

- hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

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.

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), 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

Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. No dose adjustment is required in patients with mild, moderate or severe renal impairment (see also section 5.2).

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 (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 or efficacy were observed between patients of different ethnic groups. A higher incidence of hand foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga compared with Caucasians. The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%). There is limited data on regorafenib in the black patient population.

No dose adjustment is necessary based on ethnicity (see section 5.2).

Paediatric population

There is no relevant use of Stivarga in the paediatric population in the indications of metastatic colorectal cancer, gastrointestional stromal tumours and hepatocellular carcinoma.

The safety and efficacy of Stivarga in children and adolescents (below 18 years if age) have not been established (see section 5.1).

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 hepatic failure and fatal outcomes) have been reported in a small proportion of patients (see section 4.8).

In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga, compared with Caucasians (see section 4.2).

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.

Infections

Stivarga has been associated with an increased incidence of infection events, some of which were fatal (see section 4.8).

In cases of worsening infection events, interruption of Stivarga treatment should be considered.

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. Screening for and subsequent treatment of oesophageal varices in patients with liver cirrhosis should be performed as per standard of care before starting treatment with Stivarga. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be considered.

Gastrointestinal perforation and fistula

Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patients treated with Stivarga (see section 4.8). These events are also known to be common disease‑related complications in patients with intra‑abdominal malignancies. Discontinuation of Stivarga is recommended in patients developing gastrointestinal perforation or fistula.

Cardiac ischaemia and infarction

Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (see section 4.8). Patients with unstable angina or new onset angina (within 3 months of starting Stivarga therapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded from the clinical studies.

Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction, interruption of Stivarga is recommended until resolution. The decision to re‑start Stivarga therapy should be based on careful consideration of the potential benefits and risks of the individual patient. Stivarga should be permanently discontinued if there is no resolution.

Hyperammonaemic encephalopathy

Hyperammonaemic encephalopathy has been observed with regorafenib, including fatal cases (see section 4.8). In patients who develop unexplained lethargy or changes in mental status, ammonia levels should be measured and appropriate clinical management should be initiated. If hyperammonaemic encephalopathy is confirmed, permanent discontinuation of regorafenib should be considered.

Posterior reversible encephalopathy syndrome (PRES)

PRES has been reported in association with Stivarga treatment (see section 4.8). Signs and symptoms of PRES include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES, discontinuation of Stivarga, along with control of hypertension and supportive medical management of other symptoms is recommended.

Arterial hypertension

Stivarga has been associated with an increased incidence of arterial hypertension (see section 4.8). Blood pressure should be controlled prior to initiation of treatment with Stivarga. It is recommended to monitor blood pressure and to treat hypertension in accordance with standard medical practice. In cases of severe or persistent hypertension despite adequate medical management, treatment should be temporarily interrupted and/or the dose reduced at the discretion of the physician (see section 4.2). In case of hypertensive crisis, Stivarga should be discontinued.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Stivarga, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Thrombotic microangiopathy (TMA)

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopaenic purpura (TTP), have been associated with the use of regorafenib (see section 4.8). The diagnosis of TMA should be considered in patients presenting with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological manifestation, renal impairment, and fever. Regorafenib therapy should be discontinued in patients who develop TMA and prompt treatment is required. Reversal of the effects of TMA has been observed after treatment discontinuation.

Wound healing complications

As medicinal products with anti‑angiogenic properties may suppress or interfere with wound healing, temporary interruption of Stivarga is recommended for precautionary reasons in patients undergoing major surgical procedures. The decision to resume treatment with Stivarga following major surgical intervention should be based on clinical judgment of adequate wound healing.

Dermatological toxicity

Hand‑foot skin reaction (HFSR) or palmar‑plantar erythrodysesthesia syndrome and rash represent the most frequently observed dermatological adverse reactions with Stivarga (see section 4.8). In clinical trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with Stivarga, compared with Caucasians (see section 4.2). Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use of keratolytic creams (e.g. urea‑, salicylic acid‑, or alpha hydroxyl acid‑based creams applied sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see section 4.2).

Biochemical and metabolic laboratory test abnormalities

Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are generally of mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of Stivarga should be considered in case of persistent or recurrent significant abnormalities (see section 4.2).

Important information about some of the ingredients

This medicinal product contains 56.06 mg sodium per daily dose of 160 mg, equivalent to 3% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya).

4.5. Interaction with other medicinal products and other forms of interaction

Inhibitors of CYP3A4 and UGT1A9/inducers of CYP3A4

In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate glucuronosyl transferase UGT1A9.

Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of approximately 33%, and a decrease in mean exposure of the active metabolites, M‑2 (N‑oxide) and M‑5 (N‑oxide and N‑desmethyl), of approximately 90%. It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady‑state exposure of regorafenib and its metabolites has not been studied.

Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic acid) during regorafenib treatment should be avoided, as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied.

Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately 50%, a 3‑ to 4‑fold increase in mean exposure of the active metabolite M‑5, and no change in exposure of active metabolite M‑2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John's wort) may also increase metabolism of regorafenib. Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

UGT1A1 and UGT1A9 substrates

In vitro data indicate that regorafenib as well as its active metabolite M‑2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9 whereas M‑5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state. Administration of regorafenib with a 5‑day break prior to administration of irinotecan resulted in an increase of approximately 44% in AUC of SN‑38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of approximately 28% was also observed. This indicates that co‑administration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates.

Breast cancer resistance protein (BCRP) and P‑glycoprotein substrates

Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax.

This indicates that co-administration of regorafenib may increase the plasma concentrations of other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to BCRP substrates.

Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can be given concomitantly with p-glycoprotein substrates, such as digoxin, without a clinically meaningful drug interaction.

Inhibitors of P-glycoprotein and BCRP/Inducers of P-glycoprotein and BCRP

In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-glycoprotein and BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere with the exposure of M-2 and M-5. The clinical significance of these findings is unknown (see also section 5.2).

CYP isoform‑selective substrates

In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced.

A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone) CYP2C9 (S‑warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam).

Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see also section 4.4).

Antibiotics

The concentration‑time profile indicates that regorafenib and its metabolites may undergo enterohepatic circulation (see section 5.2). Co‑administration with neomycin, a poorly absorbed antimicrobial agent used for eradicating the gastrointestinal microflora (which may interfere with the enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure, but there was an approximately 80% decrease in the exposure of the active metabolites M-2 and M-5 which showed in vitro and in vivo comparable pharmacological activity as regorafenib. The clinical significance of this neomycin interaction is unknown, but may result in a decreased efficacy of regorafenib. Pharmacokinetic interactions of other antibiotics have not been studied.

Bile salt-sequestering agents

Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation (see section 5.2). Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with regorafenib by forming insoluble complexes which may impact absorption (or reabsorption), thus resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown, but may result in a decreased efficacy of regorafenib.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must be informed that regorafenib may cause foetal harm.

Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy.

Pregnancy

There are no data on the use of regorafenib in pregnant women.

Based on its mechanism of action regorafenib is suspected to cause foetal harm when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3).

Stivarga should not be used during pregnancy unless clearly necessary and after careful consideration of the benefits for the mother and the risk to the foetus.

Breast-feeding

It is unknown whether regorafenib or its metabolites are excreted in human milk.

In rats, regorafenib or its metabolites are excreted in milk. A risk to the breast-fed child cannot be excluded. Regorafenib could harm infant growth and development (see section 5.3).

Breast-feeding must be discontinued during treatment with Stivarga.

Fertility

There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects of Stivarga on the ability to drive or use machines have been performed. If patients experience symptoms affecting their ability to concentrate and react during treatment with Stivarga, it is recommended that they do not drive or use machines until the effect subsides.

4.8. Undesirable effects

Summary of the safety profile

The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC), 132 patients with gastrointestinal stromal tumours (GIST) and 374 patients with hepatocellular carcinoma (HCC).

The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies.

The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage, gastrointestinal perforation and infection.

The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are pain, hand foot skin reaction, asthenia/fatigue, diarrhoea, decreased appetite and food intake, hypertension and infection.

Tabulated list of adverse reactions

The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by 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) and not known (cannot be estimated from the available data).

Within each frequency group, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions (ADRs) reported in clinical trials and postmarketing in patients treated with Stivarga

System Organ Class

(MedDRA)

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

Infection*

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Keratoacan-thoma/ Squamous cell carcinoma of the skin

Blood and lymphatic system disorders

Thrombocytopenia

Anaemia

Leucopenia

Thrombotic microangiopathy

Immune system disorders

Hypersensitivity reaction

Endocrine disorders

Hypothyroidism

Metabolism and nutrition disorders

Decreased appetite and food intake

Hypokalaemia

Hypophosphatemia

Hypocalcaemia

Hyponatraemia

Hypomagnesaemia

Hyperuricaemia

Dehydration

Nervous system disorders

Headache

Tremor

Peripheral neuropathy

Posterior reversible encephalopathy syndrome (PRES)

Hyperammonaemic encephalopathy

Cardiac disorders

Myocardial infarction

Myocardial ischaemia

Vascular disorders

Haemorrhage*

Hypertension

Hypertensive crisis

Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Dysphonia

Gastrointestinal disorders

Diarrhoea

Stomatitis

Vomiting

Nausea

Constipation

Taste disorders

Dry mouth

Gastrooesophageal reflux

Gastroenteritis

Gastrointestinal perforation*

Gastrointestinal fistula

Pancreatitis

Hepatobiliary disorders

Hyperbilirubinaemia

Increase in transaminases

Severe liver injury (including hepatic failure)*#

Skin and subcutaneous tissue disorders

Hand‑foot skin reaction**

Rash

Alopecia

Dry skin

Exfoliative rash

Nail disorder

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Muscle spasms

Renal and urinary disorders

Proteinuria

General disorders and administration site conditions

Asthenia/ fatigue

Pain***

Fever

Mucosal inflammation

Investigations

Weight loss

Increase in amylase

Increase in lipase

Abnormal International normalised ratio

* fatal cases have been reported

** palmar‑plantar erythrodysesthesia syndrome in MedDRA terminology

***Most frequently reported types of pain (≥10%) are abdominal pain and back pain

# according to drug‑induced liver injury (DILI) criteria of the international DILI expert working group

Description of selected adverse reactions

In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga, compared with non-Japanese patients (<0.1%).

In the placebo-controlled phase III trials, the overall incidence of haemorrhage was 18.2% in patients treated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably epistaxis (6.1%). Fatal outcome in patients treated with Stivarga was uncommon (0.7%), and included cerebral, respiratory, gastrointestinal and genitourinary events.

In the placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga, compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 23.0%), and included urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) as well as pneumonia (2.6%). Fatal outcomes associated with infection were observed more often in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), and were mainly respiratory events.

In the placebo‑controlled phase III trials, the overall incidence of hand‑foot skin reaction was higher in patients treated with Stivarga, compared to patients receiving placebo (all grades: 51.4% vs. 6.5% CRC, 66.7% vs. 15.2% GIST and 51.6% vs.7.3% HCC). Most cases of hand-foot skin reaction in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 34.3%%, CRC, 44.7%, GIST and 39.3%, HCC). The incidence of Grade 3 hand-foot skin reaction was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). The overall incidence of hand-foot skin reaction (74.8%, CRC, 88.2%, GIST and 67.1%, HCC) was higher in Stivarga-treated Asian patients, compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 20.5% (CRC), 23.5% (GIST) and 13.5% (HCC) (see sections 4.2 and 4.4).

In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Stivarga, compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 20.9%, CRC, 31.8%, GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 8.7% (CRC), 28.0% (GIST) and 15.2% (HCC). One case of Grade 4 hypertension was reported in the GIST trial.

In the placebo-controlled phase III trials, the overall incidence of treatment emergent proteinuria was 9.1% in patients treated with Stivarga, compared to 1.9% in patients receiving placebo. Of these events, 35.6% in the Stivarga arm and 54.5% in the placebo arm have been reported as not recovered/not resolved.

Across all clinical trials, cardiac disorder events (all grades) have been more often (13.7% vs. 6.5%) reported in Stivarga-treated patients aged 75 years or older (N=410), compared to Stivarga-treated patients below 75 years (N=4108).

Laboratory test abnormalities

Treatment‑emergent laboratory abnormalities observed in the placebo‑controlled phase III trials are shown in Table 4 and Table 4a (see also section 4.4).

Table 4: Treatment‑emergent laboratory test abnormalities reported in placebo‑controlled phase III trials in patients with metastatic CRC (CORRECT), GIST (GRID) and HCC (RESORCE)

mCRC (CORRECT)

GIST (GRID)

HCC (RESORCE)

Laboratory Parameter

(in % of samples investigated)

Stivarga plus BSC

(n= 500)

Placebo plus BSC

(n=253)

Stivarga plus BSC

(n= 500)

Placebo plus BSC

(n=253)

Stivarga plus BSC

(n= 132)

Placebo plus BSC

(n= 66)

Stivarga plus BSC

(n=132)

Placebo plus BSC

(n= 66)

Stivarga plus BSC

(n= 374)

Placebo plus BSC

(n=193)

Stivarga plus BSC

(n= 374)

Placebo plus BSC

(n=193)

Grade a

Grade b

Grade b

All Grades %

Grade 3/4 %

All Grades %

Grade 3/4 %

All Grades %

Grade 3/4 %

Blood and lymphatic system disorders

Haemoglobin decreased

Thrombocytopenia

Neutropenia

Lymphopenia

78.5

40.5

2.8

54.1

66.3

16.8

0

34.8

5.3

2.8

0.6

9.3

2.8

0.4

0

4.0

75.0

12.9

15.9

29.9

72.7

1.5

12.1

24.2

3.0

0.8

3.1

7.6

1.5

1.5

3.0

3.0

72.5

63.1

13.6

67.8

71.3

50.0

14.9

58.5

6.0

5.4

3.0

17.4

4.8

0

1.0

11.7

Metabolism and nutrition disorders

Hypocalcaemia

Hypokalemia

Hypophosphatemia

59.3

25.7

57.4

18.3

8.3

11.1

1.2

4.3

31.1

1.2

0.4

3.6

16.7

20.5

54.5

4.5

3.0

3.1

1.5

3.0

21.2

0

0

1.5

23.4

30.7

70.4

10.1

9.0

31.4

0.3

4.3

33.9

0

2.1

6.9

Hepatobiliary disorders

Hyperbilirubinemia

Increased AST

Increased ALT

44.6

65.0

45.2

17.1

45.6

29.8

12.2

5.9

5.5

8.4

5.2

3.2

33.3

58.3

39.4

12.1

47.0

39.4

3.8

3.8

4.6

1.5

3.0

1.5

78.2

92.7

70.4

54.5

84.3

58.6

15.9

17.8

6.2

15.7

19.9

4.7

Renal and urinary disorders

Proteinuria

83.6

61.0

1.8

0.8

59.2

52.5

3.1

3.4

51.0

36.5

16.7

3.1

Investigations

Increased INR*

Increased Lipase

Increased Amylase

23.7

46.0

25.5

16.6

18.7

16.7

4.2

11.4

2.6

1.6

4.4

2.4

9.3

14.4

-

12.5

4.6

-

1.6

0.8

-

4.7

0

-

44.4

40.5

23.0

35.4

27.0

19.0

0.7

14.2

2.8

2.1

8.7

2.7

a Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0

b Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

* International normalized ratio

BSC = Best Supportive Care

Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients enrolled.

Table 4a: Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR)

Laboratory parameter, (in % of samples investigated)

Stivarga plus BSC§

(N=136)

Placebo plus BSC§

(N=68)

All Grades*

Grade 3*

Grade 4*

All Grades*

Grade 3*

Grade 4*

Bilirubin increased

66.7

7.4

4.4

32.8

4.5

0.0

AST increased

69.6

10.4

0.7

47.8

3.0

0.0

ALT increased

54.1

8.9

0.0

29.9

1.5

0.0

§ Best Supportive Care

* Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

In the placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 34.6% of patients treated with Stivarga and in 17.2% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.5% of patients treated with Stivarga and in 1.3% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 29.2% of patients treated with Stivarga and in 20.4% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.1% of patients treated with Stivarga and 5.6% of patients receiving placebo. Overall approximately 4.6% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacement treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue.

There is no specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga should be discontinued immediately, with best supportive care initiated by a medical professional, and the patient should be observed until clinical stabilisation.