Regorafenib

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.

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.

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 C_max.

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.

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.

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.

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

For recommended measures and dose modifications in case of worsening of liver function tests considered related to treatment with regorafenib see the following table.

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

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.

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.

There are no data on the effect of regorafenib on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility.

Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation. Bile salts-equestering agents such as cholestyramine and colesevelam 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.

The concentration-time profile indicates that regorafenib and its metabolites may undergo enterohepatic circulation. 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.

Regorafenib has been associated with an increased incidence of haemorrhagic events, some of which were fatal. 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 regorafenib. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of regorafenib should be considered.

Regorafenib has been associated with an increased incidence of arterial hypertension. Blood pressure should be controlled prior to initiation of treatment with regorafenib. 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. In case of hypertensive crisis, regorafenib should be discontinued.

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

Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash represent the most frequently observed dermatological adverse reactions with regorafenib. In clinical trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with regorafenib, compared with Caucasians. 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 regorafenib, or in severe or persistent cases, permanent discontinuation of regorafenib should be considered.

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

Recommended dose modifications and measures for HFSR:

Regorafenib has been associated with an increased incidence of infection events, some of which were fatal. In cases of worsening infection events, interruption of regorafenib treatment should be considered.

Regorafenib has been associated with an increased incidence of myocardial ischaemia and infarction. Patients with unstable angina or new onset angina (within 3 months of starting regorafenib therapy), recent myocardial infarction (within 6 months of starting regorafenib 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 regorafenib is recommended until resolution. The decision to re-start regorafenib therapy should be based on careful consideration of the potential benefits and risks of the individual patient. Regorafenib should be permanently discontinued if there is no resolution.

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

Posterior reversible encephalopathy syndrome (PRES) has been reported in association with regorafenib treatment. 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 regorafenib, along with control of hypertension and supportive medical management of other symptoms is recommended.

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

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. Regorafenib 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.

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. Breast-feeding must be discontinued during treatment with regorafenib.

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.

Fertility

There are no data on the effect of regorafenib on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility.

No studies on the effects of regorafenib 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 regorafenib, it is recommended that they do not drive or use machines until the effect subsides.

Summary of the safety profile

The overall safety profile of regorafenib 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 regorafenib are severe liver injury, haemorrhage, gastrointestinal perforation and infection.

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

List of adverse reactions

The adverse drug reactions reported in clinical trials in patients treated with regorafenib are shown below. 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.

Infections and infestations

Very common: Infection*

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

Rare: Keratoacanthoma/Squamous cell carcinoma of the skin

Blood and lymphatic system disorders

Very common: Thrombocytopenia, Anaemia

Common: Leucopenia

Immune system disorders

Uncommon: Hypersensitivity reaction

Endocrine disorders

Common: Hypothyroidism

Metabolism and nutrition disorders

Very common: Decreased appetite and food intake

Common: Hypokalaemia, Hypophosphatemia, Hypocalcaemia, Hyponatraemia, Hypomagnesaemia, Hyperuricaemia, Dehydration

Nervous system disorders

Common: Headache, Tremor, Peripheral neuropathy

Rare: Posterior reversible encephalopathy syndrome (PRES)

Cardiac disorders

Uncommon: Myocardial infarction, Myocardial ischaemia

Vascular disorders

Very common: Haemorrhage*, Hypertension

Uncommon: Hypertensive crisis

Not known: Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Very common: Dysphonia

Gastrointestinal disorders

Very common: Diarrhoea, Stomatitis, Vomiting, Nausea

Common: Taste disorders, Dry mouth, Gastrooesophageal reflux, Gastroenteritis

Uncommon: Gastrointestinal perforation*, Gastrointestinal fistula, Pancreatitis

Hepatobiliary disorders

Very common: Hyperbilirubinaemia, Increase in transaminases

Uncommon: Severe liver injury*#

Skin and subcutaneous tissue disorders

Very common: Hand-foot skin reaction**, Rash

Common: Alopecia, Dry skin, Exfoliative rash

Uncommon: Nail disorder, Erythema multiforme

Rare: Stevens-Johnson syndrome, Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Common: Muscle spasms

Renal and urinary disorders

Common: Proteinuria

General disorders and administration site conditions

Very common: Asthenia/fatigue, Pain, Fever, Mucosal inflammation

Investigations

Very common: Weight loss

Common: Increase in amylase, Increase in lipase, Abnormal International normalised ratio

* fatal cases have been reported
** palmar-plantar erythrodysesthesia syndrome in MedDRA terminology
# 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 regorafenib, compared with nonJapanese patients (<0.1%).

In the placebo-controlled phase III trials, the overall incidence of haemorrhage was 18.2% in patients treated with regorafenib and 9.5% in patients receiving placebo. Most cases of bleeding events in patients treated with regorafenib were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably epistaxis (6.1%). Fatal outcome in patients treated with regorafenib 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 regorafenib, compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in patients treated with regorafenib 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 13 often in patients treated with regorafenib (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 regorafenib, 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 regorafenib 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 regorafenib-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).

In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with regorafenib, 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 regorafenib 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 regorafenib, compared to 1.9% in patients receiving placebo. Of these events, 35.6% in the regorafenib 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 regorafenib-treated patients aged 75 years or older (N=410), compared to regorafenib-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 1 and Table 1a.

Table 1. Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trials in patients with metastatic CRC (CORRECT), GIST (GRID) and HCC (RESORCE):

^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 regorafenib-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (>90%) East Asian patients enrolled.

Table 1a. Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR):

^§ 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 regorafenib and in 17.2% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.5% of patients treated with regorafenib 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 regorafenib 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 regorafenib and 5.6% of patients receiving placebo. Overall approximately 4.6% of patients treated with regorafenib developed hypothyroidism requiring hormonal replacement treatment.