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SORAfenib
Sorafenib is a multikinase enzyme inhibitor that decreases cell proliferation in vitro. Sorafenib blocks Raf kinase and inhibits tumour angiogenesis by blocking activation of involved receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR 1, 2 and 3), platelet-derived growth factor receptor-beta (PDGFRβ), FLT3, c-KIT and RET.
Oral absorption: Yes
Peak plasma levels are reached approximately 3 hours after an oral dose. Pharmacokinetics are less than dose proportional at doses > 400 mg BID. Daily dosing results in a 2.5-to 7-fold accumulation at steady state, which is reached within 7 days. Age, gender, or body weight does not appear to affect sorafenib pharmacokinetics.
| Bioavailability | 38-49%; ↓ by 29% with high fat meal. Exposure is 70% higher in DTC compared to RCC or HCC patients (clinical relevance not clear). |
Sorafenib is extensively plasma protein bound.
| Cross blood brain barrier? | No information found (unlikely) |
| PPB | 99.5% |
Sorafenib is metabolized primarily in the liver by CYP3A4 and is glucuronidated by UGT1A9.
| Active metabolites | Pyridine N-oxide |
| Inactive metabolites | yes |
Sorafenib is eliminated predominantly by fecal excretion (77% of dose within 14 days, 51% unchanged).
| Urine | 19% of dose within 14 days, as metabolites |
| Half-life | 25 - 48 hours |
• Treatment of locally advanced/metastatic clear cell renal cell carcinoma (RCC) in patients who have failed or are intolerant of prior systemic therapy
• Treatment of patients with unresectable hepatocellular carcinoma (HCC)
• Treatment of patients with locally advanced or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine
Notes:
Health Canada approval for low or intermediate risk (MSKCC) clear cell renal cell cancer was based on an increase in progression-free survival, while approval for hepatocellular carcinoma (HCC) was based on overall survival. For hepatocellular carcinoma, the pivotal trial included mainly patients with Child-Pugh A; data from other studies suggest that Child-Pugh B patients have significantly poorer outcomes and the benefit of sorafenib in these patients is as yet to be defined. Approval for differentiated thyroid carcinoma (DTC) was based on improvements in progression-free survival; an overall survival benefit was not established.
Other Uses:
- Acute myeloid leukemia (for FLT3-ITD positive patients only)
Emetogenic Potential:
Extravasation Potential: Not applicable
The following table contains adverse effects reported mainly in monotherapy in patients with RCC, where the incidence was greater in the treatment arm than in the placebo arm.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (rare) | E | |||
| Arterial thromboembolism (3%) | E | ||||
| Artery aneurysm (rare) | E D L | ||||
| Artery dissection (rare) | E D L | ||||
| Cardiotoxicity (2%) | E D | ||||
| Hypertension (17%) (may be severe) | E | ||||
| QT interval prolonged (rare) | E | ||||
| Venous thromboembolism (rare) | E | ||||
| Dermatological | Alopecia (27%) | E | |||
| Hand-foot syndrome (30%) | E | ||||
| Radiation recall reaction (rare) | E | ||||
| Rash (40%) (may be severe) | E | ||||
| Gastrointestinal | Abdominal pain (11%) | E | |||
| Anorexia, weight loss (16%) | E | ||||
| Constipation (15%) | E | ||||
| Diarrhea (43%) | E | ||||
| Dyspepsia (<10%) | E | ||||
| Dysphagia (<10%) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (11%) | E | ||||
| Nausea, vomiting (24%) | E | ||||
| General | Fatigue (37%) | E | |||
| Hematological | Hemorrhage (15%) (including GI, respiratory, CNS) | E | |||
| INR / prothrombin time increased (5%) (grade 3) | E | ||||
| Myelosuppression ± infection, bleeding (44%) (2% severe) | E | ||||
| Hepatobiliary | ↓ albumin (27%) | E | |||
| ↑ Amylase / lipase (41%) (grade 3/4: 12%) | E | ||||
| Cholecystitis (<10%) | E | ||||
| Hepatitis (drug induced; rare) | E | ||||
| ↑ LFTs (30%) (may be severe) | E | ||||
| Pancreatitis (<1%) | E | ||||
| Hypersensitivity | Hypersensitivity (<1%) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (45%) ↓ PO4 , ↓ Na, ↓ Ca, ↑/↓K (severe up to 13%) | E | |||
| Hyperthyroidism (rare) | E | ||||
| Hypothyroidism (<10%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (10%) | E | |||
| Osteonecrosis of jaw (rare) | E | ||||
| Rhabdomyolysis (rare) | E | ||||
| Neoplastic | Secondary malignancy (5%) (keratoacanthoma/squamous cell carcinoma of the skin in DTC patients) | D | |||
| Nervous System | Depression (<10%) | E | |||
| Headache (10%) | E | ||||
| Posterior reversible encephalopathy syndrome (PRES) (reversible posterior encephalopathy; rare) | E | ||||
| Sensory neuropathy (13%) | E | ||||
| Renal | Proteinuria (<10%) | E | |||
| Renal failure (rare) | E | ||||
| Respiratory | Cough, dyspnea (14%) | E | |||
| Dysphonia (9%) | E | ||||
| Pleural effusion (4%) | E | ||||
| Pneumonitis (rare) | E | ||||
| Vascular | Vasculitis (rare) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most frequently reported drug-related adverse events in clinical trials were: rash/desquamation, diarrhea, hand-foot skin reaction, fatigue, hypertension, alopecia, weight loss, nausea, abdominal pain, anorexia, infection and hemorrhage.
Most adverse reactions were reported more frequently in the DTC population and more likely to be dose-limiting.
Hypertension was usually mild-moderate, generally occurred early in the course of treatment and amenable to standard antihypertensive therapy. (For suggested treatment algorithm, see Appendix 8: Management of Angiogenesis Inhibitor (AI) Induced Hypertension).
Severe cases of artery dissection (with or without hypertension) and artery aneurysm (including rupture) have been reported in patients using VEGFR TKIs.
Management of hand-foot syndrome and rash/desquamation (typically occurring within the first 12 weeks of therapy) may include topical treatment for symptomatic relief and temporary interruption and/or sorafenib dose modification. In severe or persistent cases, permanent discontinuation of sorafenib may be necessary. Severe rashes including SJS, TEN and leucocytoclastic vasculitis have been described.
Elevated lipase and amylase levels, typically transient, were commonly reported. Clinical pancreatitis has been reported.
Drug-induced hepatitis has been reported rarely. Typical onset is 10-90 days following treatment initiation and is generally reversible, but may result in fatal liver failure.
Hemorrhage, including all sites, occurred in 15% of patients compared to 8% in placebo patients. Permanent discontinuation of sorafenib should be considered if any bleeding event necessitates medical intervention.
Sensory neuropathy events were usually mild to moderate and tended to occur in the first few cycles of treatment.
Gastrointestinal perforation is uncommon, but may occur in the absence of an intra-abdominal tumour.
Cardiac ischemia and infarction (ATE) occurred at a higher frequency than in the placebo arms; patients with unstable angina or recent infarction (within 6 months) were excluded from the clinical trials.
Osteonecrosis of the jaw has been reported rarely. Avoid invasive dentistry during treatment, especially in patients with prior bisphosphonate exposure.
Changes in thyroid function have been observed, with hypothyroidism observed more commonly.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Patients with DTC should have esophageal and upper airway infiltration controlled with local measures prior to starting treatment to reduce the risk of bleeding.
Dose levels:
|
Dose level
|
Sorafenib dose
|
|
0
|
800mg daily dose (400mg bid)
|
|
-1
|
600mg daily dose (400mg and 200mg, 12 hours apart)
|
|
-2
|
400mg daily dose (200mg bid)
|
|
-3
|
200mg daily dose (200mg od)
|
Dosage with toxicity for HCC and RCC populations:
|
Toxicity grade
|
Occurrence
|
Dose modification
|
|
Grade 1 skin
|
Any
|
Continue treatment with sorafenib and consider topical/supportive therapy for symptomatic relief.
|
|
Grade 2 skin
|
1st
|
Continue treatment, supportive care. Consider ↓ 2 dose levels for 28 days; if does not improve hold for at least 7 days until ≤ grade 1 and restart at 400mg daily. If ≤ grade 1 x 28 days, consider re-escalating to full dose.
|
|
|
2nd or 3rd
|
As for 1st occurrence, but do no re-escalate if hold required.
|
|
|
4th
|
Consider discontinuing sorafenib.
|
|
Grade 3 skin
|
1st
|
Supportive care and hold at least 7 days until ≤ grade 1, restart by ↓ 2 dose levels; if ≤ grade 1 x 28 days, consider re-escalating to full dose.
|
|
|
2nd
|
As for 1st occurrence, but do not re-escalate.
|
|
|
3rd
|
Consider discontinuing sorafenib.
|
|
Grade 3 non-hematological/related organ
|
1st
|
Hold until recovery to ≤ grade 2; ↓ 2 dose levels
|
|
|
2nd
|
Discontinue
|
|
Cardiac ischemia and/or infarction
|
Any
|
Hold; consider discontinuing
|
|
↑LFTs
|
Any
|
Hold if severe and rule out other causes. Discontinue if drug-induced hepatitis.
|
|
GI perforation, severe hypertension despite treatment, cardiac failure, ≥ grade 3 bleeding, pneumonitis, SJS or TEN, Grade 4 non-hematological/related organ
|
Any
|
Discontinue
|
Dosage with toxicity for DTC population:
|
Toxicity Grade
|
Occurrence
|
Dose Modification*
|
|
|
Grade 1 Skin
|
Any
|
Continue treatment with sorafenib and consider topical / supportive therapy for symptomatic relief.
|
|
|
Grade 2 Skin
|
1st
|
Continue treatment, supportive care. Consider ↓1 dose level. If no improvement within 7 days, hold until ≤ grade 1, then ↓ 1 dose level.
|
|
|
|
2nd
|
hold until resolved to ≤ grade 1. Resume by ↓ 1 dose level.
|
|
|
|
3rd
|
Hold until resolved to ≤ grade 1. Resume by↓ 2 dose levels.
|
|
|
|
4th
|
Discontinue
|
|
|
Grade 3 skin
|
1st
|
Hold until resolved to ≤ grade 1. Resume by ↓ 1 dose level
|
|
|
|
2nd
|
Hold until resolved to ≤ grade 1. Resume by ↓ 2 dose levels.
|
|
|
|
3rd
|
Discontinue
|
|
|
Grade 3 non
hematological/organ
|
1st
|
Hold until recovery to ≤ grade 2, Resume by ↓ 2 dose levels.
|
|
|
|
2nd
|
Discontinue
|
|
|
Cardiac ischemia and/or infarction;
|
Any
|
Hold. Consider discontinuing.
|
|
|
↑ LFTs
|
Any
|
Hold if severe and rule out other causes. Discontinue if drug-induced hepatitis.
|
|
|
GI perforation;
Severe hypertension despite treatment; Cardiac failure; ≥grade 3 bleeding; Pneumonitis; SJS or TEN; Grade 4 non- hematological/organ |
Any
|
Discontinue
|
|
|
*For patients who require a dose reduction for Grade 2 or 3 skin toxicity, dose may be increased if improved to ≤ grade 1 after 28 days of treatment at reduced dose.
|
|||
Patients with hepatocellular carcinoma (HCC) and Child-Pugh B hepatic impairment have greater systemic exposure than Child-Pugh A patients, although this difference is not seen in non-HCC patients. Exercise caution and monitor closely when treating Child-Pugh B patients with sorafenib, due to the heterogenous nature of this population. Sorafenib has not been studied in patients with Child Pugh C hepatic impairment.
(Continued on next page)
Miller 2009 suggested the following dose modifications in patients with HCC:
|
Child-Pugh |
|
Bilirubin |
Albumin |
Dose |
|
A |
AND |
≤ 1.5 x ULN |
|
400mg bid |
|
B |
AND/OR |
> 1.5 - 3 x ULN |
|
200mg bid |
|
C |
AND/OR |
> 3 x ULN |
|
Do not treat – severe toxicity likely |
|
|
|
|
≤ 25 |
200mg daily |
|
Creatinine clearance |
Dose |
|
> 40 mL/min |
400mg BID |
|
20-40 mL/min |
200mg BID |
|
< 20mL/min |
No information; avoid or use with extreme caution |
Dosage adjustment is not necessary in elderly patients.
Safety and effectiveness in children have not been established.
- Oral self-administration; drug available by outpatient prescription.
- Prescribed dose should be administered orally on an empty stomach, or with a low-fat or moderate-fat meal with a large glass of water
- Store at room temperature (15-30°C)
- Patients who have a hypersensitivity to this drug or any of its components
- Concomitant warfarin or antiplatelet agents should be used cautiously
- Temporary hold is recommended for patients undergoing major surgery
- Hypokalemia, hypomagnesemia and hypocalcemia should be corrected before treatment
- Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with localized therapy before starting sorafenib in DTC patients.
- Sorafenib may impair exogenous thyroid suppression in DTC patients.
- Sorafenib should be administered with caution in patients who have bradycardia or with increased risk of developing prolongation of the QT interval/torsades de pointes (i.e. hypokalemia or hypomagnesemia, congenital long QT syndrome, history of cardiac disease or arrhythmias, concomitant anti-arrhythmic or other medications that may prolong QT interval). Patients with unstable coronary artery disease or recent MI (within 6 months) were excluded from clinical trials.
-
Teratogenicity:
Yes
Sorafenib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 2 weeks after the last dose. -
Excretion into breast milk:
Probable
Breastfeeding is not recommended. -
Fertility effects:
Yes
Sorafenib impairs male and female fertility.
Sorafenib does not inhibit or induce CYP 3A4, 2D6 or 2C19, but does inhibit CYP2B6 and 2C8 and is a substrate for CYP3A4.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP2B6 substrates (cyclophosphamide, ifosfamide, methadone, bupropion etc.) and CYP2C8 substrates (paclitaxel etc.) | May ↑ concentration of substrates | Sorafenib inhibits CYP2B6 and CYP2C8 | Caution |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | May ↓ Sorafenib concentrations | ↑ metabolism | Caution; Avoid concurrent use of a strong CYP3A4 inducer |
| Doxorubicin | ↑ doxorubicin AUC (21%) | Unknown | Caution. Monitor for symptoms of doxorubicin toxicity. |
| Drugs metabolised by UGT1A1 and UGT1A9 (irinotecan etc.) | ↑ exposure of substrates (irinotecan and SN-38 AUC ↑ 120%) | Inhibition of UGT1A1 pathway-mediated irinotecan and SN-38 metabolism | Caution. Monitor for irinotecan toxicity. |
| docetaxel | ↑ docetaxel AUC (80%) | Unknown | Use with Caution. |
| neomycin | ↓ sorafenib (54%) bioavailability | Neomycin interferes with enterohepatic recycling of sorafenib | Avoid concomitant use |
| warfarin | ↑ INR reported, Bleeding | Possible additive effect; low risk suggested for clinically relevant CYP2C9 inhibition by sorafenib | Regular monitoring of INR and bleeding |
| Drugs that may prolong QT (i.e. Amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑QT/QTc prolonging effect | Additive | Avoid concomitant use |
| capecitabine | ↑ capecitabine exposure (50%) | Unknown | Caution |
| Paclitaxel/Carboplatin combination | ↑ sorafenib and paclitaxel exposure | Unknown | Avoid concomitant use |
| UGT1A9 inhibitors (eg. erlotinib, mefanamic acid, ketoconazole, atorvastatin) | ↑ sorafenib concentrations (theoretical) | Inhibits UGT1A9 mediated sorafenib glucuronidation | Caution |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | May ↑ sorafenib concentrations (theoretical) (Exposure not altered with ketoconazole and single sorafenib 50mg dose) | ↓ metabolism | Caution |
| Exogenous thyroid suppression (e.g. levothyroxine) in DTC patients | impaired thyroid suppression | sorafenib inhibition | Caution; monitor TSH |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
| Blood pressure | Weekly for first 6 weeks of treatment, then periodically thereafter |
| INR, for patients on warfarin | regular, especially at initiation, or discontinuation or change of dose. |
CBC |
Baseline and at each visit |
| Liver function tests, amylase and lipase | Baseline and regular |
| ECG during therapy (to monitor QT) | Baseline and periodic |
| Electrolytes, including phosphate and calcium | Baseline and regular |
| In patients with DTC, close monitoring of blood calcium and TSH levels | Baseline, monthly and as clinically indicated |
| Thyroid function tests | Baseline and regular |
Clinical toxicity ratings (bleeding, hypertension, skin changes, diarrhea, pancreatitis, congestive heart failure, hepatitis, secondary malignancies) |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| LVEF, especially in patients with cardiac risk factors | Baseline and periodic |
| Dental evaluation before starting treatment with preventative dentistry as needed |
Exceptional Access Program (EAP Website)
- SORAfenib - Metastatic renal cell carcinoma of clear cell histology as second-line treatment, with specific criteria
- SORAfenib - Advanced hepatocellular carcinoma, with specific criteria
Cheng AL, Kang YK, Chen ZD, et al. Efficacy and safety of sorafenib in patients in the Asia-pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncology 2009;10:25-34.
Escudier B, Eisen T, Stadler WM, et al. Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma. N Engl J Med 2007;356:125-34.
Hollebecque A, Cattan S, Romano O, et al. Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Ther 2011;34(10):1193-201.
Lencioni R, Kudo M, Ye SL, et al. First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafenib) non-interventional study. Int J Clin Pract 2012;66(7):675-83.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced heptatocellular carcinoma. NEJM 2008:359;378-90.
Miller AA, Murry DJ, Owzar K et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009;27(11):1800-5.
Pinter M, Sieghart W, Graziadel I, et al. Sorafenib in Unresectable Hepatocellular Carcinoma from Mild to Advanced Stage Liver Cirrhosis. Oncologist 2009;14(1):70-6.
Prescribing Information: Nexavar® (sorafenib). Bayer Healthcare Pharmaceuticals Inc. (US), December 2012.
Pressiani T, Boni C, Rimassa L, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol 2013;24(2):406-11.
Product Monograph: Nexavar® (Sorafenib). Bayer Inc., December 17, 2014.
Product Monograph Update: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). Health Canada InfoWatch, June 2020.
Sorafenib and osteonecrosis of the jaw. Canadian Adverse Drug Reaction Newsletter, volume 24, no. 4, October 2014. [Accessed: October 30, 2014]. Available from: http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v24n4-eng.php#article3
Wörns MA, Weinmann A, Pfingst K, et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol 2009;43(5):489-95.
Zhu AX, Clark JW. Commentary: Sorafenib Use in Patients with Advanced Hepatocellular Carcinoma and Underlying Child-Pugh B Cirrhosis—Evidence and Controversy. Oncologist 2009;14(1):67-9.
July 2023 added general statement on hepatitis B testing
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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