Each film-coated tablet contains:

Sorafenib Tosylate IP

1. to Sorafenib ………………200 mg

Excipients ……………………..q.s.

Colour: Yellow Oxide of Iron.

Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib inhibited tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis was seen in some human tumor xenograft models in immune-compromised mice. Sorafenib was shown to interact with multiple intracellular (CRAF, BRAF, and mutant BRAF) and cell surface kinases (KIT, FLT- 3, VEGFR- 2, VEGFR- 3, and PDGFR- ß), many of which are thought to be involved in angiogenesis

Bioavailability and half-life

After administration of Sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25 to 48 hours. Multiple dosing of Sorafenib for 7 days resulted in a 2.5- to 7-fold accumulation compared to single dose administration. Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.

Absorption and Distribution

Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal, bioavailability was similar to that in the fasted state. With a high-fat meal, sorafenib bioavailability was reduced by 29% compared to administration in the fasted state. It is recommended that Sorafenib be administered without food (at least 1 hour before or 2 hours after eating).

Metabolism and Elimination

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady state. Of the eight metabolites of Sorafenib identified so far, five have been detected in plasma. Pyridine Noxide, the main circulating metabolite of sorafenib present in plasma- has been shown to possess in vitro potency similar to that of sorafenib. It accounts for approximately 9-16% of circulating analytes at steady-state concentration. Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days. While 77% of this dose was excreted in feces and 19% in urine, essentially as glucuronidated metabolites. Feces accounted for 51% of the unchanged sorafenib dose while no unchanged drug was found in urine.

Special Populations

Pediatric

There are no pharmacokinetic data reported in pediatric patients.

Hepatic Impairment

Sorafenib is cleared primarily by the liver. In patients with mild (Child-Pugh A, n=14) or moderate (Child-Pugh B, n=8) hepatic impairment, exposure values were within the range observed in patients without hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment (See PRECAUTIONS – Patients with Hepatic Impairment section).

Renal Impairment

In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine. In four Phase 1 clinical trials, sorafenib was evaluated in patients with normal renal function (n=71) and in patients with mild renal impairment (CrCl >50–80 mL/min, n=24) or moderate renal impairment (CrCl 30–50 mL/min, n=4). No relationship was observed between renal function and steady-state sorafenib AUC at doses of 400 mg twice daily. The pharmacokinetics of sorafenib have not been studied in patients with severe renal impairment (CrCl <30 ml/min) or in patients undergoing dialysis (see PRECAUTIONS – Patients with Renal Impairment section).

CLINICAL EFFICACY

The safety and efficacy of Sorafenib in the treatment of advanced renal cell carcinoma (RCC) was studied in a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk category1 (low or intermediate) and country and randomized to Sorafenib 400 mg twice daily (N=384) or to placebo (N=385). The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the Sorafenib and placebo groups, respectively. The effect of Sorafenib on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (n=137; 65 patients receiving Sorafenib and 72 placebo), for whom the median PFS was 172 days on Sorafenib compared to 85 days on placebo. Overall, of 672 patients who were evaluable for response, 7 (2%) Sorafenib patients and 0 (0%) placebo patients had a confirmed partial response. Thus, the gain in PFS in Sorafenib-treated patients primarily reflects the stable disease population.

Sorafenib is indicated for the treatment of

• Hepatocellular carcinoma
• Advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy
• Progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.

• The recommended dose of Sorafenib in adults is 400 mg sorafenib (two tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg) given at least 1 hour before or 2 hours after food.
• Treatment is continued until no clinical benefit is seen or until unacceptable toxicity occurs.
• Doses are reduced to 400mg once daily if toxicity occurs; further reduction to a single dose of 400mg every other day may be necessary.

Dose adjustments

• Management of suspected adverse drug reactions may require temporary interruption or dose reduction of sorafenib therapy.
• When dose reduction is necessary during the treatment of hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC), Sorafenib dose should be reduced to two tablets of 200 mg sorafenib once daily (see Special Warnings and Precautions).
• When dose reduction is necessary during the treatment of differentiated thyroid carcinoma (DTC), Sorafenib dose should be reduced to 600 mg sorafenib daily in divided doses (two tablets of 200 mg and one tablet of 200 mg twelve hours apart).
• If additional dose reduction is necessary, Sorafenib may be reduced to 400 mg sorafenib daily in divided doses (two tablets of 200 mg twelve hours apart), and if necessary, further reduced to one tablet of 200 mg once daily. After the improvement of non-hematological adverse reactions, the dose of Sorafenib may be increased.

Pediatric population

The safety and efficacy of Sorafenib in children and adolescents aged < 18 years have not yet been established. No data are available.

Elderly population

No dose adjustment is required in the elderly (patients above 65 years of age).

Renal impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment. No data is available in patients requiring dialysis. The monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

Hepatic impairment

Sorafenib is mainly metabolized in the liver. Hepatic impairment might reduce exposure to Sorafenib. No dose adjustment is required in patients with Child-Pugh A or B (mild to moderate) hepatic impairment. No data is available on patients with Child-Pugh C (severe) hepatic impairment.

However, a study involving patients with varying degrees of hepatic impairment recommended the following empirical starting doses of oral sorafenib, based on tolerability and the development of dose-limiting toxicity.

(ULN: Upper Limit of Normal)

Method of administration

For oral use

It is recommended that sorafenib should be administered without food or with a low or moderate fat meal. If the patient intends to have a high-fat meal, sorafenib tablets should be taken at least 1 hour before or 2 hours after the meal. The tablets should be swallowed with a glass of water.

Warning

Pregnancy Category D

There are no data on the use of sorafenib in pregnant women. Studies in animals have shown reproductive toxicity including malformations. In rats, sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on the foetus. Sorafenib should not be used during pregnancy unless clearly necessary, after careful consideration of the needs of the mother and the risk to the foetus.

Women of childbearing potential must use effective contraception during treatment.

Nursing Mothers

It is not known whether sorafenib is secreted in human milk. Following administration of 14C-sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1. Because many drugs are secreted in human milk and because the effects of sorafenib on infants have not been studied, women should be advised against breastfeeding while receiving Sorafenib.

Fertility

Results from animal studies further indicate that sorafenib can impair male and female fertility.

Precautions:

Dermatological toxicities

• Hand foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with sorafenib. Rash and hand foot skin reaction are usually graded as CTC (Common Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib.
• Management of dermatological toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib, or in severe or persistent cases, permanent discontinuation of sorafenib.

Hypertension

• An increased incidence of arterial hypertension was observed in sorafenib-treated patients.
• Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy.
• Blood pressure should be monitored regularly and treated, if required, in accordance with standard medical practice.
• In cases of severe or persistent hypertension, or hypertensive crisis despite institution of antihypertensive therapy, permanent discontinuation of sorafenib should be considered.

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 Sorafenib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Hypoglycaemia

• Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalization due to loss of consciousness, have been reported during sorafenib treatment.
• In case of symptomatic hypoglycaemia, sorafenib should be temporarily interrupted.
• Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic medicinal product’s dosage needs to be adjusted.

Haemorrhage

An increased risk of bleeding may occur following sorafenib administration. If any bleeding event necessitates medical intervention it is recommended that permanent discontinuation of sorafenib should be considered.

Cardiac ischaemia and/or infarction

Temporary or permanent discontinuation of sorafenib should be considered in patients who develop cardiac ischaemia and/or infarction.

QT interval prolongation

Sorafenib has been shown to prolong the QT/QTc interval, which may lead to an increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may develop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia.

When using sorafenib in these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium and calcium) should be considered.

Gastrointestinal perforation

Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients taking sorafenib. In some cases, this was not associated with apparent intra-abdominal tumour. Sorafenib therapy should be discontinued.

Hepatic impairment

• No data is available on patients with Child Pugh C (severe) hepatic impairment. Since sorafenib is mainly eliminated via the hepatic route exposure might be increased in patients with severe hepatic impairment.

Warfarin co-administration

• Infrequent bleeding events or elevations in the International Normalised Ratio (INR) have been reported in some patients taking warfarin while on sorafenib therapy.
• Patients taking concomitant warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes.

Wound healing complications

• No formal studies on the effect of sorafenib on wound healing have been conducted.
• Temporary interruption of sorafenib therapy is recommended for precautionary reasons in patients undergoing major surgical procedures.
• There is limited clinical experience regarding the timing of re-initiation of therapy following major surgical intervention. Therefore, the decision to resume sorafenib therapy following a major surgical intervention should be based on clinical judgement of adequate wound healing.

Elderly population

Cases of renal failure have been reported. Monitoring of renal function should be considered.

• The most important serious adverse reactions were myocardial infarction/ischaemia, gastrointestinal perforation, drug-induced hepatitis, haemorrhage, and hypertension/hypertensive crisis.
• The most common adverse reactions were diarrhoea, fatigue, alopecia, infection, hand-foot skin reaction (corresponds to palmar-plantar erythrodysesthesia syndrome in MedDRA) and rash.

Table 1: All adverse reactions reported in patients in multiple clinical trials or through post-marketing use (Logic in % for these adverse reactions!)

* The adverse reactions may have a life-threatening or fatal outcome. Such events are either uncommon or less frequent than uncommon.

** Hand-foot skin reaction corresponds to palmar-plantar erythrodysesthesia syndrome in MedDRA.

° Cases have been reported in the post-marketing setting.

• Caution is recommended when administering sorafenib with compounds that are metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways.
• Caution is recommended when sorafenib is co-administered with docetaxel.
• Co-administration of neomycin or other antibiotics that cause major ecological disturbances of the gastrointestinal microflora may lead to a decrease in sorafenib bioavailability.
• The risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment course with antibiotics.
• Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated with sorafenib in combination with platinum-based chemotherapies. In two randomised trials investigating patients with Non-Small Cell Lung Cancer in the subgroup of patients with squamous cell carcinoma treated with sorafenib as add-on to paclitaxel/carboplatin, the HR for overall survival was found to be 1.81 (95% CI 1.19; 2.74) and as add-on to gemcitabine/cisplatin 1.22 (95% CI 0.82; 1.80). No single cause of death dominated, but higher incidence of respiratory failure, hemorrhages and infectious adverse events were observed in patients treated with sorafenib as add-on to platinum-based chemotherapies.

There is no specific treatment for sorafenib overdose. The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse events observed at this dose were primarily diarrhoea and dermatological events. In the event of suspected overdose sorafenib should be withheld and supportive care instituted where necessary.

CONTRAINDICATIONS

• Sorafenib is contraindicated in patients with known severe hypersensitivity to sorafenib or any of excipients of the formulation.
• Since increased mortality has been reported when sorafenib was administered in combination with carboplatin/paclitaxel in squamous cell lung cancer, sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.

Store at a temperature not exceeding 30ºC. Protect from light.

Bottle of 30 tablets.

• https://www.medicines.org.uk/emc/product/226/smpc (last updated 09/2019).
• The Complete Drug Reference. 39^th edition. P 875-76.
• https://www.accessdata.fda.gov/
• http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Sorafenib_monograph_1Dec2014.pdf