Sorafenib 200 Drl 200 mg Fim-coated tablets

SORAFENIB 200 DRL film coated tablets are indicated for the:

• Treatment of patients with advanced renal cell carcinoma (RCC)
• Treatment of patients with advanced inoperable hepatocellular carcinoma (HCC)
• Treatment of patients with locally advanced or metastatic differentiated (papillary and follicular- Hu00fcrthle cell) thyroid carcinoma refractory to radioactive iodine.

Posology

Recommended dose: The recommended daily dose of SORAFENIB 200 DRL is 400 mg (or 2 X 200 mg tablets) taken twice a day either without food or together with a low fat or moderate fat meal.

Duration of treatment: Treatment should be continued until the patient is no longer clinically benefitting from therapy or until unacceptable toxicity occurs.

Dose titration, dose adjustment, special monitoring advice: Dose reduction for hepatocellular carcinoma and advanced renal cell carcinoma: Management of suspected adverse reactions may require temporary interruptions and/or dose reduction of SORAFENIB 200 DRL therapy. When dose reduction is necessary during treatment of hepatocellular carcinoma (HCC) and advanced renal carcinoma (RCC), the SORAFENIB 200 DRL dose should be reduced to 400 mg daily.

Suggested dose modifications for skin toxicity with HCC and RCC:

• Grade 1 (mild): Any Institute supportive measures immediately and continue SORAFENIB 200 DRL treatment
• Grade 2 (moderate): First Institute supportive measures immediately and consider a decrease SORAFENIB 200 DRL dose to 400 mg daily for 28 days. If toxicity returns to grade 0 to 1 after dose reduction, increase SORAFENIB 200 DRL to full dose after 28 days. If toxicity does not return to grade 0 to 1 despite dose reduction, interrupt SORAFENIB 200 DRL treatment for a minimum of 7 days, until toxicity has resolved to grade 0 to 1. When resuming treatment after dose interruption, resume SORAFENIB 200 DRL at reduced dose of 400 mg daily for 28 days. If toxicity is maintained at grade 0 to 1 at reduced dose, increase SORAFENIB 200 DRL to full dose after 28 days.
• Second or third: As for first occurrence, but upon resuming SORAFENIB 200 DRL treatment, decrease dose to 400 mg daily indefinitely
• Fourth: Discontinue SORAFENIB 200 DRL treatment

Grade 3 (severe): First Institute supportive measures immediately and interrupt SORAFENIB 200 DRL treatment for a minimum of 7 days and until toxicity has resolved to grade 0 to 1. When resuming treatment after dose interruption, resume SORAFENIB 200 DRL at reduced dose of 400 mg daily for 28 days. If toxicity is maintained at grade 0 to 1 at reduced dose, increase SORAFENIB 200 DRL to full dose after 28 days. Second: As for first occurrence, but upon resuming SORAFENIB 200 DRL treatment, decrease dose to 400 mg daily indefinitely. Third: Discontinue SORAFENIB 200 DRL treatment.

Dose Reduction for Differentiated Thyroid Carcinoma: Management of suspected side-effects may require temporary interruption and/or dose reduction of SORAFENIB 200 DRL therapy. When dose reduction is necessary during the treatment of differentiated thyroid carcinoma, the SORAFENIB 200 DRL dose should be reduced to 600 mg 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 200 DRL may be reduced to one tablet of 200 mg twice daily, followed by one tablet of 200 mg once daily. After improvement of non-haematological adverse reactions, the dose of sorafenib may be increased.

Special populations:

Paediatric patients: The safety and effectiveness of SORAFENIB 200 DRL in paediatric patients has not been established.

Elderly (above 65 years); gender and body weight: No dose adjustment is required on the basis of patient age (above 65 years), gender, or body weight.

Hepatic impairment: No dose adjustment is required in patients with Child-Pugh A or B hepatic impairment. SORAFENIB 200 DRL has not been studied in patients with Child-Pugh C hepatic impairment.

Renal impairment: No dose adjustment is required in patients with mild, moderate or severe renal impairment not requiring dialysis. SORAFENIB 200 DRL has not been studied in patients undergoing dialysis. Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

Method of administration: For oral use. To be swallowed with a glass of water.

• SORAFENIB 200 DRL is contraindicated in patients with known severe hypersensitivity to sorafenib or any of the excipients in section 6.1.
• Pregnancy and lactation (see section 4.6).

Dermatological toxicities: Hand foot skin reaction (palmar - plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with SORAFENIB 200 DRL. Rash and hand-foot skin reaction are usually CTC (National Cancer Institute Common Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with SORAFENIB 200 DRL. Management of dermatological toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of SORAFENIB 200 DRL, or in severe or persistent cases, permanent discontinuation of SORAFENIB 200 DRL (see section 4.8).

Hypertension: An increased incidence of arterial hypertension was observed in SORAFENIB 200 DRL-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 200 DRL should be considered (see section 4.8).

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 200 DRL, 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 as in SORAFENIB 200 DRL treatment. In case of symptomatic hypoglycaemia, SORAFENIB 200 DRL should be temporarily interrupted. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic medicines dosage needs to be adjusted.

Haemorrhage: An increased risk of bleeding may occur following SORAFENIB 200 DRL administration. The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of SORAFENIB 200 DRL should be considered (see section 4.8).

Cardiac ischaemia and/or infarction: In a renal cell carcinoma study, the incidence of treatment-emergent cardiac ischaemia/infarction events was higher in the sorafenib group (4,9 %) compared with the placebo group (0,4 %). In a hepatocellular carcinoma study, the incidence of treatment-emergent cardiac ischaemia/infarction events was 2,7 % in sorafenib patients compared with 1,3 % in the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from these studies. Temporary or permanent discontinuation of SORAFENIB 200 DRL should be considered in patients who develop cardiac ischaemia and/or infarction (see section 4.8).

QT interval prolongation: SORAFENIB 200 DRL has been shown to prolong the QT/QTc interval on the ECG, which may lead to an increased risk for ventricular dysrhythmias. Use SORAFENIB 200 DRL 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-dysrhythmic medicines or other medicines that lead to QT prolongation, and those with electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. When using SORAFENIB 200 DRL in these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) should be considered.

Gastrointestinal perforation: Gastrointestinal perforation is an uncommon event and has been reported in less than 1 % of patients taking sorafenib as in SORAFENIB 200 DRL. In some cases, this was not associated with apparent intra-abdominal tumour. SORAFENIB 200 DRL therapy should be discontinued (see section 4.8).

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 (see section 4.2).

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 (see sections 4.5 and 4.8).

Wound healing complications: No formal studies of the effect of SORAFENIB 200 DRL on wound healing have been conducted. Temporary interruption of SORAFENIB 200 DRL therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SORAFENIB 200 DRL 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.

Medicine - medicine interactions: Caution is recommended when administering SORAFENIB 200 DRL with compounds that are metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways (see section 4.5). Caution is recommended when SORAFENIB 200 DRL is co-administered with docetaxel (see section 4.5). Co-administration of neomycin or other antibiotics that cause major ecological disturbances of the gastrointestinal microflora may lead to a decrease in sorafenib bioavailability (see section 4.5). The risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment course with antibiotics.

SORAFENIB 200 DRL has not been evaluated for use in HCC in combination with docetaxel, paclitaxel and carboplatin.

Inducers of metabolic enzymes: Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted in an average 37 % reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or glucuronidation (e.g. Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations.

CYP3A4 inhibitors: Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.

CYP2B6, CYP2C8 and CYP2C9 substrates: Sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9 in vitro with similar potency. However, in clinical pharmacokinetic studies, concomitant administration of sorafenib 400 mg twice daily with cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in a clinically meaningful inhibition. These data suggest that sorafenib at the recommended dose of 400 mg twice daily may not be an in vivo inhibitor of CYP2B6 or CYP2C8. Additionally, concomitant treatment with sorafenib and warfarin, a CYP2C9 substrate, did not result in changes in mean PT-INR compared to placebo. Thus, also the risk for a clinically relevant in vivo inhibition of CYP2C9 by SORAFENIB 200 DRL maybe expected to be low. However, patients taking warfarin or phenprocoumon should have their INR checked regularly (see section 4.4).

CYP3A4, CYP2D6 and CYP2C19 substrates: Concomitant administration of midazolam, dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did not alter the exposure of these medicines. This indicates that SORAFENIB 200 DRL is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely.

UGT1A1 and UGT1A9 substrates: In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this finding is unknown (see below and section 4.4).

In vitro studies of CYP enzyme induction: CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.

P-gp substrates: In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increased plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant treatment with SORAFENIB 200 DRL.

Combination with other anti-neoplastic medicines: In clinical studies sorafenib has been administered with a variety of other anti-neoplastic medicines at their commonly used dosing regimens including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin or cyclophosphamide.

Paclitaxel/carboplatin: Administration of paclitaxel (225 mg/m2) and carboplatin (AUC = 6) with sorafenib (u2264 400 mg twice daily), administered with a 3-day break in sorafenib dosing (two days prior to and on the day of paclitaxel/carboplatin administration), resulted in no significant effect on the pharmacokinetics of paclitaxel. Co-administration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47 % increase in sorafenib exposure, a 29 % increase in paclitaxel exposure and a 50 % increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected. These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with SORAFENIB 200 DRL with a 3-day break in SORAFENIB 200 DRL dosing (two days prior to and on the day of paclitaxel/carboplatin administration). The clinical significance of the increases in sorafenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.

Capecitabine: Co-administration of capecitabine (750 - 1050 mg/m2 twice daily, Days 1 - 14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15 u2013 50 % increase in capecitabine exposure and a 0 u2013 52 % increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure when co-administered with sorafenib is unknown.

Doxorubicin/Irinotecan: Concomitant treatment with sorafenib resulted in a 21 % increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN - 38 is further metabolised by the UGT1A1 pathway, there was a 67 - 120 % increase in the AUC of SN-38 and a 26 - 42 % increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see section 4.4).

Docetaxel: Docetaxel (75 or 100 mg/m2 administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle with a 3-day break in dosing around administration of docetaxel) resulted in a 36 - 80 % increase in docetaxel AUC and a 16 - 32 % increase in docetaxel C max. Caution is recommended when SORAFENIB 200 DRL is co-administered with docetaxel (see section 4.4).

Omeprazole: Co-administration of omeprazole has no impact on the pharmacokinetics of sorafenib as in SORAFENIB 200 DRL. No dose adjustment for SORAFENIB 200 DRL is necessary.

Combination with other medicines: Neomycin Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal flora, interferes with the enterohepatic recycling of sorafenib (see section 5.2, Metabolism and Elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average exposure to sorafenib decreased by 54 %. The clinical significance of these findings is unknown. Effects of other antibiotics have not been studied, but will likely depend on their ability to interfere with microorganisms with glucuronidase activity.

Women of childbearing potential must be apprised of the potential hazard to the foetus, which includes severe malformation (teratogenicity), failure to thrive and foetal death (embryotoxicity).

Pregnancy: Women should avoid becoming pregnant while on therapy with SORAFENIB 200 DRL. SORAFENIB 200 DRL should not be used during pregnancy. Adequate contraception should be used during therapy and for at least 2 weeks after completion of therapy.

Lactation: Breastfeeding should be discontinued during SORAFENIB 200 DRL therapy. Infants should not be breastfed during treatment with SORAFENIB 200 DRL.

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

The development of peripheral sensory neuropathy may affect the ability to drive or to operate machinery.

The most important serious adverse reactions reported 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 erythrodysaesthesia syndrome in MedDRA) and rash.

Tabulated list of adverse reactions:

* The adverse reactions may have a life-threatening or fatal outcome. ** Hand foot skin reaction corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA. In clinical trials, certain adverse drug reactions such as hand u2013 foot skin reaction, diarrhoea, alopecia, weight decrease, hypertension, hypocalcaemia and keratocanthoma/squamous cell carcinoma of skin occurred at a substantially higher frequency in patients with differentiated thyroid cancer compared to patients in the renal cell or hepatocellular carcinoma studies.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is no specific treatment for SORAFENIB 200 DRL overdose. The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhoea and dermatological events. In the event of suspected overdose, SORAFENIB 200 DRL should be withheld and supportive care instituted.