Summary Basis of Decision for Cabometyx
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Cabometyx is located below.
Recent Activity for Cabometyx
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Cabometyx
Date SBD issued: 2019-02-12
The following information relates to the new drug submission for Cabometyx.
20 mg, 40 mg, and 60 mg tablets, oral
Drug Identification Number (DIN):
- DIN 02480824 - 20 mg tablet
- DIN 02480832 - 40 mg tablet
- DIN 02480840 - 60 mg tablet
Ipsen Biopharmaceuticals Canada Inc.
New Drug Submission Control Number: 206230
On September 14, 2018, Health Canada issued a Notice of Compliance to Ipsen Biopharmaceuticals Canada Inc. for the drug product Cabometyx.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Cabometyx is favourable for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor (VEGF)-targeted therapy.
1 What was approved?
Cabometyx, an antineoplastic, was authorized for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor (VEGF)-targeted therapy.
Cabometyx is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Cabometyx was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Cabometyx (20 mg, 40 mg, and 60 mg cabozantinib) is presented as a tablet. In addition to the medicinal ingredient, the tablets also contain colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose 2910, iron oxide yellow, lactose anhydrous, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin.
Additional information may be found in the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Cabometyx approved?
Health Canada considers that the benefit-harm-uncertainty profile of Cabometyx is favourable for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor (VEGF)-targeted therapy.
The incidence of RCC is two-fold greater in men than in women. Smoking and obesity are established risk factors for RCC development. Prognosis depends on tumour stage, grade, and evidence of metastatic disease at presentation. Renal cell carcinoma primarily metastasizes to the lungs, lymph nodes, bones, liver, adrenal glands and brain.
The available therapies for advanced unresectable or metastatic RCC fall into three therapeutic classes: tyrosine kinase inhibitors (TKIs), mechanistic target of rapamycin (mTOR) inhibitors, and monoclonal antibodies. Sunitib and pazopanib are recommended as first-line agents. Nivolumab, in combination with ipilimumab, is indicated for the treatment of patients with intermediate/poor-risk advanced or metastatic RCC. Second-line treatment options include everolimus, axitinib, nivolumab, sorafenib and pazopanib. Selection of second-line therapy depends on the type of first-line treatment received.
The market authorization for Cabometyx was based primarily on one randomized, open-label, Phase III study (METEOR), which provided evidence of its safety and efficacy as a treatment for adult patients with advanced RCC who have received prior VEGF-targeted therapy. Patients were randomized in a 1:1 ratio to one of two treatment groups. One group received 60 mg Cabometyx once daily, and the other received 10 mg everolimus once daily, which is one of the standard second-line treatment options for RCC.
Progression-free survival (PFS) was the primary endpoint used to assess efficacy. This was initially evaluated by a blinded independent radiology review committee for the first 375 patients randomized. A statistically significant improvement was observed in patients receiving Cabometyx compared to patients receiving everolimus, with median PFS for these groups calculated as 7.4 months and 3.8 months, respectively. Similar values were calculated for progression-free survival in the whole study population of 658 patients.
Improvements were also observed in Cabometyx-treated patients with respect to objective response rate (ORR) and overall survival, which were assessed as secondary endpoints. The ORR for patients receiving Cabometyx was 24%, compared to 4% for those receiving everolimus. An increase in overall survival in cabozantinib-treated patients was also demonstrated through three analyses during the study. The initial interim analysis occurred at the time of the primary analysis in the first 375 randomized patients. Although results did not meet the threshold for statistical significance, a trend towards prolonged overall survival was observed in patients receiving Cabometyx. A second analysis revealed a statistically significant increase in overall survival in Cabometyx-treated patients. Patients in this treatment group had a median overall survival of 21.4 months, versus 16.5 months for those receiving everolimus. The third and final assessment showed that the overall survival benefit was maintained in patients receiving Cabometyx. This patient population had a clinically and statistically significant 4.3-month gain in overall survival compared to patients treated with everolimus (medians of 21.4 months and 17.1 months, respectively).
Adverse events were experienced by all patients. The majority were considered to be treatment-related, and similar incidences of serious adverse events were reported in both treatment groups. Severe adverse events (worst related adverse event, Grade 3 or 4) were more often associated with Cabometyx than with everolimus (experienced by 68% and 58% of patients, respectively). However, adverse events associated with death that occurred within 30 days of the last drug administration were more often observed in patients treated with everolimus (7.1%) than in patients receiving Cabometyx (4.5%).
Hypertension, diarrhea, fatigue, and palmar-plantar erythrodysesthesia syndrome (PPES) were the most frequently observed severe adverse events in patients receiving Cabometyx. Other commonly reported adverse events among Cabometyx-treated patients were nausea, decreased appetite, vomiting, decreased weight, constipation, dysgeusia, stomatitis, hypothyroidism, dysphonia, mucosal inflammation, dyspnea, asthenia, cough, increased aspartate aminotransferase (AST), anemia, back pain, abdominal pain, increased alanine aminotransferase (ALT), hypomagnesemia, rash, pain in extremities, muscle spasms, proteinuria, dyspepsia, arthralgia, hypokalemia, dry skin, headache, and hypophosphatemia.
Seventy-six percent (76%) of patients receiving Cabometyx required dose modification to manage adverse events, compared with 61% of patients receiving everolimus. Doses of Cabometyx were most often modified or reduced due to diarrhea, palmar-plantar erythrodysesthesia syndrome (PPES), fatigue, or hypertension. Decreased appetite and fatigue led to treatment discontinuation in more than 1% of patients receiving Cabometyx.
Several clinically significant adverse events have been identified for Cabometyx. Thromboembolism, gastrointestinal perforations and fistulas, and hemorrhage have all been reported, and in some cases, have led to deaths. Hypertension and hypertensive crisis, hepatotoxicity, reversible posterior leukoencephalopathy syndrome, and wound complications have also been reported. Additionally, Cabometyx has not been studied in patients with cardiac impairment, or with severe hepatic or renal impairment. These issues have been addressed in a Serious Warnings and Precautions box in the Cabometyx Product Monograph.
A Risk Management Plan (RMP) for Cabometyx was submitted by Ipsen Biopharmaceuticals Canada Inc. to Health Canada. Upon review, the RMP was considered acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Cabometyx Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Cabometyx was accepted.
Cabometyx has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Cabometyx Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Cabometyx?
A Notice of Deficiency (NOD) was issued for the initial submission, as it did not contain sufficient data to complete a benefit-risk assessment for Cabometyx with respect to the proposed indication. Two major objections were identified: additional information was required to complete the cardiac safety evaluation, and the data provided to support 60 mg as the recommended dose was not adequate or sufficient. The sponsor submitted the requested information, which was deemed acceptable upon review. The objections for which the NOD was issued are considered resolved.
The drug submission for Cabometyx was reviewed under the Priority Review Policy. Cabometyx demonstrated a significant increase in efficacy with an improved benefit-risk profile compared to existing second-line therapies for advanced renal cell carcinoma (RCC), a condition that is not adequately managed by a drug marketed in Canada. Evidence from a pivotal clinical trial indicates that Cabometyx has improved progression-free survival, overall survival, and objective response rate when compared with the standard second-line treatment for advanced RCC, everolimus.
Submission Milestones: Cabometyx
|Request for priority status
|Approval issued by Director, Bureau of Medical Sciences
|Screening Deficiency Notice issued:
|Screening Acceptance Letter issued:
|Notice of Deficiency (NOD) issued by Director General, Therapeutic Products Directorate (safety and effectiveness issues):
|Screening Acceptance Letter issued:
|Quality Evaluation complete:
|Clinical Evaluation complete:
|Biostatistics Evaluation complete:
|Review of Risk Management Plan complete:
|Labelling Review complete, including Look-alike Sound-alike brand name assessment:
|Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate:
The Canadian regulatory decision on the clinical and quality reviews of Cabometyx were based on a critical assessment of the data package submitted to Health Canada. Review reports from the European Medicines Agency (EMA) were consulted during the review of Cabometyx for relevant supplementary information.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases implicated in tumour growth and angiogenesis, pathologic bone remodeling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of hepatocyte growth factor receptor protein (MET) and vascular endothelial growth factor (VEGF) receptors. Additionally, cabozantinib inhibits other tyrosine kinases including ROS1, TYRO3, MER, TRKB, TIE-2, the GAS6 receptor (AXL), the rearranged during transfection (RET) protein, the stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3).
Pharmacokinetic studies for cabozantinib were conducted mainly with suspension or capsule formulations. However, a study was included in this submission which demonstrates bioequivalence between the capsule and tablet formulations. Given cabozantinib was originally developed as a treatment for thyroid cancer; several studies included in this submission were conducted in patients with conditions other than renal cell carcinoma (RCC). As a result, information on pharmacokinetics after multiple dosing with 20 mg, 40 mg and 60 mg tablets is limited.
The food effects study, XL184-004, was conducted with a capsule formulation rather than the tablet formulation intended for marketing of Cabometyx. Results of this study demonstrated that administration of cabozantinib following a high-fat meal significantly increased systemic exposure in healthy subjects. Patients taking Cabometyx are therefore advised not to take it with food, and not to eat for at least two hours before and one hour after administration.
The bioequivalence between the capsule and tablet formulations of Cabometyx was evaluated in study XL184-001. Results of this study demonstrated that the rate of absorption and extent of exposure to cabozantinib were similar between the two formulations. Based on these results, the conclusions drawn from the food effects study using the capsule formulation are considered applicable to the tablet formulation.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Cabometyx have been well characterized in patients and healthy volunteers. Pharmacokinetic data suggests that cabozantinib may undergo enterohepatic recirculation, which may extend the half-life of the drug. Terminal half-life was calculated as approximately 99 hours following administration of 20 mg, 40 mg, and 60 mg doses. Additionally, four metabolites of cabozantinib were detected in plasma at concentrations greater than 10% of the parent concentration. Overall the pharmacokinetic data support use of Cabometyx for the approved indication.
Compared to healthy subjects, exposure to cabozantinib was 81% higher in patients with mild hepatic impairment and 63% higher in patients with moderate hepatic impairment. Elevated exposure levels correlated with lower clearance rates, and together, these extend the mean terminal half-life by 70-75% in patients with hepatic impairment. A decreased starting dose of 40 mg is therefore recommended for patients with mild to moderate hepatic impairment. Cabometyx is not recommended for individuals with severe hepatic impairment, as it has not been studied in this population.
Higher values were also reported for peak plasma concentration and exposure to cabozantinib in patients with renal impairment versus healthy subjects. The ratios of geometric least squares mean for plasma cabozantinib, Cmax and AUC0-inf, were 19% and 30% higher in patients with mild renal impairment, and 2% and 6-7% higher in patients with moderate renal impairment. Patients with mild to moderate renal impairment are advised to use Cabometyx with caution. Additionally, it is not recommended for patients with severe renal impairment, as it has not been studied in this population.
Co-administration of Cabometyx and strong cytochrome P450 (CYP) 3A4 inhibitors must be done cautiously, as this decreases cabozantinib clearance by 29% and increases single dose plasma cabozantinib exposure by 38%. Chronic concurrent use of Cabometyx with CYP3A4 inducers should be avoided, as this increases cabozantinib clearance 4.3-fold and decreases cabozantinib exposure by 77%.
Results of in vitro experiments have shown that cabozantinib is a substrate of multidrug resistance-associated protein 2 (MRP2), and inhibits pump P-glycoprotein (P-gp).
Co-administration of Cabometyx with MRP2 inhibitors or substrates of P-gp may result in increased cabozantinib exposure.
For further details, please refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.
The clinical efficacy of Cabometyx in patients with advanced renal cell carcinoma (RCC) was based primarily on one pivotal study referred to as METEOR. METEOR was a randomized, open-label, Phase III study comparing Cabometyx against the standard second-line treatment for advanced RCC, everolimus. All 658 patients enrolled in this study had advanced RCC, and had previously received at least one VEGF receptor tyrosine kinase inhibitor. Patients were randomized in a 1:1 ratio to one of two treatment groups, to receive either 60 mg cabozantinib or 10 mg everolimus once daily. Treatment continued until the patient's condition progressed, or until the patient experienced an unacceptable level of toxicity. Tumour assessments occurred every eight weeks for the first 12 months, and every 12 weeks thereafter.
The primary efficacy endpoint was progression-free survival (PFS). A blinded independent radiology review committee conducted the primary analysis of PFS among the first 375 patients randomized. A statistically significant increase in PFS was reported in patients treated with cabozantinib, compared to those treated with everolimus (7.4 months and 3.8 months, respectively). Results of an analysis in the complete patient population were consistent with those from the primary population.
Objective response rate (ORR) was assessed as a secondary endpoint in the whole patient population, and was significantly higher in patients receiving cabozantinib than in patients receiving everolimus. As determined by clinical investigators, the ORR was 24% for cabozantinib and 4% for everolimus. An independent review committee calculated corresponding values of 17% and 3% for cabozantinib and everolimus.
Overall survival was also a secondary efficacy endpoint, and was analyzed three times during the course of the study. The first analysis was carried out at the time of the PFS analysis in the primary population. Results did not meet the threshold for statistical significance, but a trend towards prolonged overall survival was detected in patients receiving cabozantinib. The second analysis revealed a statistically significant increase in overall survival in patients treated with cabozantinib. Median overall survival values of 21.4 months and 16.5 months were reported for patients treated with cabozantinib and everolimus, respectively. The third and final analysis yielded median values of 21.4 months and 17.1 months in connection with cabozantinib and everolimus, respectively. This increase of 4.3 months was statistically significant, and confirmed that the overall survival benefit of cabozantinib treatment was maintained.
|Sponsor's proposed indication
|Health Canada-approved indication
|Cabometyx (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior therapy.
|Cabometyx (cabozantinib) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor (VEGF)-targeted therapy.
For more information, refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.
The clinical safety of Cabometyx was based primarily on safety data derived from the pivotal Phase III METEOR study previously described in the Clinical Efficacy section. The outcomes of this study demonstrated that PFS, overall survival, and ORR are higher for cabozantinib (the medicinal ingredient in Cabometyx), than for the standard second-line treatment for advanced RCC, everolimus.
Adverse events were experienced by all patients enrolled in this study, with similar incidences of serious adverse events observed in both treatment groups. Severe adverse events (worst related adverse event, Grade 3 or 4) were more often associated with Cabometyx than with everolimus (68% versus 58% of patients). Adverse events associated with death within 30 days of the last drug administration were more frequent among everolimus-treated patients (7.1%) than Cabometyx-treated patients (4.5%).
Dose modifications were needed to manage adverse events in 76% of patients receiving Cabometyx and 61% of patients receiving everolimus. Diarrhea, palmar-plantar erythrodysaesthesia syndrome (PPES), and fatigue required dose interruption in at least 10% of Cabometyx-treated patients. These three adverse events, along with hypertension, were also the most frequently associated with dose reduction. Decreased appetite and fatigue led to treatment discontinuation in more than 1% of patients.
The most common adverse events, experienced by 10% or more of Cabometyx-treated patients, were diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, decreased weight, constipation, dysgeusia, stomatitis, hypothyroidism, dysphonia, mucosal inflammation, dyspnea, asthenia, cough, increased aspartate aminotransferase (AST), anemia, back pain, abdominal pain, increased alanine aminotransferase (ALT), hypomagnesemia, rash, pain in extremities, muscle spasms, proteinuria, dyspepsia, arthralgia, hypokalemia, dry skin, headache, and hypophosphatemia.
Several clinically significant adverse events have been associated with Cabometyx, which are also characteristic of other tyrosine kinase inhibitors. These include gastrointestinal (GI) perforation, GI and non-GI fistulas, thromboembolic events, severe hemorrhage (Grade 3 or above), wound complications, reversible posterior leukoencephalopathy syndrome, hypertension, and hepatotoxicity, which are all highlighted in a Serious Warnings and Precautions box in the Cabometyx Product Monograph. Other adverse events associated with tyrosine kinase inhibitors include diarrhea, PPES, hypothyroidism, osteonecrosis, proteinuria, and QT prolongation.
A Notice of Deficiency (NOD) was issued for the initial new drug submission for Cabometyx. Two major objections were identified: insufficient information to conduct a thorough analysis of cardiac safety, and the absence of a Phase I dose-finding study to justify the recommended starting dose of 60 mg. The sponsor supplied the outstanding data in a response to the NOD. These were found to be acceptable upon review, and the objections are considered resolved.
Health Canada has determined that appropriate measures are in place to address the safety concerns identified for Cabometyx, and to promote its safe and effective use. Overall, the risk-benefit profile of Cabometyx is favourable and there are no issues within this submission which preclude authorization of the product. For more information, refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Primary pharmacodynamics analyses revealed that cabozantinib (the medicinal ingredient of Cabometyx) inhibits a wide range of proteins which have the potential to contribute to oncogenic growth. These include the proto-oncogenic proteins MET, AXL, and RET, as well as certain clinically relevant mutants of RET and MET. The broad anti-tumorigenic effects of cabozantinib were also observed in mouse xenograft models of human thyroid cancer, lung cancer and breast cancer, as well as in a rat C6 glioma tumour model.
In safety pharmacology studies, no concerns were detected with respect to effects of cabozantinib on the cardiovascular, respiratory, and central nervous systems.
In vivo studies in mice, rats, dogs, and monkeys indicated rapid absorption, and studies in rats suggest that cabozantinib is widely distributed. In dogs, cabozantinib was metabolized through various pathways, and the main process seems to be oxidative defluorination. In both rats and dogs, cabozantinib is excreted mainly through the feces.
Non-clinical studies also identified several drugs that may interact with or be affected by cabozantinib. Inhibitors and inducers of multidrug resistance-associated protein 2 (MRP2) may affect circulating levels of cabozantinb, as it is likely a substrate of MRP2. Drug-drug interactions may also occur between cabozantinib and P-glycoprotein (P-gp), OAT3, MATE1 and MATE2K substrates. Additionally, results indicate that CYP3A4 may contribute to metabolizing cabozantinib. Drugs affecting CYP3A4 catalytic pathways may therefore modify the pharmacokinetics of cabozantinib.
Repeat-dose toxicity studies in rats, dogs, and mice provided evidence of toxicity at doses lower than the clinical dose, affecting numerous organs and organ systems. Clear signs of toxicity were observed in the GI system, bone marrow, lymphoid tissues, reproductive tract, endocrine tissues, kidneys, and skin. Evidence of reproductive toxicity was also observed in dogs. An increased incidence of chronic progressive nephropathy was observed in rats. Additionally, long-term use of cabozantinib led to the development of adrenal gland tumours in rats, indicating that cabozantinib may be carcinogenic.
The reproductive and developmental toxicity of cabozantinib was also demonstrated through studies in rats and rabbits. In rats, cabozantinib affected male and female reproductive performance, fertility, embryo-fetal development, and juvenile toxicity at doses lower than clinical dose. Signs of embryotoxicity were observed in rabbits.
Cabozantinib tested negative for genotoxicity in the Ames test, signifying that it is unlikely to be mutagenic. Additionally, it did not induce clastogenic effects in mouse lymphoma L5178Y TK+/- cells or micronuclei in polychromatic erythrocytes from mouse bone marrow, which are indicators of chromosomal damage. However, the Ames test showed that the metabolite para-fluoroaniline (p-FA) and four impurities of cabozantinib had potential to be genotoxic at high concentrations, and should be closely monitored and controlled.
Appropriate warnings and precautions are listed in the Cabometyx Product Monograph to address the identified safety concerns. In view of the intended use of Cabometyx, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Cabometyx has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.
Cabozantinib, the drug substance, is produced as cabozantinib (S)-malate. The manufacturing process has been validated to ensure that the N-2 polymorphic form is consistently produced, as it can also exist in the N-1 polymorphic form. Manufacturing process controls have also taken threshold levels for impurities into account. Proposed limits of drug-related impurities are considered adequately qualified.
The manufacturing process for Cabometyx, the drug product, involves wet milling and drying, blending, compression, and film coating steps. All three strengths are compositionally proportional and made from a common blend. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15ºC to 25ºC).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. Lactose, one of the excipients in Cabometyx tablets, is of animal origin. Lactose used in the production of Cabometyx is not considered a risk for bovine spongiform encephalopathy or transmissible spongiform encephalopathy (BSE or TSE). A certification letter attesting to these claims was provided by the sponsor.
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