Cometriq

Cabozantinib is usually taken once per day. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take cabozantinib on an empty stomach, at least 1 hour before or 2 hours after you eat anything.

Take this medicine with a full glass of water.

Do not open a cabozantinib capsule. Swallow it whole.

Your blood pressure will need to be checked often.

If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using cabozantinib. You may need to stop using the medicine for a short time.

If you have stopped taking cabozantinib for any reason, talk with your doctor before you start taking it again. You may need to restart the medication at a lower dose.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 12 hours away. Do not take extra medicine to make up the missed dose.

Mechanism Of Action

In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, ROS1, TYRO3, MER, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Pharmacodynamics

The effect of orally administered COMETRIQ 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 -15 ms was observed at 4 weeks after initiating COMETRIQ. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No COMETRIQ-treated patients had a QTcF > 500 ms [see Clinical Studies].

Pharmacokinetics

A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. Repeat daily dosing of COMETRIQ at 140 mg for 19 days resulted in 4-to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15.

Following oral administration of COMETRIQ, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose.

A 19% increase in the Cmax of the tablet formulation (CABOMETYX™) compared to the capsule formulation (COMETRIQ) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations [see DOSAGE AND ADMINISTRATION].

Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral COMETRIQ dose.

The oral volume of distribution (V/F) of cabozantinib is approximately 349 L. Cabozantinib is highly protein bound in human plasma ( ≥ 99.7%).

The predicted effective half-life is approximately 55 hours and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.

Cabozantinib is a substrate of CYP3A4 in vitro.

Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140 mg dose of an investigational 14C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection.

Specific Populations

The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (20-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m² as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m² ) as estimated by MDRD equation or renal impairment requiring dialysis.

Following a single oral 60 mg COMETRIQ, mean AUC0-inf for cabozantinib increased by 81% in subjects with mild (C-P A) hepatic impairment and 63% in subjects with moderate (C-P B) hepatic impairment compared to subjects with normal hepatic function [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].

The pharmacokinetics of cabozantinib has not been studied in patients with severe (C-P C) hepatic impairment [see Use in Specific Populations].

The pharmacokinetics of cabozantinib has not been studied in the pediatric population [see Use in Specific Populations].

Drug Interactions

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%.

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%.

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) was observed when co-administered with cabozantinib at steady-state plasma concentrations ( ≥ 100 mg/day daily for a minimum of 21 days) in patients with solid tumors.

No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers.

Metabolic Pathways

Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by > 80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a < 20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.

Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Drug Transporter Systems

Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.

Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.

Clinical Studies

The safety and efficacy of COMETRIQ was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive COMETRIQ 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age ( ≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.

Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, and 92% had undergone a thyroidectomy. The RET mutation status determined by a research-use assay was positive in 51%, negative in 14%, and was unknown in 35%. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.

A statistically significant prolongation in PFS was demonstrated among COMETRIQ-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p < 0.0001], with median PFS times of 11.2 months and 4.0 months in the COMETRIQ and placebo arms, respectively.

Partial responses were observed only among patients in the COMETRIQ arm (27% vs. 0; p < 0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with COMETRIQ. There was no statistically significant difference in overall survival (median OS: 26.6 months in the COMETRIQ arm vs. 21.1 months in the placebo arm [HR = 0.85 (95% CI: 0.64, 1.12), p = 0.2409]).

Figure 1: Progression-Free Survival

Cometriq is part of the drug class:

• Protein kinase inhibitors

Before you take Cometriq, tell your healthcare provider if you:

• have high blood pressure
• have a recent history of coughing up blood or bleeding or any unusual bleeding
• have an open wound
• have had recent surgery or plan to have surgery or a dental procedure
• have liver problems
• have any other medical conditions
• are pregnant or you or your partner plan to become pregnant. Cometriq can cause harm to your unborn baby. Talk to your healthcare provider if you are pregnant or if you or your partner plan to become pregnant.
• are a female who is able to become pregnant, or are a male whose female partner is able to become pregnant; you should use effective birth control during your treatment with Cometriq and for at least 4 months after your last dose of Cometriq.
• are breastfeeding or plan to breastfeed. It is not known if Cometriq passes into your breast milk. You and your healthcare provider should decide if you will take Cometriq or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, and herbal supplements. Cometriq and certain other medicines may affect each other causing side effects.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Based on how this medication works, it is expected to cause harm to a fetus (unborn baby) is exposed to Cometriq. Talk to your healthcare provider about birth control methods to prevent pregnancy while you are taking Cometriq. Tell your healthcare provider right away if you or your female partner becomes pregnant while taking Cometriq.

Cabozantinib interferes with the growth of some cancer cells.

Cabozantinib is used to treat thyroid cancer that has spread to other parts of the body.

Cabozantinib is also used to treat kidney cancer after other cancer medicines have been tried without success.

Cabozantinib may also be used for purposes not listed in this medication guide.

You should not use cabozantinib if you are allergic to it.

To make sure cabozantinib is safe for you, tell your doctor if you have:

• high blood pressure;

• liver disease;

• an open wound or sore on your skin;

• a bleeding or blood-clotting disorder;

• a pre-existing dental problem;

• if you have recently had surgery or dental work; or

• if you have recently had any unusual or heavy bleeding.

Cabozantinib can harm an unborn baby.

• If you are a woman, do not take cabozantinib if you are pregnant.

• If you are a man, use effective birth control if your sexual partner is able to get pregnant. An unborn baby can be harmed if a man fathers the child while he is taking cabozantinib.

• Use birth control to prevent pregnancy while you are receiving cabozantinib, whether you are a man or a woman. Keep using birth control for at least 4 months after treatment ends.

• Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking cabozantinib.

It is not known whether cabozantinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine, and for at least 4 months after your last dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Storage

Oral

20–25°C (may be exposed to 15–30°C).1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of cabozantinib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of cabozantinib tablets in the elderly.

Appropriate studies have not been performed on the relationship of age to the effects of cabozantinib capsules in the geriatric population. However, no geriatric-specific problems have been documented to date.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Boceprevir
• Carbamazepine
• Ceritinib
• Clarithromycin
• Cobicistat
• Conivaptan
• Enzalutamide
• Fosphenytoin
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Mitotane
• Nefazodone
• Nelfinavir
• Netupitant
• Phenytoin
• Posaconazole
• Rifampin
• Ritonavir
• Saquinavir
• St John's Wort
• Telaprevir
• Telithromycin
• Voriconazole
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bleeding problems or
• Blood clots or
• Heart attack, acute or
• Hypertension (high blood pressure) or
• Proteinuria (protein in the urine) or
• Stomach fistula or perforation (a hole in the stomach) or
• Stroke, recent—Use with caution. May make these conditions worse.

• Dental or tooth problems or
• Dental procedures or surgery or
• Poor oral hygiene or
• Tooth infection—May increase risk for severe jaw problems.

• Hemoptysis (coughing up blood), recent or
• Hemorrhage (severe bleeding), recent history—Should not be used in patients with these conditions.

• Liver disease, mild or moderate—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Liver disease, severe—Use is not recommended in patients with these conditions.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take on an empty stomach. Take 1 hour before or 2 hours after meals.
• Swallow whole. Do not chew, break, or crush.
• Take with a full glass of water.
• Do not open the capsules.
• To gain the most benefit, do not miss doses.
• Keep taking Cometriq as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it and go back to your normal time.
• If it is less than 12 hours until the next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Mechanism of Action

In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, ROS1, TYRO3, MER, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Pharmacodynamics

Cardiac Electrophysiology

The effect of orally administered Cometriq 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating Cometriq. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No Cometriq-treated patients had a QTcF > 500 ms [see Clinical Studies (14)].

Pharmacokinetics

A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. Repeat daily dosing of Cometriq at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15.

Absorption

Following oral administration of Cometriq, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose.

A 19% increase in the Cmax of the tablet formulation (CABOMETYX™) compared to the capsule formulation (Cometriq) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (Cometriq) formulations [see Dosage and Administration (2.1)].

Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral Cometriq dose.

Distribution

The oral volume of distribution (V/F) of cabozantinib is approximately 349 L. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).

Elimination

The predicted effective half-life is approximately 55 hours and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.

Metabolism

Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion

Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140 mg dose of an investigational 14C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection.

Specific Populations

The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (20-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m2) as estimated by MDRD equation or renal impairment requiring dialysis.

Hepatic Impairment

Following a single oral 60 mg Cometriq, mean AUC0-inf for cabozantinib increased by 81% in subjects with mild (C-P A) hepatic impairment and 63% in subjects with moderate (C-P B) hepatic impairment compared to subjects with normal hepatic function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)].

The pharmacokinetics of cabozantinib has not been studied in patients with severe (C-P C) hepatic impairment [see Use in Specific Populations (8.6)].

Pediatric Population

The pharmacokinetics of cabozantinib has not been studied in the pediatric population [see Use in Specific Populations (8.4)].

Drug Interactions

CYP3A4 Inhibition on Cabozantinib

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%.

CYP3A4 Induction on Cabozantinib

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%.

Cabozantinib on CYP2C8 substrates

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) was observed when co-administered with cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily for a minimum of 21 days) in patients with solid tumors.

Gastric pH modifying agents on Cabozantinib

No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers.

In vitro Studies

Metabolic Pathways

Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.

Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Drug Transporter Systems

Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.

Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice.

Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Based on nonclinical findings, male and female fertility may be impaired by treatment with Cometriq. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.

Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the recommended dose) exhibited ovarian necrosis.

You should not use Cometriq if you are allergic to cabozantinib.

To make sure cabozantinib is safe for you, tell your doctor if you have:

• high blood pressure;

• liver disease;

• an open wound or sore on your skin;

• a bleeding or blood-clotting disorder;

• a pre-existing dental problem;

• if you have recently had surgery or dental work; or

• if you have recently had any unusual or heavy bleeding.

Cometriq can harm an unborn baby.

• If you are a woman, do not take Cometriq if you are pregnant.

• If you are a man, use effective birth control if your sexual partner is able to get pregnant. An unborn baby can be harmed if a man fathers the child while he is taking Cometriq.

• Use birth control to prevent pregnancy while you are receiving Cometriq, whether you are a man or a woman. Keep using birth control for at least 4 months after treatment ends.

• Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking Cometriq.

It is not known whether cabozantinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine, and for at least 4 months after your last dose.

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 12 hours away. Do not take extra medicine to make up the missed dose.

Many drugs can interact with cabozantinib. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• St. John's wort;

• an antibiotic--clarithromycin, telithromycin;

• antifungal medicine--itraconazole, ketoconazole, posaconazole, voriconazole;

• heart or blood pressure medicine--nicardipine, quinidine;

• antiviral medicine to treat hepatitis or HIV/AIDS--atazanavir, boceprevir, cobicistat, delavirdine, efavirenz, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir;

• seizure medicine--carbamazepine, phenytoin; or

• tuberculosis medicine--isoniazid, rifampin.

This list is not complete and many other drugs can interact with cabozantinib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.