Cabozantinib - A Descriptive Overview

Overview

Cabozantinib is a drug approved by the FDA (Food and Drug Administration) that can be used in the treatment of renal cell carcinoma, renal cell adenocarcinoma, or cancer of the kidney in adults and pediatric patients of 12 years of age and older. Kidneys are the organs that filter toxic substances from the body. Kidneys contain connecting tube-like structures called ureters that collect urine. Cancer can occur in the ureters too, which is different from renal cell carcinoma. The drug Cabozantinib works by inhibiting the receptors responsible for cancer formation. The drug is available as a tablet that should be administered orally once a day. Patients have been informed of the various precautions to take when administering this drug.

How Does Cabozantinib Work?

Cabozantinib works by inhibiting certain receptors of tyrosine kinase (an enzyme) that, in turn, inhibit the growth and development of cancer-producing cells, hence decreasing the intensity of the growth in cancer cells.

What Are the Available Doses and Dosage Forms?

Available doses and dosage forms

• Cabozantinib is available in tablets of 20 milligrams (mg), 40 milligrams, and 60 milligrams.

• A 60-milligram tablet is administered orally.

• A 40-milligram tablet is administered orally in combination with Nivolumab (240 milligrams).

The tablets are available in the following shapes and colors.

• 30 oval-shaped yellow film tablets containing 60 mg of Cabozantinib are in one bottle.

• 40-milligram tablets of Cabozantinib are triangle-shaped and yellow film-coated.

• 20-milligram yellow filmed Cabozantinib tablets with round shapes are available in bottles of 30 tablets.

Warnings and Precautions:

• Hemorrhage - Internal bleeding due to a ruptured vessel is called hemorrhage. Under such circumstances, Cabozantinib should not be administered.

• Fistulas and Perforations - Any abnormal connection between two organs, or the organ and the external surface of the body, should be checked prior, and Cabozantinib is discontinued.

• Hypertension - Increased blood pressure is a common condition in most individuals due to lifestyle changes. The blood pressure is monitored in every patient, and Cabozantinib is discontinued if the blood pressure is elevated.

• Diarrhea - Increased bowel movements cause diarrhea. Stop Cabozantinib immediately when there is severe diarrhea.

• Proteinuria - If protein in urine is detected, then Cabozantinib is discontinued.

• Impaired Wound Healing - Cabozantinib is withheld for at least three weeks before any surgery.

For Patients:

What Is Renal Cell Carcinoma?

Renal cell carcinoma is also called cancer of the kidney or kidney cancer. It is a disease in which cancer cells are present in the kidney's tubule linings (filtering tubules). Habits such as smoking, high doses of pain medications, conditions like obesity, high blood pressure, and a history of renal cell carcinoma in family members are all risk factors predisposing to renal cell carcinoma.

Signs and Symptoms of Renal Cell Carcinoma:

• Presence of blood in the urine.

• Mass or lump in the abdomen.

• Lack of appetite.

• Anemia.

Diagnosis of Renal Cell Carcinoma:

Renal cell carcinoma can be diagnosed with the help of a proper medical history, physical examination, ultrasound examination, urine analysis, a CT (computed tomography) scan, an MRI (magnetic resonance imaging), and a biopsy.

Renal cell carcinoma can be divided into four stages (stages one to four). The stages are divided depending on the intensity of the developing cancer cells.

• Stage I - Tumor of two and a half inches present only in the kidney.

• Stage II - A tumor larger than two and a half inches is found in the kidney.

• Stage III - The tumor can spread more than two and a half inches to the adjacent lymph nodes through the blood vessels.

• Stage IV - The spread of the tumor to adjacent glands, such as the adrenal gland above the kidney, is also seen.

The treatment of renal cell carcinoma is decided based on surgery, chemotherapy, radiation therapy, and targeted therapy.

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What Are the Things to Inform the Doctor Before Taking Cabozantinib?

Certain things should be discussed with the physician to prevent future complications. The drug dosage also varies depending on the clinical history of the patient. As there are chances for the drug to interact and react with the drugs already being taken, any ongoing treatments should also be informed in priority. A dentist must also be informed regarding all these to obtain better care for the mouth during the treatment.

Following are the conditions that should be informed.

• Presence of high blood pressure.

• The presence or previous history of having a weakening or enlargement in the blood vessel wall (aneurysm) or a blood vessel tear.

• Presence of diarrhea.

• Any recent history of profuse bleeding.

• Recent history of undergoing surgery within the last month (surgeries that can include even dental procedures).

• Presence of any disease such as ulcerative colitis, Crohn’s disease, or appendicitis.

• Having a recent history of stroke, blood clotting in the leg, or heart attack.

• Presence of kidney or liver disease.

• Presence of issues related to thyroid. History of getting tired more easily, feeling colder, and deepening voice when taking this drug should be noted and informed.

What Are the Side Effects of Cabozantinib?

Cabozantinib can cause serious side effects, including the following:

• Hemorrhage (Bleeding): Severe continuous bleeding that can lead to death can occur. This bleeding can be in the form of the following:

  • Coughing up blood.

  • Blood vomiting.

  • Stools in red or black color.

  • Unusual heavy bleeding.

• Perforation and Fistula: A tear in the intestinal wall or stomach is called a perforation, and any connection between two body organs is called a fistula. This can present as pain or tenderness in the abdomen region.

• Heart Attack: Stroke, chest pain, and blood clots in the blood vessels can be seen. The presenting symptoms are listed below.

  • Pain or swelling in the arms.

  • Trouble speaking or confusion.

  • Profuse sweating.

  • Weakness or numbness in the face, more often on one side of the body.

  • Severe sudden headache.

• Hypertension (High Blood Pressure): A common side effect occurs along with the drug. It can be mild and sometimes very severe. Medicines are prescribed to reduce hypertension. Symptoms such as tiredness, chest pain, vision changes, irregular heartbeat, and heavy breathing should all be noted and informed to the physician.

• Diarrhea: Commonly occurring side effects with administering the drug Cabozantinib. Frequent watery and loose stools and increased bowel movements should be told to the physician.

• Hand-Foot Skin Reaction: It can present as a severe condition showing redness, rashes, swelling, pain, or blisters on the soles of the feet and hands.

• Liver Problems: Problems with the liver can occur during treatment with Cabozantinib. When the drug is taken along with Nivolumab, changes in liver function tests are higher compared to those that occur with Cabozantinib alone. Liver function tests are done before and during the treatment to detect changes occurring. Symptoms occurring due to the changes in the liver are yellowing of the eyes and skin, pain in the right side of the abdominal region, dark-colored urine, and easy bruising or bleeding.

• Adrenal Gland Problems: Extreme tiredness. Weakness, fainting, or dizziness are all symptoms of issues with the adrenal gland. Corticosteroids or hormone replacement therapies are advised by the physician when there are changes in the functioning of the adrenal gland.

• Kidney Problems: Swelling in the arms, legs, or feet can denote high chances of kidney problems. When the patient is treated with Cabozantinib, the physician usually checks for any presenting symptoms.

• Jaw Bone Problems: The dentist examines the mouth before starting the treatment with Cabozantinib. As there are high chances of jaw pain, sores on the mucosa and gums, and toothache during the treatment, the symptoms should be reported to the physician.

• Wound Healing Issues: In certain cases, a delay in the healing of the wound has been reported. Any surgery that is planned during the treatment with Cabozantinib should be taken care of so that the drug is stopped three weeks before the surgery.

• Reversible Posterior Leukoencephalopathy Syndrome: Severe headaches, confusion, seizures, and thinking problems are all symptoms that can occur due to reversible posterior leukoencephalopathy syndrome.

Side effects listed below are noted, and the physician will change the dose, temporarily stop, or completely stop the treatment with Cabozantinib:

• Tiredness.

• Nausea.

• Vomiting.

• Weightloss.

• Constipation.

The side effects can occur when the Cabozantinib drug is used along with Nivolumab:

• Mouth sores or ulcers.

• Rashes.

• Decreased thyroid levels.

• Tiredness.

• Abdominal pain.

• Taste changes.

• Respiratory tract infection.

How to Use Cabozantinib?

• The medicine is consumed exactly as prescribed by the physician, as the dosage can differ due to clinical variations.

• Usually, Cabozantinib is taken once daily; 60 milligrams is the usual dose. The recommended dose of 40 milligrams is given when the drug is combined with Nivolumab, which treats renal cell carcinoma.

• Cabozantinib is not taken with food. It is advised not to consume food before two hours and after one hour of taking the medicine. It should be noted that the tablet should not be crushed, and the medicine is to be swallowed with one full glass of water.

What Should Be Done If a Dose Is Missed?

• If one forgets to take the tablet and there are still 12 hours or more left before the next dose, the missed dose can be taken as and when one remembers.

• The next dose can be taken at the usual time.

• When there are less than 12 hours until the dose is to be skipped and the next dose is taken as usual.

• It is done because there are high chances of taking double the dose simultaneously.

Can One Stop Taking Cabozantinib?

Stopping the drug in between can lead to a stoppage of the drug's effect. It is only on the doctor's advice that the drug should be stopped.

What Should Be Done to Treat Cabozantinib Overdose?

An overdose occurs when Cabozantinib is taken twice or more than the recommended dose. The patient presents with memory loss, a change in mental status, cognitive disturbance, and weight loss. The presenting symptoms are treated, but the recovery rate is still questionable.

How to Store Cabozantinib?

Cabozantinib is available in a bottle containing 30 tablets, which should be stored at room temperature, away from children and sunlight.

Avoid Self-Medication

Taking the drug Cabozantinib on the advice of a patient who has already used it or under the advice of anyone other than the physician should be avoided. As there can be dose modifications and interactions that can occur with the drugs already being taken, the drug Cabozantinib is administered only under a physician's prescription.

For Doctors:

What Is the Clinical Pharmacology?

Mechanism of Action:

The tyrosine kinase activity of certain receptors like MET, AXLL, RET, MER, KIT, TRKB, and TIE-2 is all inhibited by administering Cabozantinib. These receptors of tyrosine kinases are responsible for both normal cellular functioning and pathological processes such as tumor angiogenesis, metastasis, oncogenesis, maintenance of the tumor microenvironment, and drug resistance.

Pharmacodynamics:

The response to the concentration of the drug-exposed or the safety relationship has not been established. Cabozantinib's effect on QTc interval, when studied in patients with medullary thyroid cancer, was increased to 10 to 15 ms four weeks after administration. A definitive QTc relationship with the concentration of the drug cannot be established. Changes in the waveform morphology of the heat or new rhythms are not observed. All the studies were done through cardiac electrophysiology.

Pharmacokinetics:

A daily administration of normal dosage of Cabozantinib formulation twenty times resulted in the accumulation of the drug five times more than the administration of a single dose.

Absorption:

The maximum concentration of Cabozantinib was found at its peak time three to four hours after the dose. A nearly 20 % increase in concentration was observed in the Cabozantinib single dose 140-milligram capsule formulation.

Nonclinical Toxicology:

• Carcinogenesis, mutagenesis, and impairment of fertility can occur due to toxicity.

• Cabozantinib's carcinogenic potential is being evaluated and was found to be effective on reproductive tract tissues.

• Male and female fertility is impaired with the treatment of Cabozantinib. Impairment is seen with lowered sperm counts and the weight of the reproductive organ. Loss of pre and post-implantation embryos is seen most commonly in females.

What Are the Drug Interactions of Cabozantinib?

• Strong CYP3A4 Inhibitors - Using a strong CYP3A4 inhibitor along with Cabozantinib increased the exposure to the drug. The increase in exposure can lead to an increased risk of exposure-related toxicity. Management can be done by avoiding the CYP3A4 inhibitors, or when that cannot be done, reducing the drug dosage can be done.

• Strong CYP3A Inducers - Cabozantinib exposure is decreased when it is used along with CYP3A4 inducers as compared to the administration of the drug alone. A decrease in exposure to the drug can lead to a reduction in efficacy. Prevention or management can be done by increasing the drug dosage when CYP3A4 inducers cannot be avoided.

Use in Specific Populations:

• Pregnancy: Cabozantinib can cause fetal harm when administered to pregnant women. There is no associated risk with the drug. The potentiality of the drug as a hazard to the fetus must be explained to the patient. The risk of birth defects or miscarriage for pregnant women is still being studied and recorded at nearly five percent.

• Lactation: No trace amounts of the drug can be found in the milk of humans. There is no known effect, even on the breastfed infant. As there is a high chance that side effects can be caused by this drug, a lactating woman is not advised to breastfeed during the treatment with Cabozantinib, at least for four months after the final dose.

• Contraception: For females, the fetus can be harmed when the drug is administered to a pregnant woman. For this reason, females are advised to use contraception when they are being treated with the drug Cabozantinib.

• Infertility: The fertility potential can be altered in males and females of reproductive potential.

• Pediatric Use: The effectiveness and safety of the drug in pediatric patients are being researched. Effects such as bone abnormalities, tooth abnormalities, and reduced bone mineral content and density can be noticed. Partially, the bony defects were resolved, but the effects on the kidneys and genital organs, such as nephropathy, and glomerulonephritis, can persist after the treatment has stopped.

• Geriatric Use: Almost 50 percent of patients aged 65 were treated with this drug. Adverse reactions occurred frequently, and no difference in safety or efficacy was noted between younger and older patients.

• Hepatic Impairment: Cabozantinib exposure has been associated with serious adverse reactions in cases of mild to moderate hepatic impairment.