Toceranib Capsules

Toceranib

10mg/15mg/50mg

Capsules

Antineoplastic for oral use in dogs only

Description：

Toceranib, a multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK), is the phosphate salt of toceranib. The empirical formula is C22H25FN4O2H3O4P and the molecular weight is 494.46. The chemical name is (Z)-5-[(5-Fluoro-2-oxo-1,2-dihydro-3H -indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide phosphate. Toceranib phosphate is a small molecule with an indolinone chemical structure.

The chemical structure of toceranib phosphate is:

Indications：

Toceranib Capsules are indicated for the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs.

Dosage and Administration:

Always provide Client Information Sheet with prescription. Administer an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day. Dose reductions of 0.5 mg/kg (to a minimum dose of 2.2 mg/kg (1.0 mg/lb) every other day) and dose interruptions (cessation of Toceranib for up to two weeks) may be utilized, if needed, to manage adverse reactions. Adjust dose based on approximately weekly veterinary assessments for the first 6 weeks and approximately every 6 weeks, thereafter. Toceranib may be administered with or without food. Do not split Capsules.

Contraindications:

Do not use in dogs used for breeding, or for pregnant or lactating bitches.

Warnings:

Toceranib may cause vascular dysfunction which can lead to edema and thromboembolism, including pulmonary thromboembolism. Discontinue drug until clinical signs and clinical pathology have normalized. To assure vasculature homeostasis, wait at least 3 days after stopping drug before performing surgery.

Serious and sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred rarely in dogs treated with Toceranib. If gastrointestinal ulceration is suspected, stop drug administration and treat appropriately.

Human Warnings:

NOT FOR USE IN HUMANS. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Children should not come in contact with Toceranib. Keep children away from feces, urine, or vomit of treated dogs. To avoid exposure to drug, wash hands with soap and water after administering Toceranib and wear protective gloves to prevent direct contact with feces, urine, vomit, and broken or moistened Toceranib Capsules. Place all waste materials in a plastic bag and seal before general disposal. If eyes are accidentally exposed to the drug, rinse eyes with water immediately. In case of accidental ingestion by a person, seek medical advice immediately, show the package insert or label to the physician. Gastrointestinal discomfort such as vomiting or diarrhea may occur if this drug is accidentally ingested.

Pregnant women, women who may become pregnant, or nursing mothers should pay special attention to these handling precautions. (See handling instructions above.) Toceranib, like other drugs in its class, prevents the formation of new blood vessels in tumors. In a similar manner, Toceranib may affect blood vessel formation in the developing fetus and may harm an unborn baby (cause birth defects). For pregnant women, accidental ingestion of Toceranib may have adverse effects on pregnancy.

Adverse Reactions:

Toceranib is used for treating certain types of cancer in dogs.The side effects of Toceranib can vary in severity and frequency, and not all dogs will experience them. Here are some of the commonly reported side effects:

Gastrointestinal Issues: Diarrhea, vomiting, decreased appetite, and weight loss are among the most common side effects. In some cases, dogs may also experience abdominal pain.

Fatigue and Lethargy: Dogs may show signs of general weakness, lethargy, or decreased activity levels.

Changes in Blood Counts: Toceranib can affect the bone marrow, leading to changes in blood cell counts, including neutropenia (low neutrophil count) and anemia (low red blood cell count).

Skin and Footpad Issues: Some dogs may develop problems in the skin or footpads, such as redness, swelling, or sores.

Liver Function Changes: Elevated liver enzymes may occur, indicating changes in liver function.

Kidney Function Changes: Renal function may also be affected, as indicated by changes in kidney-related blood tests.

Behavioral Changes: Some dogs may experience behavioral changes, including increased irritability or agitation.

Protein Loss in Urine: Proteinuria, or the presence of excess protein in the urine, has been observed in some cases.

It's important for any dog receiving Toceranib to be closely monitored by a veterinarian. The vet can help manage side effects and may adjust the treatment plan as necessary, including altering the dosage or frequency of administration. Regular blood tests and check-ups are often required to monitor the dog’s health and response to the medication.

Information for Dog Owners:

Always provide Client Information Sheet with prescription and review with owners. Owners should be advised on possible adverse reactions and when to stop drug and call the veterinarian. Owners should be advised of the handling instructions.

Clinical Pharmacology:

Mechanism of Action:

Toceranib phosphate is a small molecule that has both direct antitumor and antiangiogenic activity. In non-clinical pharmacology studies, Toceranib selectively inhibited the tyrosine kinase activity of several members of the split kinase receptor tyrosine kinase (RTK) family, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Toceranib inhibited the activity of Flk-1/KDR tyrosine kinase (vascular endothelial growth factor receptor, VEGFR2), platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (Kit) in both biochemical and cellular assays. Toceranib has been shown to exert an antiproliferative effect on endothelial cells in vitro. Toceranib treatment can induce cell cycle arrest and subsequent apoptosis in tumor cell lines expressing activating mutations in the split kinase RTK, ckit. Canine mast cell tumor growth is frequently driven by activating mutations in c-kit.1, 2

Other compounds in the antiangiogenesis class of antineoplastic agents are known to increase embryolethality and fetal abnormalities. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of Toceranib should be expected to result in adverse effects on the pregnancy in the bitch.

Pharmacokinetics:

The pharmacokinetics of Toceranib, particularly in its use for treating dogs with cancer, involve how the drug is absorbed, distributed, metabolized, and eliminated in the body. Understanding these aspects is essential for optimizing its therapeutic efficacy and managing potential side effects. Here's an overview based on available information:

Absorption: Toceranib is administered orally and is absorbed from the gastrointestinal tract. The rate and extent of absorption can be influenced by factors like the presence of food in the stomach, which tends to increase its bioavailability.

Distribution: After absorption, Toceranib is distributed throughout the body. It is known to have a large volume of distribution, indicating extensive tissue penetration. This is important for reaching cancer cells in various tissues.

Metabolism: Toceranib undergoes metabolism primarily in the liver. The enzymes of the cytochrome P450 system, particularly CYP3A4, play a significant role in its metabolic process. The metabolic pathways involve demethylation and oxidation.

Elimination: The elimination of Toceranib and its metabolites occurs through both the kidneys and the liver. It is excreted in the feces and urine.

Half-life: The half-life of Toceranib in dogs is variable but is generally in the range of several hours, which influences the dosing frequency. This variability can be attributed to individual differences in metabolism among dogs.

Steady-State Concentrations: Achieving steady-state concentrations, where the rate of drug administration equals the rate of elimination, is important for maintaining effective therapeutic levels. This is typically considered when determining the dosing regimen.

Therapeutic Monitoring: Due to variations in response and potential for side effects, therapeutic drug monitoring might be recommended, particularly for long-term treatment or in dogs with concurrent health issues.

It's important to note that individual responses to Toceranib can vary based on factors like the dog's size, breed, overall health, liver and kidney function, and the presence of other medical conditions or medications. Veterinarians take these pharmacokinetic properties into account when prescribing Toceranib, adjusting the dose as necessary based on the dog's response to treatment and any side effects observed. Regular veterinary visits and monitoring are crucial for dogs undergoing treatment with Toceranib.

Storage Conditions:

Store at controlled room temperature 20° to 25° C (68° to 77° F).

Generic medication and its counterpart to have the same active ingredients, strength, quality, route of administration, and safety standards.All of our products are produced in GMP factories, Your pet’s health is our top priority.

This summary contains important information about Toceranib. You should read this information before you start giving your dog Toceranib and review it each time the prescription is refilled as there may be new information. This sheet is provided only as a summary and does not take the place of instructions from your veterinarian. Talk with your veterinarian if you do not understand any of this information or if you want to know more about Toceranib.

What is Toceranib?

Toceranib a tyrosine kinase inhibitor, is a drug used to treat mast cell tumors, a common form of cancer that affects dogs.

Toceranib works in two ways:

• By killing tumor cells.
• By cutting off the blood supply to the tumor.

Your veterinarian has decided to include Toceranib as a part of your dog's treatment plan for mast cell tumor. Other types of treatment, such as surgery, drug treatment and/or radiation may be included in the plan. Be sure to speak with your veterinarian about all parts of your dog's treatment plan.

What do I need to tell my veterinarian about my dog before administering Toceranib?

Tell your veterinarian about all other medications your pet is taking, including: prescription drugs; over the counter drugs; heartworm, flea & tick medications; vitamins and supplements, including herbal medications.

Tell your veterinarian if your dog is pregnant, nursing puppies, or is intended for breeding purposes.

How do I give Toceranib to my dog?

Toceranib should be given to your dog by mouth (orally).

Toceranib may be hidden inside a treat; be certain your dog swallows the entire tablet(s).

Follow your veterinarian's instructions for how much and how often to give Toceranib.

See the Handling Instructions section below in order to administer Toceranib safely to your dog.

How will Toceranib affect my dog?

Toceranib may help shrink your dog's tumor. Like other cancer treatments, it can be difficult to predict whether your dog's tumor will respond to Toceranib, and if it does respond, how long it will remain responsive to Toceranib. Regular check ups by your veterinarian are necessary to determine whether your dog is responding as expected, and to decide whether your dog should continue to receive Toceranib.

What are some possible side effects of Toceranib?

Like all drugs, Toceranib may cause side effects, even at the prescribed dose. Serious side effects can occur, with or without warning, and may in some situations result in death.

The most common side effects which may occur with Toceranib include diarrhea, decreased/loss of appetite, lameness, weight loss and blood in the stool.

Stop Toceranib immediately and contact your veterinarian if you notice any of the following changes in your dog:

• Refusal to eat
• Vomiting or watery stools (diarrhea), especially if more frequent than twice in 24 hours
• Black tarry stools
• Bright red blood in vomit or stools
• Unexplained bruising or bleeding
• Or if your dog experiences other changes that concern you

There are other side effects which may occur. For a more complete list, ask your veterinarian.

Handling Instructions:

What do I need to know to handle Toceranib safely?

Because Toceranib is an anti-cancer drug, extra care must be taken when handling the tablets, giving the drug to your dog, and cleaning up after your dog.

• Toceranib is not for use in humans.
• You should keep Toceranib in a secure storage area out of the reach of children.
• Children should not come in contact with Toceranib. Keep children away from feces, urine, or vomit of treated dogs.
• If you are pregnant, a nursing mother, or may become pregnant and you choose to administer Toceranib to your dog, you should be particularly careful and follow the handling procedures described below.
• Toceranib prevents the formation of new blood vessels in tumors. In a similar manner, Toceranib may affect blood vessel formation in the developing fetus and may harm an unborn baby (cause birth defects). For pregnant women, accidental ingestion of Toceranib may have adverse effects on pregnancy.
• If Toceranib is accidentally ingested by you or a family member, seek medical advice immediately. It is important to show the treating physician a copy of the package insert or label. In cases of accidental human ingestion of Toceranib, you may experience gastrointestinal discomfort, including vomiting or diarrhea.

The following handling procedures will help to minimize exposure to the active ingredient in Toceranib for you and other members of your household:

• Anyone who administers Toceranib to your dog should wash their hands after handling tablets.
• When you or others are handling the tablets:
• Do not split or break the tablets to avoid disrupting the protective film coating.
• Toceranib Capsules should be administered to your dog immediately after they are removed from the bottle.
• Protective gloves should be worn if handling broken or moistened tablets. If your dog spits out the Toceranib Capsule, the capsule will be moistened and should be handled with protective gloves.
• If the Toceranib Capsule is "hidden" in food, make sure that your dog has eaten the entire dose. This will minimize the potential for exposure to children or other household members to Toceranib.
• Cleaning up after your dog:
• Because Toceranib is present in the stool, urine and vomit of dogs under treatment, you must wear protective gloves to clean up after your treated dog.
• While your dog receives Toceranib, place the stool, feces or vomit, and any disposable towels used to clean up in a plastic bag which should be sealed for general household disposal. This will minimize the potential for exposure to people in contact with the trash.
• You should not wash any items soiled with stool, urine or vomit from your dog with other laundry.

What if I miss giving my pet the medication?

If you miss a dose, contact your veterinarian for further instructions, as this medication must be dosed very carefully.

What drug interactions should be noted when using Toceranib?

When using Toceranib in dogs, particularly for the treatment of cancer, it's important to be aware of potential drug interactions. These interactions can affect how Toceranib or the other medications work, and in some cases, might lead to serious side effects. Here are some key drug interactions to consider:

Cytochrome P450 (CYP450) Enzyme Interactions: Toceranib is metabolized by the CYP450 enzyme system in the liver. Drugs that inhibit or induce these enzymes can affect the metabolism of Toceranib, potentially leading to increased toxicity or decreased efficacy. For example, ketoconazole (an antifungal medication) is a known inhibitor of CYP3A4 and could increase Toceranib levels.

Other Chemotherapeutic Agents: The use of Toceranib in combination with other chemotherapeutic drugs should be done cautiously. There may be an increased risk of additive toxicity, especially to the bone marrow.

Immunosuppressants: Since Toceranib has immunosuppressive effects, using it in conjunction with other immunosuppressants can enhance these effects, potentially increasing the risk of infections.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Combining Toceranib with NSAIDs can increase the risk of gastrointestinal ulcers or kidney damage.

Corticosteroids: Similar to NSAIDs, the concurrent use of corticosteroids with Toceranib may increase the risk of gastrointestinal side effects or other complications.

Heart Medications: Dogs on heart medications should be monitored closely, as there could be interactions affecting cardiac function.

Anticoagulants: If the dog is on blood thinners or anticoagulants, there may be an increased risk of bleeding.

Antibiotics: Certain antibiotics may interact metabolically with Toceranib or have additive side effects.

It's essential to inform the veterinarian about all medications and supplements the dog is taking before starting treatment with Toceranib. This allows the vet to consider any potential interactions and manage them by adjusting dosages or choosing alternative treatments. Regular monitoring and follow-up are also important to ensure the safe and effective use of Toceranib, particularly if the dog is on multiple medications.

Is there any monitoring that needs to be done with this medication?

Your veterinarian will monitor complete blood cell counts, percent red blood cells, blood proteins, kidney values, and phosphate levels weekly for the first 6 weeks, and then every 6 weeks thereafter. Blood pressure, urinalysis, chemistry profiles, and urine protein:creatinine ratios may be monitored every 6-8 weeks.

Your veterinarian may monitor your pet to be sure that the medication is working and monitor tumor size. Monitor your pet for serious side effects; if diarrhea persists after a few days or if there is blood in stools occur for more than 2 days, contact your veterinarian.

What should I do in case of emergency?

If you suspect an overdose or an adverse reaction to the medication, call your veterinary office immediately. If they are not available, follow their directions in contacting an emergency facility.