Kinavet-CA1

This page contains information on Kinavet-CA1 for veterinary use.
The information provided typically includes the following:
  • Kinavet-CA1 Indications
  • Warnings and cautions for Kinavet-CA1
  • Direction and dosage information for Kinavet-CA1

Kinavet-CA1

This treatment applies to the following species:
Manufacturer: AB Science USA

(masitinib mesylate)

Tablet

Antineoplastic

For oral use in dogs only

Conditionally approved by FDA pending a full demonstration of effectiveness under application number 141-308.

Kinavet-CA1 Caution

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Use only as directed. It is a violation of Federal law to use this product other than as directed in the labeling.

Description

Masitinib is a tyrosine kinase inhibitor. The molecular weight of masitinib base is 498.67. The empirical formula is C28H30N6OS. The structural formula is:

KINAVET-CA1 tablets are round, biconvex, orange, coated tablets, containing either 50 mg or 150 mg masitinib base as masitinib mesylate. Each tablet is engraved with logo on one side and dosage strength on the other side.

Kinavet-CA1 Indications

For the treatment of nonresectable Grade II or III cutaneous mast cell tumors in dogs that have not previously received radiotherapy and/or chemotherapy except corticosteroids.

Dosage and Administration

Always provide Client Information Sheet with prescription.

Administer KINAVET-CA1 at an initial dose of 12.5 mg/kg/day (5.7 mg/lb/day) orally, once daily with food (see Table 1). Dose reductions to 9 mg/kg/day (4.1 mg/lb/day, see Table 2) and dose interruptions may be utilized, if needed, to manage adverse reactions (see Table 3 as well as WARNINGS and PRECAUTIONS). Do not split or crush tablets.

Table 1. Initial Dose, 12.5 mg/kg/day Dose Chart

Dog Body Weight

Dose

Number of Tablets

Pounds

Kilograms

50 mg

150 mg

15.4 - 22.9

7.0 - 10.4

100 mg

2

 

23.0 - 30.6

10.5 - 13.9

150 mg

 

1

30.7 - 39.4

14.0 - 17.9

200 mg

1

1

39.5 - 48.2

18.0 - 21.9

250 mg

2

1

48.3 - 57.0

22.0 - 25.9

300 mg

 

2

57.1 - 65.8

26.0 - 29.9

350 mg

1

2

65.9 - 74.6

30.0 - 33.9

400 mg

2

2

74.7 - 83.4

34.0 - 37.9

450 mg

 

3

83.5 - 92.2

38.0 - 41.9

500 mg

1

3

92.3 - 101.0

42.0 - 45.9

550 mg

2

3

101.1 - 110.2

46.0 - 49.9

600 mg

 

4

110.3 - 118.6

50.0 - 53.9

650 mg

1

4

118.7 - 127.4

54.0 - 57.9

700 mg

2

4

127.5 - 136.2

58.0 - 61.9

750 mg

 

5

136.3 - 145.0

62.0 - 65.9

800 mg

1

5

145.1 - 153.8

66.0 - 69.9

850 mg

2

5

153.9 - 162.6

70.0 - 73.9

900 mg

 

6

162.7 - 171.4

74.0 - 77.9

950 mg

1

6

171.5 - 220

78.0 - 100.0

1000 mg

2

6

*KINAVET-CA1 cannot be safely dosed at the target dose of 12.5 mg/kg in dogs weighing less than 7.0 kg (15.4 lbs)

Table 2. Reduced Dose, 9 mg/kg/day Dose Chart

Dog Body Weight

Dose

Number of Tablets

Pounds

Kilograms

50 mg

150 mg

15.4 - 22.9

7.0 - 10.4

Discontinue treatment*

23.0 - 31.7

10.5 - 14.4

100 mg

2

 

31.8 - 42.7

14.5 - 19.4

150 mg

 

1

42.8 - 54.8

19.5 - 24.9

200 mg

1

1

54.9 - 67.1

25.0 - 30.5

250 mg

2

1

67.2 - 79.4

30.6 - 36.1

300 mg

 

2

79.5 - 91.5

36.2 - 41.6

350 mg

1

2

91.6 - 103.8

41.7 - 47.2

400 mg

2

2

103.9 - 115.9

47.3 - 52.7

450 mg

 

3

116.0 - 128.3

52.8 - 58.3

500 mg

1

3

128.4 - 140.4

58.4 - 63.8

550 mg

2

3

140.5 - 152.7

64.0 - 69.4

600 mg

 

4

152.8 - 164.8

69.5 - 74.9

650 mg

1

4

164.9 - 177.1

75.0 - 80.5

700 mg

2

4

177.1 - 220

80.6 - 100.0

750 mg

 

5

*KINAVET-CA1 cannot be effectively dosed at 9 mg/kg in dogs weighing less than 10.5 kg (23.0 lbs)

Table 3. Managing Adverse Reactions with Dose Interruption or Reduction

Toxicity

Adjustment

Renal Toxicities and Protein Loss Syndrome

Hypoalbuminemia (serum albumin < 0.75X LLNa)

Proteinuria (UPC > 1)

Azotemia (BUN or Creatinine > 1.5X ULNb)

If the current dose is 12.5 mg/kg, discontinue treatment until resolution, then resume treatment at 9 mg/kg.

If the current dose is 9 mg/kg then permanently discontinue treatment.

Non-Regenerative Anemia and Hemolytic Anemia

Hematocrit < 30%

Hemoglobin < 10 g/dL

Permanently discontinue treatment.

Neutropenia

Neutrophils < 1500/µL

If the current dose is 12.5 mg/kg, discontinue treatment until resolution, then resume treatment at 9 mg/kg.

If the current dose is 9 mg/kg, permanently discontinue treatment.

Hepatic Toxicity

ALT or AST > 3X ULN

Bilirubin > 1.5X ULN

If the current dose is 12.5 mg/kg, discontinue treatment until resolution, then resume treatment at 9 mg/kg.

If the current dose is 9 mg/kg, permanently discontinue treatment.

Gastrointestinal Toxicity

Vomiting and Diarrhea

Grade 3 or greaterc

If the current dose is 12.5 mg/kg, discontinue treatment until resolution, then resume treatment at 9 mg/kg.

If the current dose is 9 mg/kg, permanently discontinue treatment.

Other Adverse Reactions

Severe Weight Loss

Permanently discontinue treatment.

a LLN = lower limit of normal

b ULN = upper limit of normal

c Grade 3 diarrhea is an increase of > 6 stools per day over baseline. Grade 3 vomiting is > 5 vomiting episodes in 24 hours, or vomiting for > 4 days.1

Contraindications

Do not initiate KINAVET-CA1 tablet treatment in dogs with:

● Hypoalbuminemia (serum albumin < 1X LLN)

● Proteinuria (urine protein to creatinine [UPC] ratio > 1)

● Azotemia (elevated blood urea nitrogen or creatinine > 1 ULN)

● Anemia (hematocrit <30% or hemoglobin < 10 g/dL)

● Neutropenia (< 2000/µL)

● AST or ALT elevations (> 3X ULN)

● Hyperbilirubinemia (> 1.5X ULN)

Do not use in dogs that are pregnant, lactating, or intended for breeding. Masitinib caused impaired fertility, fetal resorptions and abnormal development (delayed ossification) in rats.

Do not use in dogs that have a hypersensitivity to masitinib.

Warnings

Masitinib was associated with life-threatening or fatal hypoalbuminemia and anemia in field studies and the 39-week safety study. The studies provide evidence that severe adverse reactions may be prevented if dogs are monitored for hypoalbuminemia every 2 weeks and for anemia every 4 weeks, and treatment is discontinued if hypoalbuminemia, proteinuria or anemia occur (see Table 3 and ANIMAL SAFETY).

HUMAN WARNINGS:

NOT FOR USE IN HUMANS. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Children should not come into contact with KINAVET-CA1. Keep children away from feces, urine, or vomit of treated dogs.

To avoid exposure to drug, wash hands with soap and water after administering KINAVET-CA1 and wear protective gloves to prevent contact with feces, urine, vomit, and broken or crushed KINAVET-CA1 tablets. Place all waste material 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.

Pregnant women, women who may become pregnant, or nursing mothers should pay special attention to these handling precautions (see handling instructions above). KINAVET-CA1 may harm an unborn baby (cause birth defects). For pregnant and nursing women, accidental ingestion of KINAVET-CA1 may have adverse effects on pregnancy or the nursing baby.

Precautions

Dogs on KINAVET-CA1 tablets should be monitored as follows:

Every 2 weeks: Hypoalbuminemia, Proteinuria

Every 4 weeks: Azotemia, Anemia, Neutropenia, Elevated AST or ALT, Hyperbilirubinemia

In case of a positive semi-quantitative test for proteinuria (dipstick protein ≥ 30 mg/dL) or clinical signs of anemia or hemolysis, urine protein should be confirmed with a quantitative test (UPC ratio) and the dog should be tested for hypoalbuminemia, anemia, and azotemia.

Refer to Table 3 under DOSAGE AND ADMINISTRATION for management of adverse reactions.

The safe use of KINAVET-CA1 tablets has not been evaluated in dogs younger than 2 years of age. KINAVET-CA1 cannot be safely dosed in dogs weighting less than 7 kg (15.4 lbs).

KINAVET-CA1 is metabolized in the liver. The influence of concomitant drugs that may inhibit metabolism of KINAVET-CA1 tablets has not been evaluated in dogs. Drug compatibility should be assessed for dogs requiring concomitant therapy. Concomitant treatment with drugs which are metabolized by CYP450 isoenzymes (3A4, 3A5, 2C9, 2D6) may result in higher or lower plasma levels of either KINAVET-CA1 or those drugs, and should be used with caution (see CLINICAL PHARMACOLOGY).

The concomitant use of potentially nephrotoxic drugs and KINAVET-CA1 has not been evaluated.

Vascular homeostasis in dogs taking KINAVET-CA1 that require surgery has not been evaluated.

Adverse Reactions

Adverse reactions associated with KINAVET-CA1 treatment include:

General: lethargy, weakness, dehydration, behavioral changes, death

Gastrointestinal: vomiting, diarrhea, bloody stools, melena, constipation, decreased appetite, anorexia

Renal: azotemia, proteinuria, elevated UPC, polyuria, polydypsia, hemoglobinuria, hematuria, nephrotic/protein loss syndrome

Hepatic: elevated liver enzymes, elevated bilirubin, ascites, icterus

Cardiorespiratory: cough, pleural effusion, possible pulmonary thromboembolism, dyspnea, hypertension, tachycardia, cardiomegaly, syncope, circulatory collapse, aspiration pneumonia

Metabolic: pancreatitis, weight loss, tumor lysis syndrome, mast cell degranulation, periodic hypoglycemia

Hematologic: anemia, hemolytic anemia, non-regenerative anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia

Ocular: hyphema

Skin: alopecia, increased incidence of lipomas, subcutaneous edema, pruritis

Other: lymphadenopathy, hemoabdomen, back pain

Refer to Table 3, under DOSAGE AND ADMINISTRATION for management of adverse reactions.

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions, contact AB Science, USA at 973-218-2436 or contact@ab-science.com.

INFORMATION FOR DOG OWNER:

The dog owner or person responsible for administering KINAVET-CA1 to the dog should receive and read the Client Information Sheet, which describes how to safely administer KINAVET-CA1, monitor for possible adverse reactions and clean up any urine, feces or vomit from dogs treated with KINAVET-CA1. The Client Information Sheet also contains warnings for humans and what to do in case of accidental human exposure to KINAVET-CA1.

Clinical Pharmacology

Masitinib is a protein-tyrosine kinase inhibitor. Protein tyrosine kinases are thought to be activated in cancer cells and to drive tumor progression. Tyrosine kinase inhibitor drugs act by interfering with these cell communications and may prevent tumor growth. In vitro, masitinib selectively inhibits the mutated form of the c-Kit receptor (a receptor tyrosine kinase) in the juxtamembrane region and the c-Kit wild-type receptor. It also inhibits the platelet-derived growth factor receptor and the fibroblast growth factor receptor 3.

Following oral administration of 11.2 ± 0.5 mg/kg masitinib, as KINAVET-CA1 tablets, in dogs, masitinib was rapidly absorbed reaching a mean (± 1SD) peak plasma concentration of 895 (± 283) ng/mL at 2.29 (± 0.83) hours. The mean area under the plasma concentration time-curve (AUC 0-24) was 5.70 (± 1.93) µg x hr/mL. The mean elimination half-life (t1/2) is 3.24 (± 0.42) hours. Following administration of KINAVET-CA1 tablets, the fed Cmax was 136% (90% Confidence Limits: 98 - 190%) and the fed AUC was 114% (52 - 252%) of the fasted Cmax and AUC, respectively.

The plasma total body clearance and volume of distribution of masitinib in normal healthy Beagle dogs is approximately 14 mL/min/kg and 17 L/kg, respectively. Masitinib is approximately 90% bound to plasma proteins. Minimal accumulation occurs when masitinib is administered daily at a dose of 12.5 mg/kg. Based on masitinib plasma concentrations at clinically relevant doses in toxicity studies, the inter-animal coefficient of variation in AUC (representing bioavailability) is expected to be about 25%.

Masitinib is metabolized predominantly by N-dealkylation. Elimination is principally in the bile and gastrointestinal tract. In vitro testing with human liver microsomes demonstrated that masitinib inhibits the activity of cytochrome P450 isozymes CYP2C9, 2D6, 3A4 and 3A5. Results of in vitro testing with human hepatocytes were inconsistent; therefore, the potential for masitinib to induce the activity of cytochrome P450 isozymes is unclear.

Effectiveness

Reasonable Expectation of Effectiveness

Effectiveness has not been demonstrated for KINAVET-CA1. A reasonable expectation of effectiveness for conditional approval was based on time to progression (TTP) in a subpopulation of dogs in the following study.

A randomized, placebo controlled, double masked, multi-center field study was conducted to evaluate the safety and effectiveness of KINAVET-CA1 in dogs with Grade II or III cutaneous mast cell tumors recurrent after surgery or nonresectable without regional lymph node involvement. Two hundred and two dogs of various breeds, were enrolled, 161 received KINAVET-CA1 at a starting dose of 12.5 mg/kg orally and 41 received placebo, daily for 6 months, or until disease progression or withdrawal from the study for another cause.

The primary variable, objective response rate after 4 months of treatment, confirmed after 6 months of treatment, failed to show a statistically significant difference between the KINAVET-CA1 and placebo treated dogs: 16.1% of dogs administered KINAVET-CA1 had a complete or partial response compared to 14.6% of dogs administered placebo.

The primary variable failed. However, one of the secondary variables, TTP, in a subpopulation of dogs that did not receive previous chemotherapy and/or radiotherapy except corticosteroids, demonstrated a reasonable expectation of effectiveness. One hundred and thirteen dogs treated with KINAVET-CA1 had an increase in median TTP of 52.5 days compared to 30 dogs treated with placebo (p-value=0.0143). The median TTP in the KINAVET-CA1 group was 118 days, 80% longer than the placebo group with a median time to progression of 65.5 days. The study was not designed for TTP to support substantial evidence of effectiveness.

ANIMAL SAFETY:

The margin of safety and toxicity profile of masitinib (not commercial formulation) was evaluated in three laboratory safety studies (for 4, 13, and 39 weeks) in healthy 6 to 7 month old Beagle dogs. Masitinib has a narrow margin of safety, and one death occurred after 33 weeks of treatment with 20.9 mg/kg/day, a dose comparable to 1.4X the maximum KINAVET-CA1 label dose of 15.0 mg/kg/day. (See Safety Study Results, below. See Table 3, WARNINGS and PRECAUTIONS for risk management.) The results of the safety studies provide the following toxicity profile for masitinib: bone marrow suppression (anemia, neutropenia, and bone marrow hypocellularity), evidence of red blood cell sequestration (splenic hemosiderosis), proteinuria and hypoalbuminemia without kidney lesions on histopathology, liver abnormalities (mildly increased liver enzymes, histopathologic lesions), gastrointestinal signs, and increased coagulation values. The 13-week safety study provides evidence that these adverse effects are reversible.

Safety Studies Results: There were no signs of toxicity at 2.1 mg/kg (0.14X) for 39 weeks or 3.5 mg/kg (0.23X) for 13 weeks.

In the 4, 13, and 39-week studies at 7.0 mg/kg (0.5X) and 10.5 mg/kg (0.7X), clinical signs included transient and infrequent vomiting, soft feces, lethargy, and muscle weakness; erythema of the neck or muzzle, pallor, mild anemia, and mild proteinuria. After 39 weeks at 7.0 mg/kg (0.5X), histopathology findings included splenic hemosiderosis, brownish pigment deposits in hepatic Kupffer cells and lymph nodes, and increased lipoid tissue in the bone marrow.

In the 39-week study at 20.9 mg/kg (1.4X), a female developed severe hypoalbuminemia and proteinuria, and moderate anemia, by week 25. She was euthanized in week 33 because of ascites, emaciated appearance, decreased appetite, lateral recumbency, pallor, and severe anemia, hypoalbuminemia, hypoproteinemia, and proteinuria. She had thrombocytosis, hematuria, lymphopenia, and increased activated partial thromboplastin time (APTT), fibrinogen, and blood urea nitrogen. Necropsy and histopathology findings included pericardial, subcutaneous, and tissue edema, and severe lymphoid depletion of the thymus. Other dogs on 20.9 mg/kg (1.4X) masitinib had vomiting, lethargy, pallor, erythema of the neck, hind leg stiffness, mild anemia, neutropenia, hypoalbuminemia, and proteinuria. Histopathology findings were similar to those at 7.0 mg/kg (0.5X), but more pronounced.

In the 4 and 13-week studies at 35.1 mg/kg (2.3X), clinical signs included vomiting, diarrhea, pallor, and lethargy. Clinical pathology findings included anemia, neutropenia, decreased eosinophils, and mild hypoalbuminemia, and mild increases in APTT, fibrinogen, and liver enzymes (alanine aminotransferase and alkaline phosphatase). Histopathology findings included slight hepatocellular hypertrophy, bile canalicular plugs, vacuolated and brownish pigment-laden Kupffer cells in the liver, cystic epithelial hyperplasia of the gall bladder, foamy macrophages in the mesenteric lymph node, chronic interstitial pneumonitis, acute esophagitis, increased lipoid tissue in the bone marrow, and bone marrow hypocellularity.

After 13 weeks of treatment, a subset of dogs from the 35.1 mg/kg (2.3X) treatment group were given a 4-week treatment-free recovery period. At the end of this period, the recovery dogs did not have the adverse clinical pathology and histopathology findings that were observed in dogs at the end of the 13 weeks of treatment.

In the 4-week study at 105.5 mg/kg (7.0X), clinical signs, clinical pathology, and histopathology results were similar but more severe than at 35.1 mg/kg (2.3X), and also included blood-tinged feces, decreased appetite, increased heart rate, weight loss, proteinuria, hematuria, hepatomegaly, vacuolated hepatocytes, a markedly increased myeloid to erythroid ratio, lymphoid depletion of the thymus, histiocytosis in the spleen, and foamy alveolar macrophages in the lungs.

STORAGE CONDITIONS:

Keep at controlled room temperature (15-25°C; 59-77°F), in the original packaging, away from a source of heat or humidity.

How Supplied

KINAVET-CA1 is supplied in white high density polyethylene (HDPE) bottles containing 30 tablets of 50mg masitinib base or 150mg masitinib base.

References

1. Veterinary co-operative oncology group - common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol 2004;2(4):195-213.

Manufactured by: Catalent Pharma Solutions, Somerset, NJ 08873 USA

Manufactured for: AB Science, 3, Avenue George V, 75008 - PARIS (France)

7910 Kinavet CA1 V01

NAC No.: 15420001

AB SCIENCE USA, L.L.C.
51 JFK PARKWAY, FIRST FLOOR WEST, SHORT HILLS, NJ, 07078
Telephone:   973-218-2437
Fax:   973-218-2401
Website:   www.ab-science.com
Email:   contact@ab-science.com
Every effort has been made to ensure the accuracy of the Kinavet-CA1 information published above. However, it remains the responsibility of the readers to familiarize themselves with the product information contained on the US product label or package insert.

Copyright © 2014 North American Compendiums. Updated: 2014-04-11

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