Palladia: Product Information (Page 2 of 5)

Contraindications

Do not use in dogs used for breeding, or for pregnant or lactating bitches (see Clinical Pharmacology).

Warnings

PALLADIA 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 (see Adverse Reactions).

Serious and sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred rarely in dogs treated with PALLADIA (see Adverse Reactions). 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 PALLADIA. Keep children away from feces, urine, or vomit of treated dogs. To avoid exposure to drug, wash hands with soap and water after administering PALLADIA and wear protective gloves to prevent direct contact with feces, urine, vomit, and broken or moistened PALLADIA tablets. 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.) PALLADIA, like other drugs in its class, prevents the formation of new blood vessels in tumors. In a similar manner, PALLADIA may affect blood vessel formation in the developing fetus and may harm an unborn baby (cause birth defects). For pregnant women, accidental ingestion of PALLADIA may have adverse effects on pregnancy.

Precautions

Temporarily discontinue the use of PALLADIA if anemia, azotemia, hypoalbuminemia, and hyperphosphatemia occur simultaneously. Resume treatment at a dose reduction of 0.5 mg/kg after 1 to 2 weeks when values have improved and albumin is >2.5 g/dL. Temporary treatment interruptions may be needed if any one of these occurs alone: hematocrit <26%, creatinine ≥2.0 mg/dL or albumin <1.5 g/dL. Then resume treatment at a dose reduction of 0.5 mg/kg once the hematocrit is >30%, the creatinine is <2.0 mg/dL, and the albumin is >2.5 g/dL.

Temporarily discontinue the use of PALLADIA if neutrophil count is ≤1000/μL. Resume treatment after 1 to 2 weeks at a dose reduction of 0.5 mg/kg, when neutrophil count has returned to >1000/μL. Further dose reductions may be needed if severe neutropenia reoccurs.

The presence of systemic mast cell tumor prior to treatment may predispose a dog to clinically significant mast cell degranulation with possible severe systemic adverse reactions when treated with PALLADIA. Attempts should be made to rule out systemic mastocytosis prior to initiation of treatment with PALLADIA.

PALLADIA has been associated with severe diarrhea or GI bleeding that requires prompt treatment. Dose interruptions and dose reductions may be needed depending upon the severity of clinical signs. (See Table 2 in Dosage and Administration.)

Use non-steroidal anti-inflammatory drugs with caution in conjunction with PALLADIA due to an increased risk of gastrointestinal ulceration or perforation.

PALLADIA is metabolized in the liver. Co-administration of PALLADIA with strong inhibitors of the CYP3A4 family may increase PALLADIA concentrations. The effect of concomitant medications that may inhibit the metabolism of PALLADIA has not been evaluated. Drug compatibility should be monitored in patients requiring concomitant medications.

The safe use of PALLADIA has not been evaluated in dogs less than 24 months of age or weighing less than 5 kg.

Adverse Reactions

A US clinical field study comprised of a 6-week masked phase, followed by an open-label phase, evaluated the safety and effectiveness of PALLADIA in 151 client-owned dogs that had Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement. The most common adverse reactions reported during the masked phase are summarized in Table 3; those reported during the entire study (masked phase combined with the open-label phase) are summarized in Table 4.

Table 3. Summary of the most common adverse reactions during the masked phase *
Placebo (n = 64) PALLADIA (n = 87)
*
The mean time on study during the masked phase was 37.0 days for PALLADIA-treated dogs (median, 42.0 days) and 27.6 days for placebo-treated dogs (median, 21.0 days); no adjustments were made in the statistical comparisons for this disparity.
Investigators assigned severity grade of 1, 2, 3 or 4 (1 — least severe; 4 — most severe).
Grading of laboratory abnormalities was based on the National Cancer Institute’s Common Toxicity Criteria guideline adapted for canines (1 — least severe; 4 — most severe).
Adverse Reaction Any Grade Grade 3 or 4 Any Grade Grade 3 or 4
Diarrhea 26.6% 3.1% 46.0% 6.9%
Anorexia 31.3% 6.3% 39.1% 6.9%
Lethargy 29.7% 3.1% 35.6% 4.6%
Vomiting 32.8% 6.3% 32.2% 9.2%
Lameness 9.4% 0.0% 17.2% 0.0%
Weight loss 3.1% 0.0% 14.9% 1.1%
Blood in stool/GI bleed/hemorrhagic diarrhea 3.1% 0.0% 12.6% 2.3%
Musculoskeletal disorder 6.3% 0.0% 11.5% 1.1%
Dehydration 4.7% 0.0% 9.2% 2.3%
Dermatitis 9.4% 1.6% 9.2% 0.0%
Pruritus 4.7% 0.0% 9.2% 0.0%
Tachypnea 4.7% 0.0% 8.0% 1.1%
Localized pain 4.7% 0.0% 8.0% 0.0%
Nausea 3.1% 0.0% 8.0% 1.1%
General pain 4.7% 1.6% 6.9% 0.0%
Polydipsia 7.8% 0.0% 6.9% 0.0%
Pyrexia 3.1% 0.0% 5.7% 2.3%
Flatulence 3.1% 0.0% 5.7% 0.0%
Pigmentation disorder 1.6% 0.0% 5.7% 0.0%
Laboratory Abnormality Any Grade Grade 3 or 4 Any Grade Grade 3 or 4
Neutropenia 6.3% 0.0% 46.0% 0.0%
Thrombocytopenia 20.3% 0.0% 24.1% 0.0%
Increased alanine aminotransferase 21.9% 4.7% 24.1% 1.1%
Hypoalbuminemia 7.8% 0.0% 12.6% 0.0%
Decreased hematocrit 7.8% 0.0% 5.7% 3.4%
Hyperbilirubinemia 1.6% 1.6% 5.7% 0.0%
Increased creatinine 4.7% 0.0% 5.7% 0.0%
Urinary tract infection 1.6% 0.0% 5.7% 0.0%
Table 4. Summary of the most common adverse reactions during the study (masked phase combined with the open-label phase)*
PALLADIA (n = 145) *
Other adverse events were reported but occurred in < 5% of dogs. Any individual dog may have had multiple adverse events.
*
The duration of treatment with PALLADIA ranged from 2 to 812 days (mean, 144 days; median, 68 days). All dogs received at least 1 dose of PALLADIA.
Investigators assigned severity grade of 1, 2, 3 or 4 (1 – least severe; 4 – most severe).
Grading of laboratory abnormalities was based on the National Cancer Institute’s Common Toxicity Criteria guideline adapted for canines (1 – least severe; 4 – most severe).
Adverse Reactions Any Grade Grade 3 or 4
Diarrhea 58.6% 8.3%
Anorexia 49.7% 8.3%
Vomiting 47.6% 9.7%
Lethargy 39.3% 4.1%
Lameness 22.8% 0.0%
Weight loss 21.4% 2.8%
Blood in stool/GI bleed/hemorrhagic diarrhea 18.6% 2.8%
Dehydration 15.2% 2.1%
Pruritus 12.4% 0.0%
Pigmentation disorder 11.7% 0.0%
Dermatitis 11.0% 0.0%
Musculoskeletal disorder 11.0% 0.0%
General pain 8.3% 0.0%
Otitis externa 8.3% 0.0%
Tachypnea 8.3% 0.0%
Nausea 7.6% 1.4%
Polydipsia 7.6% 0.0%
Pyrexia 6.9% 2.8%
Arthritis 6.2% 0.0%
Localized edema 6.2% 0.0%
Bacterial skin infection 5.5% 0.0%
Conjunctivitis 5.5% 0.0%
Laboratory Abnormality Any Grade Grade 3 or 4
Neutropenia 44.8% 1.4%
Hypoalbuminemia 28.3% 1.4%
Thrombocytopenia 28.3% 2.1%
Increased alanine aminotransferase 27.6% 4.1%
Decreased hematocrit 11.0% 2.8%
Increased creatinine 13.8% 1.4%
Hyperbilirubinemia 6.9% 0.0%
Urinary tract infection 7.6% 0.0%

There were 5 deaths during this study that were possibly drug related. Pathology findings generally revealed evidence of vascular dysfunction including pulmonary thromboembolism (post-operative); multi-organ failure associated with vasculitis and thrombosis; vascular thrombosis with disseminated intravascular coagulopathy (DIC) and pancreatitis; and vasculitis with DIC. One dog died secondary to gastric perforation; the duration of treatment with PALLADIA was 221 days and there was no evidence of mast cell tumor at necropsy. These deaths occurred in the presence or absence of gross-disease; treatment durations ranged from 18 to 221 days.

The relationship of the following deaths to drug are unknown. One dog, first treated for 3 weeks with a placebo, died of unknown cause 7 days after initiation of PALLADIA therapy. Another dog died of unknown cause 92 days after initiation of PALLADIA therapy. No necropsy was conducted in either dog.

Twenty seven dogs developed some form of gastrointestinal bleeding with 2.8% of dogs having severe bleeding. One dog developed gastric ulceration which was possibly drug related. Three dogs died from gastric (1 dog) or duodenal (2 dogs) perforations during the study. One dog with a duodenal perforation received only 1 dose of study drug and, therefore, was not considered drug related.

Seven dogs developed nasal depigmentation within the first few weeks of treatment. Eleven dogs developed coat color or skin changes during the study. Two of these dogs had complete coat color changes from fawn to white and from deep red to blonde. Seven dogs experienced alopecia.

There is a drug related effect on body weight: 20.0% of dogs had >13% weight loss in the masked plus open-label phase attributable to drug. Of these, 5 dogs had >25% weight loss. Three dogs had seizure-like activity while on study drug. It can not be determined if these were drug related.

Two dogs developed epistaxis that was not associated with thrombocytopenia. Another dog developed epistaxis with concurrent disseminated intravascular coagulopathy.

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse events call Zoetis at 1-888-963-8471.

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