Tanovea-CA1: Product Information (Page 3 of 5)

Serious Adverse Reactions

Serious adverse events (SAEs) were reported in 20% of dogs in the TANOVEA group (24 of 120 dogs) and 13% of dogs in the placebo group (five of 38 dogs). In the 24 TANOVEA dogs, SAEs included pulmonary fibrosis (five dogs) and dermatopathy (six dogs) as described below. Other SAEs included three cases of progressive disease (Grade 5), three cases of unrelated neoplasia/comorbidities, and one case each of hepatopathy (Grade 3), renal insufficiency (Grade 3), neutropenia (Grade 4), nausea (Grade 3), lymph node abscess (Grade 3), colitis (Grade 3), and hematochezia (Grade 3).

Pulmonary Fibrosis

Five dogs in the TANOVEA group developed severe adverse reactions associated with pulmonary fibrosis. The clinical signs included dyspnea, tachypnea, and orthopnea. Four of these dogs also had pneumomediastinum, pneumothorax, and/or emphysema diagnosed radiographically. All five dogs had radiographic findings that could be associated with pulmonary fibrosis along with accompanying pulmonary clinical signs. All five dogs were euthanized (four dogs) or died (one dog) due to the pulmonary fibrosis (either during the study or after removal from the study). Two of these dogs had a histologic confirmation of fibrosis on necropsy. The median time from randomization to first detection of clinical signs was 87 days (range 84 to 140) and the median time from randomization to death was 127 days (range 112 to 172). At the time of withdrawal (due to adverse reactions), all five dogs had a complete response to treatment. Pulmonary fibrosis may be an idiosyncratic adverse reaction with an unknown mechanism of action.

Dermatopathy

Over half of the patients (67/120 dogs) treated with TANOVEA experienced one or more dermatologic adverse reactions during their treatment. These adverse reactions were predominantly Grade 1 and primarily included otitis, alopecia, dermatitis, erythema, pruritus, hyperpigmentation, skin ulcerations, and bacterial skin infections.

Dermatologic adverse reactions typically presented by Cycle 3 (after the third dose), suggesting a cumulative effect of TANOVEA-associated dermatopathy. Dose reductions and dose delays were implemented to mitigate dermal adverse reactions. Six dogs in the TANOVEA group had Grade 3 or Grade 4 dermal adverse reactions which appeared in Cycle 2 (two dogs), Cycle 3 (three dogs), and Cycle 5 (one dog). Grade 3 adverse reactions included bacterial skin infections, skin ulcerations, desquamation, and dermatitis. Grade 4 adverse reactions included skin ulceration (severe erythema and ulceration of skin on limbs, ventrum, and foot pads) and desquamation (moist desquamation along the inguinal region and encompassing perivulvar area).

Euthanasia

Nine dogs in the TANOVEA group (8%) and two dogs in the placebo group (5%) were euthanized while on study. Reasons for euthanasia included four cases of progressive lymphoma (one with multiple comorbidities and pre-existing dermatopathy), two cases of pulmonary fibrosis, one case of probable hemangiosarcoma, one case of pyelonephritis/renal failure, and one case was unspecified. An additional three dogs died/were euthanized after withdrawal from the study due to suspected pulmonary fibrosis. One dog was euthanized after withdrawal from the study due to sepsis secondary to dermatopathy.

Dose Reductions and Dose Delays

Twenty-nine dogs in the TANOVEA group dogs received dose reductions (from 1 to 0.8 mg/kg), which were typically employed on the second to fourth dose of TANOVEA. Four dogs received a second stepwise reduction (from 0.8 to 0.66 mg/kg), which were employed on the third to fifth dose. The primary reason for dose reduction was gastrointestinal toxicity (diarrhea, vomiting, nausea), followed by dermatopathies, weight loss, anorexia/hyporexia, neutropenia, thrombocytopenia, and hypoalbuminemia. All dogs continued on the reduced dose(s) for the remainder of the study or until withdrawn.

Fourteen dogs in the TANOVEA group had a dose delay, which typically was one week beyond the intended treatment day. The primary reason cited in all cases was dermatopathy, and one case also cited weight loss. Eight dogs had both a dose reduction and delay, primarily attributable to dermatopathies.

Infusion Site Observations

On the day of treatment, two incidences of bruising were reported in dogs in the TANOVEA group. Infusion site observations seven days after treatment in dogs in the TANOVEA group included pigmentation (seven incidences), scaling (five incidences), erythema (three incidences), and swelling (two incidences).

Conditional Approval Experience:

Rabacfosadine for injection was conditionally approved and marketed from 2016-2021 under the proprietary name TANOVEA-CA1. The adverse events voluntarily reported for TANOVEA-CA1 (i.e., reports not associated with the clinical study) were similar to those described in the ADVERSE REACTIONS section above.

CONTACT INFORMATION:

To report suspected adverse events, for technical assistance, or to obtain a copy of the Safety Data Sheet, contact VetDC, Inc at 1-877-468-3832.

For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae.

INFORMATION FOR DOG OWNERS:

Always provide the Client Information Sheet and review it with the dog owner or person responsible for care of the dog. Advise dog owners about possible adverse reactions, when to contact a veterinarian, and how to clean up any feces, urine, vomit, or saliva from dogs treated with TANOVEA. The Client Information Sheet also contains warnings for humans and what to do in case of accidental human exposure to TANOVEA.

CLINICAL PHARMACOLOGY:

Rabacfosadine is a prodrug of 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2, 6-diaminopurine (cPrPMEDAP) and 9-(2-phosphonylmethoxyethyl) guanine (PMEG). Rabacfosadine is hydrolyzed intracellularly to cPrPMEDAP and subsequently deaminated to PMEG. PMEG is then converted to its active phosphorylated form, PMEG diphosphate (PMEGpp), which is a potent, chain-terminating inhibitor of the major nuclear, replicative deoxyribonucleic acid (DNA) polymerases. The two prodrug moieties present in rabacfosadine increase the permeability and accumulation of metabolites in various cell types including peripheral blood mononuclear cells (PBMCs).

In vitro rabacfosadine has been demonstrated to inhibit DNA synthesis, resulting in S phase arrest and induction of apoptosis. Also in vitro rabacfosadine inhibits the proliferation of mitogen-stimulated lymphocytes and lymphoma/leukemia cell lines.

The in vivo data from studies in healthy dogs and dogs with lymphoma illustrated rapid clearance of rabacfosadine following a 30-minute intravenous infusion resulting in plasma exposure to the metabolite cPrPMEDAP and undetectable levels of the generally more cytotoxic agent PMEG. The exposure of rabacfosadine and cPrPMEDAP was linear with no gender differences. The mean peak plasma concentrations (Cmax ) for rabacfosadine and cPrPMEDAP occurred at approximately 30 minutes (Tmax ) and 1-2 hours, respectively. In dogs with lymphoma, rabacfosadine and cPrPMEDAP had a plasma half-life of <0.5 hour and 6 hours, respectively. In contrast to plasma, high concentrations of PMEG were readily detectable in PBMCs. Following rabacfosadine administration at 1 mg/kg over 30 minutes by intravenous infusion (once every two or three weeks), cPrPMEDAP and PMEGpp concentrations in lymphoid cells and tissues (represented by PBMCs) were 131 and 1,420 nM, respectively. In lymphoid cells, high concentrations of the active metabolite PMEGpp accumulated and persisted for greater than 24 hours. In PBMCs, the metabolites cPrPMEDAP and PMEGpp showed a terminal half-life of 25 hours and 68.7 hours, respectively. The observed PMEGpp concentrations in lymphoid cells and tissues are sufficient to allow for the desired antiproliferative effect following a single intravenous infusion administered once every three weeks.

Following intravenous administration of [14 C]-rabacfosadine to dogs, the excretion of radiolabeled material was similar in both feces and urine accounting for 42.4% and 32.5% of the dose, respectively, at 120 hours.

By 24 hours, radioactivity was widely distributed throughout the body. Some of the highest concentrations in tissues observed, with the exception of excretory organs, were found in lymphoid tissues. The mean overall elimination of radioactivity after intravenous dosing was 79.7% over 120 hours.

Approximately 10% of the administered dose was retained in tissues. The overall mass balance including radioactivity retained in the tissues would be estimated to be a mean of 88.8%. No central nervous system penetration was observed.

While the cytotoxic agent PMEG has been observed in PBMCs, PMEG was not observed in the liver, kidney, bile, or urine following administration of [14C]-rabacfosadine to dogs. Because the effective clinical plasma concentration is anticipated to be <2 μM and rabacfosadine is a prodrug that has a short half-life in dogs, rabacfosadine is unlikely to be a clinically relevant inhibitor or inducer of the major CYP450 pathways.

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