Ingenol Mebutate

IDENTIFICATION AND USE: Ingenol mebutate is a white to pale yellow crystalline powder. As the drug Picato, it is used as a gel for the topical treatment of actinic keratosis. HUMAN EXPOSURE AND TOXICITY: Results from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirradiation, or photoallergic potential. However, topical overdosing could result in an increased incidence of local skin reactions. ANIMAL STUDIES: In rats given repeat IV dosing for 28 days, treatment-related effects included transient tachypnea, which was not dose-related, lethargy and/or subdued behavior and decreased food consumption. In mice dosed for 7 consecutive days, one animal receiving 60 ug/kg/day and all animals receiving >/= 80 ug/kg/day were killed prematurely after </= 4 days of dosing because of the severity of physical signs, which were dose-related. In mini-pigs, no deaths occurred at 5 ug/kg/day ingenol mebutate for 4 consecutive days or 3 ug/kg/day for 28 days. Treatment-related effects were limited to sporadic and transient subdued behavior, emesis and slightly reduced body weight gain post-dose at 2.5 ug/kg/day. An increase in embryo-fetal mortality as well as increased incidence of fetal visceral and skeletal variations was noted in pregnant rabbits exposed to ingenol mebutate intravenously. No treatment related effects on embryofetal toxicity or teratogenicity were noted after intravenous administration to pregnant rats. Ingenol mebutate was not mutagenic in an in vitro Ames test, mouse lymphoma assay, and in vivo rat micronucleus test. An in vitro Syrian hamster embryonic (SHE) cell transformation assay was positive. A 6-month repeat dose IV rat study in 154 rats found that one male and one female dosed twice weekly with 15 ug/kg had a kidney tubular adenoma and tubular hyperplasia of the kidney. A pituitary adenoma was also present in the female with the renal adenoma. At the 1-month recovery kill, one male had a thyroid follicular cell carcinoma.

/HUMAN EXPOSURE STUDIES/ Healthy volunteers were enrolled in single-center, randomized, controlled, within-subject comparison trials. PEP005-005 was designed as a repeat-insult patch test study. In PEP005-023, treatment areas were examined after irradiation for photoirritation potential; dermal reactions were evaluated. In PEP005-024, irradiation was performed to determine the photoallergic (photosensitizing) potential of the medication. All treatment areas were graded immediately prior to irradiation and 24, 48, and 72 hours following irradiation. In all studies, local tolerability was assessed visually using an ordinal scoring system at set intervals before and after medication application/irradiation. In PEP005-005 (n=238), a significant difference (p<0.001) was seen between ingenol mebutate and vehicle for mean and total cumulative irritation scores. In PEP005-023 (n=34), mild erythema in all irradiated treatment areas was as expected for the ultraviolet dose. There was no clinically significant irritation in response to ingenol mebutate or vehicle, irrespective of irradiation. In PEP005-024 (n=60), there was no significant irritation in response to either ingenol mebutate or vehicle at their irradiated treatment areas. Results from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirritation, or photoallergic potential.

/SIGNS AND SYMPTOMS/ Topical overdosing of Picato gel could result in an increased incidence of local skin reactions.

/CASE REPORTS/ Actinic keratoses (AKs) are defined as cutaneous areas of atypical squamous transformation that are regarded as an early step in the continuum of alterations leading from normal skin to invasive and metastatic squamous cell carcinoma (SCC). AKs are classified as precancerous lesions by some authors and in situ SCC by others. The rate of evolution of a given AK to an invasive SCC has been estimated as 0.075-0.096% per lesion per year. These rates are similar to those estimated for gynaecological intraepithelial neoplasia. We describe two cases of SCC with rapid onset that developed after the application of ingenol mebutate gel for the treatment of AKs.

/ALTERNATIVE and IN VITRO TESTS/ PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKC delta and inhibiting PKC alpha. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterized for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC(50) of PEP005 ranged from 0.01-140 microM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 microM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKC delta and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 hr lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimize clinical trials with PEP005-based combinations in patients with solid tumors.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In rats, no deaths, or macroscopic or microscopic findings of systemic toxicity were observed following 28 days repeat IV dosing at < or = 15 ug/kg/day. Treatment-related effects included transient tachypnea, which was not dose-related, lethargy and/or subdued behavior and decreased food consumption at doses > or = 5 ug/kg/day. A NOAEL of 7.5 ug/kg/day was identified.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In mice dosed for 7 consecutive days, one animal receiving 60 ug/kg/day and all animals receiving > or = 80 ug/kg/day were killed prematurely after < or = 4 days of dosing because of the severity of physical signs, which were dose-related. Treatment-related effects observed at > or = 30 ug/kg/day were piloerection, subdued behavior, hunched appearance, irregular respiration; at > or = 60 ug/kg/day, unkempt appearance, prostration, skin cold to the touch, slow respiration and partially closed eyes; at > or = 80 ug/kg/day, body tremors; and at 100 ug/kg/day, dark extremities, discolored skin and bulging eyes. There were no treatment-related effects on body weight, food consumption, or macroscopic or microscopic findings. The NOAEL for IV repeat dose ingenol mebutate was 30 ug/kg/day in mice.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In mini-pigs, no deaths occurred at 5 ug/kg/day ingenol mebutate for 4 consecutive days or 3 ug/kg/day for 28 days. Treatment-related effects were limited to sporadic and transient subdued behavior, emesis and slightly reduced body weight gain post-dose at 2.5 ug/kg/day. There were no toxicologically significant macroscopic or microscopic findings. The NOAEL was 3 ug/kg/day.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ IV administration of ingenol mebutate for six-months at doses > or = 1.5 ug/kg/day twice weekly or at 15 ug/kg/day once weekly was associated with labored/rapid respiration, lethargy, and premature death related to pulmonary vessel thrombosis. Reversible minor effects on body weight gain and food consumption were noted in rats given > or = 7.5 ug/kg/day ingenol mebutate. Renal tubular adenoma (n = 2), and pituitary adenoma (n = 1) were observed in rats given 15 ug/kg/day ingenol mebutate twice weekly. Hyperplasia of the renal tubules was also seen in the animals with renal adenomas, and hyperplasia of the pituitary was seen in one male at 7.5 ug/kg/day and in 1, 5, 2, 0 and 1 female at 0, 1.5, 7.5, 15 twice per week and 15 ug/kg/day once per week. However, pituitary tumors are common in laboratory animals and the incidences were not dose-related. At recovery necropsy, a thyroid carcinoma (n = 1) was observed in one male at 15 g/kg/day twice per week. The NOAEL for bolus IV administration of ingenol mebutate was <1.5 g/kg/day in rats.

For more Non-Human Toxicity Excerpts (Complete) data for Ingenol mebutate (10 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ingenol mebutate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.