Piperacillin/Paboxinib

[otw_shortcode_tabslayout tabs=”10″ tab_1_title=”Indications” tab_1_content=”This product is indicated for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer and should be used in combination with an aromatase inhibitor as initial endocrine therapy in postmenopausal female patients.” tab_2_title=”Dosage” tab_2_content=”Treatment with this product should be initiated and supervised by a physician experienced in the use of anticancer drugs. Recommended Dose The recommended dose of piperacillin is 125 mg once daily for 21 days, followed by a 7-day discontinuation (3/1 dosing regimen) for a 28-day treatment cycle. Treatment should be continued unless the patient no longer has clinical benefit or develops unacceptable toxicity. When used in combination with letrozole, the recommended dose of letrozole is 2.5 mg orally, once daily, continuously throughout a 28-day treatment cycle. See approved instructions for letrozole for details. Method of administration Oral. It should be taken with food, preferably with a meal to ensure consistent exposure to piperacillin (see [Pharmacokinetics]). Pipercillin should not be taken with grapefruit or grapefruit juice (see [Drug Interactions]). Pipercillin capsules should be swallowed whole (capsules should not be chewed, crushed, or opened before swallowing). Capsules should not be taken if they are broken, cracked, or otherwise incomplete. Patients should be encouraged to take the medication at approximately the same time each day. If a patient vomits or misses a dose, the dose should not be made up that day. The next dose should be taken as usual. Dose Adjustment It is recommended that the dose of piperacillin be adjusted according to individual safety and tolerability. Some adverse reactions may require temporary interruption/delayed dosing and/or dose reduction or permanent discontinuation for control, so refer to the regimens provided in Tables 1, 2, and 3 for dose adjustment (see [Precautions] and [Adverse Reactions]). For patients with grade 1 or 2 neutropenia of maximum severity occurring within the first 6 cycles of therapy, complete blood count monitoring should be performed every 3 months, prior to the start of each cycle, and when clinically indicated, for subsequent cycles. It is recommended that piperacillin be received when the Absolute Neutrophil Count (ANC) is ≥1,000/mm3 and the platelet count is ≥50,000/mm3. Table 2. Dose Adjustment and Management of Piperacillin-Hematologic Toxicity Special Populations Elderly Piperacillin dose adjustment is not required in patients ≥65 years of age (see [Pharmacokinetics]). Pediatric Population The safety and efficacy of piperacillin in pediatric and adolescent patients ≤18 years of age have not been established. No data are available. Hepatic Injury No dose adjustment of piperacillin is required in patients with mild or moderate hepatic injury (Child-Pugh Class A and B). The recommended dose for patients with severe hepatic impairment (Child-Pugh Class C) is 75 mg once daily on a 3/1 dosing regimen (see [Precautions] and [Pharmacokinetics]). Renal impairment No dose adjustment of piperacillin is required in patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min). Data from patients requiring hemodialysis are insufficient to provide any dose adjustment recommendations for this population (see [Precautions] and [Pharmacokinetics]). Dose Adjustment in Combination with CYP3A Potent Inhibitors Avoid concomitant use of CYP3A potent inhibitors and consider substitution for other concomitant agents with no or minimal CYP3A inhibition. If patients must be co-administered with a potent CYP3A inhibitor, reduce the dose of piperacillin to 75 mg once daily. If the potent inhibitor is discontinued, increase the dose of piperacillin to the dose prior to starting the potent CYP3A inhibitor (after 3 to 5 half-lives of the inhibitor) [see [Drug Interactions] and [Pharmacokinetics]” tab_3_title=”Adverse Reactions” tab_3_content=”This instruction describes the effects observed in clinical trials that were judged to be adverse reactions that may be caused by piperacillin and their approximate incidence. Because conditions in each clinical trial vary, the incidence of adverse reactions observed in one clinical trial is not directly comparable to the incidence of adverse reactions observed in another clinical trial and may not reflect the actual incidence in clinical practice. The overall safety profile of piperacillin was evaluated from a combined data set of 872 patients treated with piperacillin in combination with endocrine therapy (527 in combination with letrozole and 345 in combination with fulvestrant) in randomized studies of HR-positive, HER2-negative advanced or metastatic breast cancer [including study PALOMA-1 (A5481003), study PALOMA-2 (A5481008), study PALOMA-3 (A5481023)]. The most common (≥20%) adverse reactions of any grade reported by patients treated with piperacillin in clinical studies were neutropenia, infection, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, and diarrhea. The most common (≥2%) Grade ≥3 adverse reactions to piperacillin were neutropenia, leukopenia, anemia, fatigue, and infection. The safety of piperacillin (125 mg/day) in combination with letrozole (2.5 mg/day) was evaluated in study PALOMA-2 against placebo in combination with letrozole. The median duration of treatment was 19.8 months for piperacillin in combination with letrozole compared with 13.8 months for placebo in combination with letrozole. Dose reductions due to adverse reactions of any grade occurred in 36% of patients treated with piperacillin in combination with letrozole. 43/444 (9.7%) patients treated with piperacillin in combination with letrozole and 13/222 (5.9%) patients treated with placebo in combination with letrozole experienced permanent discontinuation associated with adverse reactions. Adverse reactions leading to permanent discontinuation in patients treated with piperacillin in combination with letrozole included neutropenia (1.1%) and elevated alanine transaminase (0.7%). List of Adverse Reactions Table 4 reports adverse reactions from the combined data set of 3 randomized studies [Study PALOMA-1 (A5481003), Study PALOMA-2 (A5481008), Study PALOMA-3 (A5481023)]. The median duration of piperacillin treatment in the combined dataset was 12.7 months. Table 5 reports abnormal laboratory tests in the combined data set of the 3 randomized studies. Adverse reactions are listed by system organ classification and frequency of occurrence. Frequency was defined as very common (≥1/10), common (≥1/100 to <1/10), and occasional (≥1/1,000 to <1/100). Table 4. Adverse reactions based on the combined dataset of 3 randomized studies (N=872) Two studies, PALOMA-2 and PALOMA-3, enrolled 200 patients of Asian descent. The incidence of grade 3 or 4 neutropenia and leukopenia was reported more frequently in Asian patients receiving piperacillin than in non-Asian patients, and consequently dose interruptions, dose reductions, and cycle delays occurred slightly more frequently in Asian patients than in non-Asian patients, but overall safety was controlled by protocol-specified dose adjustments, and Asian patients had similar median treatment duration as non-Asian patients. Based on a cumulative analysis of available data on piperacillin dose exposure, safety and efficacy, a starting dose of 125 mg once daily is appropriate for Asian patients. The dose of piperacillin should be adjusted according to the safety and tolerability of the individual patient and in strict accordance with the instructions. Overall, 703 (80.6%) patients treated with piperacillin regardless of the combination regimen reported any grade of neutropenia in the 3 randomized studies, with 482 (55.3%) and 88 (10.1%) patients reporting grade 3 and 4 neutropenia, respectively (see Table 4). In the 3 randomized clinical studies, the median time to first neutropenia of any grade was 15 days (12-700 days), and the median duration of grade ≥3 neutropenia was 7 days. Febrile neutropenia was reported by 0.9% of patients receiving piperacillin in combination with fulvestrant and 2.1% receiving piperacillin in combination with letrozole. In the overall clinical study, approximately 2% of patients treated with piperacillin had reported febrile neutropenia.” tab_4_title=”Contraindications” tab_4_content=”Contraindicated in cases of hypersensitivity to the active ingredient or to any of the excipients listed under [Ingredients] in the section. The use of products containing St. John’s wort is prohibited (see [Drug Substitute Interactions]).” tab_5_title=”Special Populations” tab_5_content=”Population Use Pregnant/Lactating Elderly Children ” tab_6_title=”Precautions” tab_6_content=”Pre/Perimenopausal Women Given the mechanism of action of aromatase inhibitors, pre/perimenopausal women receiving piperacillin in combination with an aromatase In view of the mechanism of action of aromatase inhibitors, premenopausal/perimenopausal women receiving piperacillin in combination with an aromatase inhibitor must undergo ovariectomy or use a luteinizing hormone releasing hormone (LHRH) agonist to suppress ovarian function. Piperacil in combination with fulvestrant has been studied in premenopausal/perimenopausal women in combination with LHRH agonists only. Critical Visceral Disease (Metastasis) The efficacy and safety of piperacillin have not been studied in critically ill patients with visceral disease (metastasis) (see [Clinical Trials]). Hematologic Toxicity Neutropenia was the most frequently reported adverse effect in clinical studies, with febrile neutropenia having been reported in approximately 2% of patients treated with piperacillin in clinical studies and one death due to neutropenic sepsis reported. Complete blood counts should be monitored before the start of piperacillin therapy, at the beginning of each cycle, on day 15 of the first two cycles, and at the onset of clinical indications. For patients with grade 3 or 4 neutropenia, interruption of dosing, dose reduction, or delayed start of treatment cycles with close monitoring is recommended. (See [DOSAGE AND ADMINISTRATION] and [ADVERSE REACTIONS]). Physicians should advise patients to report any febrile events immediately. Infections Because of the myelosuppressive properties of piperacillin, it may predispose patients to infections. Several randomized studies have reported higher rates of infection in the piperacillin group than in the respective control groups. Grade 3 and 4 infections occurred in 4.5% and 0.7% of patients treated with any combination of piperacillin, respectively (see [Adverse Reactions]). Patients should be monitored for signs and symptoms of infection and treated when appropriate (see [DOSAGE]). Report immediately any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness, or increased tendency to bleeding and/or bruising. Hepatic Injury Pipercept should be used with caution in patients with moderate or severe hepatic injury and closely monitored for signs of toxicity (see [DOSAGE AND ADMINISTRATION] and [PHARCOSYNTHESIS]). Renal injury Piperisil should be used with caution in patients with moderate or severe renal injury and closely monitored for signs of toxicity (see [Dosage] and [Pharmacokinetics]). Combination therapy with CYP3A4 inhibitors or inducers Potent CYP3A4 inhibitors may result in increased toxicity (see [Drug Interactions]). Combination with potent CYP3A inhibitors should be avoided during piperacillin therapy. Concomitant use should be considered only after careful evaluation of potential benefits and risks. If concomitant use with a potent CYP3A inhibitor cannot be avoided, the dose of piperacillin should be reduced to 75 mg once daily. When discontinuing a potent inhibitor, the dose of piperacillin (after 3-5 half-lives of the inhibitor) should be increased to the dose prior to initiation of a potent CYP3A inhibitor (see [Drug Interactions]). Concomitant use with CYP3A inducers may result in reduced exposure to piperacillin, so there is a risk of lack of efficacy. Therefore, the combination of piperacillin with potent CYP3A4 inducers should be avoided. No dose adjustment is necessary when piperacillin is used concomitantly with a moderately potent CYP3A inducer (see [Drug Interactions]). Females of childbearing potential or their spouses Females of childbearing potential or their male spouses must use a highly effective method of contraception during treatment with piperacillin (see [Use in Pregnant and Lactating Women]). Lactose Piperisil contains lactose. Pipercept should not be administered to patients with rare genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption disorder. Effects on the ability to drive and operate machinery Pipercillin has minimal effects on the ability to drive and operate machinery. However, piperacillin may cause fatigue and patients should use caution when driving or operating machinery.” tab_7_title=”Interactions” tab_7_content=”Piperacillin is primarily metabolized by CYP3A and the sulphotransferase (SULT) enzyme SULT2A1. In vivo, piperacillin is a weak time-dependent inhibitor of CYP3A. Effects of other drugs on the pharmacokinetics of piperacillin Effects of CYP3A inhibitors Simultaneous administration of multiple doses of 200 mg itraconazole with a single dose of 125 mg piperacillin increased the systemic exposure (AUCinf) and peak concentration (Cmax) of piperacillin by approximately 87% and 34%, respectively, compared with a single dose of 125 mg piperacillin alone. Combinations with potent CYP3A inhibitors, including but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice should be avoided (see [DOSAGE] and [PRECAUTIONS]). No dose adjustment is necessary when combined with mild and moderate CYP3A inhibitors. Effects of CYP3A inducers Concomitant administration of multiple doses of 600 mg rifampin with a single dose of 125 mg piperacillin decreased piperacillin AUCinf and Cmax by approximately 85% and 70%, respectively, compared to a single dose of 125 mg piperacillin alone. Combination with potent CYP3A inducers, including but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s wort, should be avoided (see [Contraindications] and [Precautions]). Concomitant administration of multiple daily doses of 400 mg modafinil, a moderate-acting CYP3A inducer, with a single dose of 125 mg piperacil reduced piperacil AUCinf and Cmax by approximately 32% and 11%, respectively, relative to a single dose of 125 mg piperacil given alone. No dose adjustment is required when combined with a moderately potent CYP3A inducer (see [Precautions]). Effects of Antacids Concomitant administration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg piperacillin after a meal (ingestion of a medium-fat meal) reduced piperacillin Cmax by 41% compared with a single dose of 125 mg piperacillin alone, but had a limited effect on AUCinf (13% reduction). Concomitant administration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg piperacillin under fasting conditions reduced piperacillin AUCinf and Cmax by 62% and 80%, respectively. Therefore, piperacillin should be taken with food, preferably with a meal (see [Dosage] and [Pharmacokinetics]). Given that H2 receptor antagonists and topical antacids have less effect on intragastric pH than PPIs, no clinically relevant effect of H2 receptor antagonists or topical antacids on piperacillin exposure is expected when piperacillin is taken with food. Effect of piperacillin on the pharmacokinetics of other drugs Piperacillin is a weak time-dependent CYP3A inhibitor when given at 125 mg daily to reach steady state. Midazolam AUCinf and Cmax values increased by 61% and 37%, respectively, when multiple doses of piperacillin were administered concomitantly with midazolam compared with midazolam alone. Sensitive CYP3A4 substrates for the treatment of index stenosis (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may require dose reductions when administered concomitantly with piperacil because piperacil can increase their exposure. Drug-Drug Interaction between Pipercillin and Letrozole Data from the Drug-Drug Interaction (DDI) evaluation section of a clinical study in breast cancer patients showed no drug-drug interaction between pipercillin and letrozole when the two drugs were used in combination. Effect of Tamoxifen on Pipercillin Exposure Data from a DDI study in healthy male subjects showed that single-dose pipercillin administered concomitantly with multiple doses of tamoxifen resulted in comparable exposure to pipercillin when administered alone. Drug interactions between piperacillin and fulvestrant Data from a clinical study in patients with breast cancer showed no clinically relevant drug interactions between the two drugs when piperacillin was administered in combination with fulvestrant. Drug-drug interactions between piperacillin and oral contraceptives The DDI between piperacillin and oral contraceptives has not been studied (see [Medication for Pregnant and Lactating Women]). In vitro studies with transport proteins Based on data from in vitro studies, piperacillin is expected to inhibit intestinal P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP)-mediated transport. Therefore, the combination of piperacillin with P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, resulvastatin, lorazepam) substrates may increase their therapeutic effects and adverse effects. Based on data from in vitro studies, piperacillin inhibits the uptake of the transporter organic cation transporter protein OCT1 and therefore increases exposure to substrate analogues of this transporter protein (e.g., metformin).” tab_8_title=”Pharmacokinetics ” tab_8_content=”The pharmacokinetic profile of piperacillin was studied in patients with solid tumors, including advanced breast cancer, and in healthy volunteers. Absorption Piperacillin generally reaches peak concentration (Cmax) between 6-12 hours after oral administration. The mean absolute bioavailability of piperacillin was 46% after an oral dose of 125 mg. The Area Under the Curve (AUC) and Cmax generally increase proportionally with dose in the 25-225 mg dose range. Steady state was reached within 8 days after once-daily repeat dosing. Accumulation of piperacillin may occur with a median accumulation ratio of 2.4 (range: 1.5-4.2) with once-daily repeat dosing. Food Effects Absorption and exposure of piperacillin is extremely low in approximately 13% of the fasting population. In this small population, feeding increased piperacillin exposure, but in the remainder of the population, feeding had no clinically relevant effect on piperacillin exposure. Compared with overnight fasting, AUCinf and Cmax were increased by 21% and 38% with high-fat food, 12% and 27% with low-fat food, and 13% and 24% with medium-fat food 1 hour before and 2 hours after piperacillin administration, respectively. In addition, eating significantly reduced inter- and intra-individual differences in piperacillin exposure. Based on these results, piperacillin should be taken with food (see [DOSAGE AND ADMINISTRATION]). Distribution In vitro, piperacillin is 85% bound to human plasma proteins without concentration dependence. In vivo, the mean free fraction (fu) of piperacillin in human plasma increases progressively with deterioration of hepatic function. In vivo, there was no significant trend in the mean fu of piperacillin in human plasma with deterioration of renal function. In vitro, human hepatocytes take up piperacillin mainly by passive diffusion. Piperacillin is not a substrate for OATP1B1 or OATP1B3. Biotransformation In vitro and in vivo studies have shown that piperacillin is extensively metabolized by hepatocytes. Following a single oral dose of [14C]-labeled piperacillin 125 mg in humans, the major metabolic pathways of piperacillin are sulfonation and oxidation, and the minor pathways are glucosylation and acylation. The main drug detected in the blood circulation was piperacillin prototype. Most of it is excreted as metabolites. The sulfamate conjugate of piperacillin was the major drug-related component found in feces, accounting for 25.8% of the administered dose. In vitro studies using human hepatocytes, hepatic cytosol and human liver S9 fractions and recombinant sulfotransferase (SULT) enzymes indicated that the enzymes primarily involved in piperacillin metabolism were CYP3A and SULT2A1. Elimination In patients with advanced breast cancer, the geometric mean apparent oral clearance (CL/F) of piperacillin was 63 L/h and the mean plasma elimination half-life was 28.8 h. 6 subjects A single oral dose of [14C] piperacillin in healthy male subjects recovered 92% (median) of the total radioactivity over 15 days; feces (74% of the dose) was the primary route of excretion, and 17% of the dose was recovered in urine. The recovery of the prototype piperacillin excreted via feces and urine was 2% and 7% of the administered dose, respectively. In in vitro studies, piperacillin was not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, nor an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations. In vitro evaluations have shown that piperacillin, at clinically relevant concentrations, has a positive effect on Organic Anion Transporter (OAT)1, OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide (OCTP), and Organic Anion Transporter (OCTP). OAT1, OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide (OATP)1B1, OATP1B3 and Bile Salt Export Pump (BSEP) activity were weakly inhibited. Special Populations Age, Sex, and Body Weight Based on a population pharmacokinetic analysis including 183 cancer patients (50 men and 133 women, age range: 22-89 years, weight range: 38-123 kg), sex had no effect on piperacillin exposure, and age and body weight had no clinically meaningful effect on piperacillin exposure. Pediatric population The pharmacokinetics of piperacillin have not been evaluated in patients aged ≤18 years. A pharmacokinetic trial was conducted in subjects with varying degrees of hepatic function and showed that free piperacillin exposure (free AUCinf) was 17% lower in subjects with mild hepatic impairment (Child-Pugh class A) and 34% higher in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, compared with subjects with normal liver function. Free piperacillin peak concentration (Cmax) increased by 7%, 38%, and 72% in subjects with mild, moderate, and severe liver injury, respectively. In addition, based on a population pharmacokinetic analysis including 183 patients with advanced cancer, including 40 patients with mild liver injury (based on NCI classification; total bilirubin ≤ ULN and AST> ULN, or total bilirubin> 1.0-1.5 × ULN and any level of AST), mild liver injury had no effect on the pharmacokinetics of piperacillin. A pharmacokinetic trial was conducted in subjects with varying degrees of renal function and the data showed that compared with subjects with normal renal function (CrCl ≥ 90 mL/min), mild (60 mL/min ≤ CrCl <90 mL/min), moderate (30 mL/min ≤ CrCl <60 mL/min) and severe (CrCl <30 mL/min) renal impairment had no effect on the pharmacokinetics of piperacillin. ;30 mL/min) subjects with renal impairment had 39%, 42%, and 31% increases in total exposure (AUCinf) to piperacillin; and 17%, 12%, and 15% increases in peak exposure (Cmax) to piperacillin, respectively. In addition, based on a population pharmacokinetic analysis including 183 patients with advanced cancer, including 73 patients with mild renal impairment and 29 with moderate renal impairment, there was no effect of mild and moderate renal impairment on the pharmacokinetics of piperacillin. The pharmacokinetics of piperacillin have not been studied in patients requiring hemodialysis. Asian Population A pharmacokinetic trial was conducted in healthy Japanese volunteers, and piperacillin AUCinf and Cmax were 30% and 35% higher after a single oral dose in Japanese subjects compared to non-Asian subjects. However, these results were not observed in Japanese or Asian breast cancer patients who received multiple doses in a follow-up study. Analysis of cumulative pharmacokinetic, safety and efficacy data based on Asian and non-Asian populations does not require dose adjustment based on Asian ethnicity. Chinese population Study A5481019 (n=26) evaluated the PK characteristics of piperacillin in combination with letrozole in Chinese patients with ER-positive, HER2-negative postmenopausal advanced breast cancer who had not received any prior systemic anticancer therapy for advanced disease. The pharmacokinetic profile of piperacillin observed in Chinese patients in this study was consistent with that of non-Chinese patients in the PALOMA-2 and PALOMA-3 studies. The trough concentrations in Chinese patients in the A5481019 study were consistent with those observed in the PALOMA-2 study and did not require dose adjustment based on the Chinese population.” tab_9_title=”Ingredients” tab_9_content=”The main ingredient of this product is piperacillin. Its chemical name is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one Chemical structure formula: Excipients: microcrystalline cellulose, monohydrate lactose tab_10_title=”Pharmacology and Toxicology” tab_10_content=”Pharmacology Piperacillin is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. The cyclins D1 and CDK4/6 are located downstream of the cell proliferation signaling pathway. In vitro, it reduces cell proliferation in estrogen receptor (ER)-positive breast cancer cell lines by blocking cells from G1 phase to S phase. The combination of piperacillin and estrogen antagonists in breast cancer cell lines reduces retinoblastoma (Rb) protein phosphorylation, which leads to a decrease in E2F expression and its signaling, resulting in a stronger growth inhibition than the drugs alone. The combination of piperacillin and estrogen antagonists in ER-positive breast cancer cell lines resulted in increased cellular aging compared with each drug alone, an effect that lasted up to 6 days after piperacillin discontinuation, but resulted in greater cellular aging when anti-estrogen therapy was continued. In vivo studies in human ER-positive breast cancer xenograft models have shown that the combination of piperacillin and letrozole produced stronger inhibition of Rb phosphorylation, downstream signaling, and tumor growth than did the drugs alone. In vitro administration of piperacillin to human bone marrow mononuclear cells, with or without anti-estrogen treatment, did not result in cellular senescence, and cell proliferation resumed after removal of piperacillin. Toxicological studies General toxicity: Cardiovascular effects (prolonged QTc, decreased heart rate, prolonged RR interval, and increased systolic blood pressure) were seen in a canine telemetry test at doses administered at more than 4 times the human clinical exposure (Cmax). In a 27-week repeated dosing toxicity trial in rats immature in the early phase of the trial, altered glucose metabolism (urinary glucose, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuole formation), eyes (cataracts, lens degeneration), kidneys (tubular vacuole formation, chronic progressive nephropathy), and adipose tissue (atrophy) was found, a phenomenon that was observed in piperacillin administered orally at The highest incidence was observed in male rats at doses ≥30 mg/kg/day (AUC approximately 11 times the adult human exposure at the clinically recommended dose). Some of these adverse reactions (urinary glucose/hyperglycemia, islet cell vacuolation, and renal tubular vacuolation) were less frequent and less severe in a 15-week repeat dosing toxicity test in immature rats. No alterations in glucose metabolism or changes in pancreatic, ocular, renal, or adipose tissue were seen in the 27-week repeat dosing toxicity test in rats that were mature at the start of the test, or in the 39-week repeat dosing toxicity test in dogs. Dental toxicity unrelated to altered glucose metabolism was seen in rats. Piperacillin administered at 100 mg/kg for 27 weeks (AUC approximately 15 times the adult human exposure at the clinically recommended dose) resulted in abnormal incisor growth (discoloration, enamel cell degeneration/gangrene, mononuclear cell infiltration) in rats. Genotoxicity: Negative results in piperacillin Ames test and in vitro human lymphocyte chromosome aberration test, positive results in Chinese hamster ovary cell in vitro test, male rat bone marrow test micronucleus test. Reproductive toxicity: In the female rat fertility assay, no effects of piperacillin on mating or fertility were observed at doses as high as 300 mg/kg/day (AUC approximately 4 times the human clinical exposure). In repeated dose toxicity tests in rats and dogs, no adverse effects on female reproductive organs were observed at doses up to 300 mg/kg/day in rats and 3 mg/kg/day in dogs (AUCs approximately 6 times the clinically recommended human exposure and comparable to human exposure, respectively). Adverse effects of piperacillin on the male reproductive system and fertility were seen in repeated dose toxicity tests in rats and dogs, and in the male fertility test in rats. In repeated dose toxicity tests, dose related decreases in testicular, epididymal, prostatic and seminal vesicle organ weight, atrophy or degeneration, sperm reduction, tubular cell fragmentation and decreased secretion were seen in rats and dogs given piperacillin ≥30 mg/kg/day and ≥0.2 mg/kg/day (AUCs ≥10 and ≥0.1 times the clinically recommended human exposure, respectively), respectively. These effects on the male reproductive organs of rats and dogs were partially reversible after a 4-week and 12-week withdrawal period, respectively. In the male rat fertility and early embryonic development toxicity assay, no effects on mating were observed at a dose of 100 mg/kg/day of piperacillin (extrapolating the AUC to approximately 20 times the clinically recommended human exposure), but a slight decrease in fertility was observed, as evidenced by lower sperm viability and density. In female rats, oral administration of piperacillin from 15 days prior to mating to day 7 of gestation did not result in embryotoxicity at doses up to 300 mg/kg/day (maternal systemic exposure approximately 4 times the clinically recommended human exposure) in fertility and early embryonic development toxicity tests. In the rat and rabbit embryo-fetal development assays, oral administration of piperacillin up to 300 mg/kg/day and 20 mg/kg/day during organogenesis in pregnant animals caused fetal toxicity in rats at a maternal toxic dose of 300 mg/kg/day, resulting in decreased fetal body weight and an increased incidence of skeletal variation at doses ≥100 mg/kg/day (increased incidence of ribs in the seventh cervical vertebrae). (increased incidence of ribs in the seventh cervical vertebra). In rabbits, the incidence of skeletal variation (including the little toe bone of the forelimb) increased at a maternal toxicity dose of 20 mg/kg/day. The maternal systemic exposure (AUC) at 300 mg/kg/day in rats and 20 mg/kg/day in rabbits was approximately 4 and 9 times the human exposure at the clinically recommended dose, respectively. In the literature, CDK4/6 double knockout mice were reported to die of severe anemia during late fetal development (day 14.5 of gestation to birth). However, due to differences in the degree of target inhibition, the data from knockout mice may not be predictive of effects in humans. Carcinogenicity: Carcinogenicity tests have not been performed.”] [/otw_shortcode_tabslayout]