Pipercillin Capsules Instructions

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Table 5. Abnormalities in laboratory tests based on the combined dataset of 3 randomized studies (N=872)

WBC-white blood cells; AST-aspartate aminotransferase; ALT-alanine aminotransferase; N-number of patients; N/A-not applicable.
Note: Laboratory findings were graded according to NCI CTCAE version 4.0 severity level.
* Letrozole or fulvestrant
 
In the PALOMA-2 and PALOMA-3 studies, 200 patients of Asian descent were included. The incidence of grade 3 or 4 neutropenia and leukopenia reported in Asian patients receiving piperacillin was higher 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 regimen-specified dose adjustments, and Asian patients had similar median treatment durations as non-Asian patients. Based on a cumulative analysis of available data on piperacillin dose exposure, safety, and efficacy, 125 mg once daily is an appropriate starting dose for Asian patients. The dose of piperacillin needs to be adjusted according to the safety and tolerability of the individual patient and in strict compliance with the instructions.
 
Description of Specific Adverse Reactions 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).
The median time to first onset of neutropenia of any grade in the 3 randomized clinical studies was 15 days (12-700 days), and the median duration of grade ≥3 neutropenia was 7 days.
 
Febrile neutropenia was reported in 0.9% of patients receiving piperacillin in combination with fulvestrant and 2.1% of patients receiving piperacillin in combination with letrozole.
 
In the overall clinical study, approximately 2% of patients treated with piperacillin had reported febrile neutropenia.
 
[Contraindication].
Contraindicated in patients with hypersensitivity to the active ingredient or any of the excipients listed under [Ingredients] in the section.
Products containing St. John’s wort are contraindicated (see [Drug Substitution Interactions]).
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[Precautions].
Premenopausal/ Perimenopausal women
 
Given the mechanism of action of aromatase inhibitors, ovariectomy or suppression of ovarian function with a Luteinizing Hormone Releasing Hormone (LHRH) agonist is mandatory in premenopausal/perimenopausal women receiving piperacillin in combination with an aromatase inhibitor. In studies of piperacillin in combination with fulvestrant in premenopausal/perimenopausal women, it was used only in combination with an LHRH agonist.
 
Critical visceral disease (metastasis) The efficacy and safety of piperacillin have not been studied in patients with critically ill visceral disease (metastasis) (see [Clinical Trials]).

Hematologic toxicity Neutropenia was the most commonly reported adverse effect in clinical studies, with febrile neutropenia having been reported in approximately 2% of patients treated with piperacillin in clinical studies and 1 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.

Infection
Infection
Because piperacillin has myelosuppressive properties, it can predispose patients to infections.
 
Several randomized studies have reported higher rates of infection in patients in the piperacillin group than in their respective control groups. Grade 3 and 4 infections occurred in 4.5% and 0.7% of patients treated with any combination regimen of piperacillin, respectively (see [Adverse Reactions]).
 
Patients should be monitored for signs and symptoms of infection and treated when appropriate (see [DOSAGE]).
 
Patients should 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.
Liver injury
 
Piperacillin should be used with caution in patients with moderate or severe hepatic injury and closely monitored for signs of toxicity (see [Dosage] and [Pharmacokinetics]).
Renal injury
 
Use piperacillin with caution in patients with moderate or severe renal injury and monitor signs of toxicity closely (see [Dosage] and [Pharmacokinetics]).
Co-therapy with CYP3A4 inhibitors or inducers
Potent CYP3A4 inhibitors can lead to 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 the potent CYP3A inhibitor (see [Drug Interactions]).
 
Concomitant use with CYP3A inducers can 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 required when piperacillin is used concomitantly with a moderately potent CYP3A inducer (see [Drug Interactions]).
 
Females of childbearing potential or their spouses 
Women 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

Piperacillin contains lactose. Piperisil should not be given 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
 
The effects of piperacillin on the ability to drive and operate machinery are minimal. However, piperacillin may cause fatigue and patients should use caution when driving or operating machinery.
 
[For pregnant and lactating women].
Females of childbearing potential/ Contraception
Women of childbearing potential or their male partners receiving this drug should use adequate contraception (eg, double-barrier contraception) during treatment and for at least 3 weeks (women) or 14 weeks (men) after completing treatment, respectively (see [Drug-Related Effects]).
Pregnancy
Pregnancy
 
There is a lack of data or limited data on the use of piperacillin in pregnant women. Animal studies have shown piperacillin to be reproductively toxic (see [Pharmacologic Toxicology]). Piperisil is not recommended for use in pregnant women and women of childbearing potential who are not using contraception.

Lactation.
 
Studies have not been performed in humans or animals to evaluate the effect of piperacillin on lactation, its presence in breast milk, or its effect on breastfed infants. It is not known whether piperacillin is secreted into human breast milk. Piperisil-treated patients should not be breastfed.
Fertility
Fertility
 
No effects on the estrous cycle (females) or on mating and fertility (males and females) in rats were observed in non-clinical reproductive toxicity studies. Clinical data on effects on human fertility have not been obtained. Based on changes in male reproductive organs (testicular varicocele degeneration, decreased epididymal spermatozoa, decreased sperm viability and density, and decreased prostate secretion) in non-clinical safety studies, piperacillin treatment may impair male fertility (see [Pharmacologic Toxicology]). Therefore, men should consider preserving semen before starting piperacillin treatment.
Pediatric use]
The safety and efficacy of piperacillin in pediatric and adolescent patients 18 years of age and younger have not been established. No data are available.

Geriatric Use
Of the 444 patients treated with piperacillin in the PALOMA-2 study, 181 (41%) were ≥65 years of age and 48 (11%) were ≥75 years of age. No differences were found in the safety or efficacy of piperacillin between these patients and younger patients, and no dose adjustment of piperacillin was required in patients 65 years of age and older (see [Pharmacokinetics]).
[Drug Interactions].
Piperacillin is primarily metabolized by CYP3A and the sulphotransferase (SULT) enzyme SULT2A1. In vivo, piperacillin is a time-dependent weak inhibitor of CYP3A.
 
Effect of other drugs on the pharmacokinetics of piperacillin Effect of CYP3A Inhibitors
Concomitant administration of multiple doses of 200 mg itraconazole with a single dose of 125 mg piperacillin increased systemic exposure (AUC_inf) and peak concentration (C_max) of piperacillin by approximately 87% and 34%, respectively, relative to a single dose of 125 mg piperacillin given 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 ADMINISTRATION] and [PRECAUTIONS]).
 
No dose adjustment is necessary when combined with mild and moderate CYP3A inhibitors.
 
Effect of CYP3A Inducers
Concomitant administration of multiple doses of 600 mg rifampin with a single dose of 125 mg piperacillin resulted in approximately 85% and 70% reductions in piperacillin AUC_inf and C_max, respectively, relative to a single dose of 125 mg piperacillin given 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 piperacillin resulted in an approximately 32% and 11% reduction in piperacillin AUC_inf and C_max, respectively, relative to a single dose of 125 mg piperacillin given alone. No dose adjustment is required when combined with a moderately potent CYP3A inducer (see [Precautions]).

Effects of antacids The 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 C_max by 41% relative to a single dose of 125 mg piperacillin alone, but had a limited effect on AUC_inf (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 AUC_inf and C_max by 62% and 80%, respectively. Therefore, piperacillin should be taken with food, preferably with a meal (see [DOSAGE] and [PHARMACOLOGY]).
 
Given the small effect of H2 receptor antagonists and topical antacids on intragastric pH compared with PPIs, no clinically relevant effect of H2 receptor antagonists or topical antacids on piperacillin exposure is expected when piperacillin is taken with food.
 
Effects of piperacillin on the pharmacokinetics of other drugs After steady-state is achieved with 125 mg given daily, piperacillin is a weak time-dependent CYP3A inhibitor. Midazolam AUC_inf and C_max 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 reduction when administered concomitantly with piperacillin, which can increase their exposure.
 
Drug interactions between piperacillin and letrozole Data from the Drug-Drug Interaction (DDI) evaluation portion of a clinical study in patients with breast cancer showed no drug-drug interactions between piperacillin and letrozole when the two drugs were combined.
 
Effect of tamoxifen on piperacillin exposure 
Data from a DDI study in healthy male subjects showed that single-dose piperacillin administered concomitantly with multiple doses of tamoxifen resulted in comparable exposures to piperacillin 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 piperacillin and fulvestrant when the two drugs were given in combination.
 
Drug interactions between piperacillin and oral contraceptives The DDI between piperacillin and oral contraceptives has not been studied (see [Medications for Pregnant and Lactating Women]).
 
In vitro studies with transporter 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 substrate analogs of P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, resulvastatin, lorazepam) 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 analogs of this transporter protein (eg, metformin).

Drug overdose]
There is no specific antidote for piperacillin. If piperacillin is overdosed, gastrointestinal (eg, nausea, vomiting) and hematologic (eg, neutropenia) toxicity may occur and general supportive therapy should be given.
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[Clinical trial].

Randomized Phase III Study PALOMA-2: Piperacillin in combination with letrozole as initial endocrine therapy in patients with estrogen receptor (ER) positive, HER2 negative advanced or metastatic breast cancer
A randomized, double-blind, placebo-controlled, international multicenter study was conducted to evaluate the efficacy of piperacillin in combination with letrozole and letrozole in combination with placebo in ER-positive, HER2-negative patients with locally advanced breast cancer that cannot be cured by surgical resection or radiotherapy or in patients with advanced breast cancer who have not received prior systemic therapy targeting metastases.
 
A total of 666 postmenopausal women were randomly assigned in a 2:1 ratio to either the piperacillin + letrozole or placebo + letrozole groups and were stratified by site of disease (visceral, non-visceral), disease-free interval from completion of (neo)adjuvant therapy to disease recurrence (neo-metastasis, £12 months, >12 months), and type of prior (neo)adjuvant antitumor therapy (prior hormonal therapy, no prior hormonal therapy) Stratification. Patients with advanced, symptomatic, visceral metastases with potentially life-threatening complications in the short term (including large uncontrolled effusions [pleural effusion, pericardial fluid, peritoneal effusion], pulmonary lymphangitis, and liver involvement exceeding 50% of the area) were excluded from the study.
 
Patients continue to receive their assigned treatment until objective disease progression, symptom worsening, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. Cross-treatment between treatment groups was not allowed.
 
Baseline demographics as well as prognostic characteristics of patients were comparable between the piperacillin + letrozole group and the placebo + letrozole group. The median age of patients enrolled in this study was 62 years (range: 28-89 years), most patients were Caucasian (78%), and most patients had an Eastern Cooperative Oncology Group (ECOG) physical status (PS) of 0 or 1 (98%). Prior to diagnosis of advanced breast cancer, 48.3% of patients had received chemotherapy and 56.3% had received anti-hormonal therapy, and 37.2% had received no prior systemic therapy. Most patients (97.4%) had metastatic lesions at baseline, with 23.6% having only bone metastases and 49.2% having visceral metastases.
 
The primary endpoint of the study was Progression-Free Survival (PFS) as assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary efficacy endpoints included Objective Response Rate (ORR), Clinical Benefit Response (CBR), safety and Quality of Life (QoL) changes.
 
The study met its primary endpoint. The median PFS was 24.8 months (95% CI: 22.1, NE) and 14.5 months (95% CI: 12.9, 17.1) for patients in the piperacillin + letrozole group versus the placebo + letrozole group, respectively. The Hazard Ratio (HR) was 0.576 (95% CI: 0.46, 0.72), with a one-sided stratified log-rank test p value <0.000001.

The efficacy data from the PALOMA-2 study are summarized in Table 6, and Kaplan-Meier curves for PFS are shown in Figure 1.