1) ADVERSE EFFECTS: COMMON: The most common events reported with pertuzumab in combination with trastuzumab and docetaxel include: nausea, diarrhea, neutropenia, fatigue, rash, peripheral neuropathy and alopecia. HEMATOLOGIC: Hematologic events have included neutropenia, anemia, leukopenia and febrile neutropenia with therapeutic use of pertuzumab in combination with trastuzumab and docetaxel. Grade 3/4 neutropenic toxicity has been observed. At present, thrombocytopenia has not been reported with pertuzumab therapy. INFREQUENT: Infusion reactions include: fever, chills, fatigue, headache, asthenia, hypersensitivity and vomiting. SEVERE: Hypersensitivity and anaphylaxis may develop; severe grade 3 or 4 toxicity is rare.

1) OVERDOSE: There have been no reports of overdose. Signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic adverse events.
2) MILD TO MODERATE TOXICITY: Nausea, diarrhea, fatigue, neutropenia and peripheral neuropathy may develop. A decrease in left ventricular dysfunction has occurred with agents that block HER2 activity, including pertuzumab.
3) SEVERE TOXICITY: Hypersensitivity and anaphylaxis may develop. Myelosuppression appears to be infrequent or not reported following pertuzumab monotherapy. However, severe neutropenia along with anemia, leukopenia and febrile neutropenia may occur following a significant overdose when combined with other therapies. Moderate to severe left ventricular dysfunction may lead to significant congestive heart failure and cardiac toxicity.

1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes and IV fluids as needed. Treat significant diarrhea with IV fluids and antidiarrheal agents as necessary. Monitor vital signs, fluid status and assess for dyspnea in patients with evidence of cardiac dysfunction.

1) Treatment is symptomatic and supportive. Overdose has not been reported. Cardiac dysfunction may develop with pertuzumab therapy. A decrease in left ventricular ejection fraction has occurred when combined with trastuzumab and docetaxel. Obtain an echocardiogram to assess left ventricular ejection fraction. Hematologic events have been observed with combination therapy. Consider the use of colony stimulating factors (filgrastim or sargramostim) in patients who develop severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe anemia or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.

1) PREHOSPITAL: Gastrointestinal decontamination is not necessary as pertuzumab is administered intravenously.
2) HOSPITAL: Gastrointestinal decontamination is not necessary as pertuzumab is administered intravenously. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.

1) Intubate if patient is unable to protect airway or if unstable due to cardiac toxicity, an infusion reaction, severe respiratory distress syndrome, or CNS depression.

1) There is no known antidote for pertuzumab.

1) MILD: Antihistamines; SEVERE: Airway management, epinephrine, cardiac monitoring and IV fluids.

1) Hematologic events have been observed with combination therapy but not with pertuzumab monotherapy. Administer colony stimulating factors in patients who develop severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential daily for evidence of recovery. Transfusion of platelets and/or packed red cells may be needed in patients with severe anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation.

1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).

1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.

1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).

1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. It has not been studied in the setting of chemotherapy overdose. In patients with pertuzumab overdose, consider administering palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

1) There are no reports of inadvertent intrathecal injection with pertuzumab. However, this drug has caused peripheral neuropathy following intravenous use in combination with trastuzumab and docetaxel. Severe neurotoxicity may develop after intrathecal injection. The following recommendations are based on experience with antineoplastic agents. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

1) HOME CRITERIA: There is no data to support home management.
2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring, and daily monitoring of CBC.
3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

1) It is unlikely that hemodialysis would be useful after overdose because of the size of pertuzumab (molecular weight 148 kDa).

1) Pertuzumab is a recombinant DNA-derived humanized monoclonal antibody that binds to the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 (HER2) protein. The resulting inhibition of ligand-initiated intracellular signalling results in cell growth arrest and apoptosis. Pertuzumab has linear pharmacokinetics at a dose range of 2 to 25 mg/kg. The median half-life of pertuzumab in a population pharmacokinetics study was 18 days. Volume of distribution is 4.4 to 5.2 Liters. The median clearance of pertuzumab in a population pharmacokinetics study (n=481) was 0.24 L/day.

1) Symptoms of overdose are likely similar to reported side effects of pertuzumab. Early symptoms of overdose may be delayed or not evident (ie, congestive heart failure), so reliable follow-up is imperative. Patients taking pertuzumab may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, cardiotoxicity, myelosuppression).

1) Clinical events may be related to other chemotherapeutic agents that may be used in combination with pertuzumab therapy (ie, cardiac toxicity (eg, anthracyclines) or myelosuppression (eg, trastuzumab). Preexisting heart disease or a borderline or low left ventricular ejection fraction.

1) In a randomized, multicenter, placebo-controlled trial in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (n=804), 18.7% of patients receiving pertuzumab plus trastuzumab and docetaxel (n=407) and 17.9% of patients receiving placebo plus trastuzumab and docetaxel (n=397) experienced pyrexia of any grade (Prod Info PERJETA(TM) intravenous injection, 2012).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) No human studies of pregnancy outcomes after exposure to pertuzumab have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy (Prod Info PERJETA(R) intravenous injection, 2015).

1) There are no adequate and well-controlled studies of pertuzumab use during pregnancy. Pertuzumab can cause fetal harm during all trimesters of pregnancy. In postmarketing use with another human epidermal growth factor receptor 2 (HER2)/neu receptor antagonist, trastuzumab, during pregnancy, cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. Inform women of the potential hazard to the fetus with prenatal pertuzumab exposure, particularly in combination with trastuzumab during pregnancy or within 7 months prior to conception. Monitor women who received pertuzumab combined with trastuzumab during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, conduct fetal testing that is appropriate for gestational age and consistent with standards of care (Prod Info PERJETA(R) intravenous injection solution, 2016).

1) Report any prenatal pertuzumab exposures or exposure to pertuzumab plus trastuzumab within 7 months of conception to Genentech at 1-888-835-2555. Encourage patients exposed to pertuzumab in combination with trastuzumab during pregnancy or within 7 months prior to conception to enroll in the MotHER Registry by calling 1-800-690-6720 or visiting www.motherpregnancyregistry.com (Prod Info PERJETA(R) intravenous injection solution, 2016).

1) Verify pregnancy status prior to treatment initiation (Prod Info PERJETA(R) intravenous injection, 2015)

1) Pertuzumab can cause fetal harm when administered during pregnancy. Women of reproductive potential should use effective contraception during and for at least 7 months after treatment (Prod Info PERJETA(R) intravenous injection, 2015).

1) EMBRYOTOXICITY

1) It is not known whether pertuzumab is excreted into human breast milk; however, human IgG is excreted in human milk but does not enter the circulation of neonates or infants in substantial amounts. Consider the developmental and health benefits of breastfeeding versus the mother's clinical need for the drug and the potential adverse effects on the infant from nursing or the underlying maternal condition. In addition, take into account the elimination half-life of pertuzumab (18 days) and the trastuzumab washout period of 7 months (Prod Info PERJETA(R) intravenous injection solution, 2016).

A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), cardiac monitoring, and daily monitoring of CBC.

A) There is no data to support home management.

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.

A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

1) The recommended initial dose of docetaxel with pertuzumab is 75 mg/m(2) as an IV infusion; may be escalated to 100 mg/m(2) administered every 3 weeks if initial dose is well tolerated (Prod Info PERJETA(R) intravenous injection, 2013a).

1) Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer:

1) The steady state concentration of pertuzumab is reached after the first maintenance dose when the standard pertuzumab regimen is administered (pertuzumab 840 mg IV loading dose followed by 420 mg IV every 3 weeks). It has linear pharmacokinetics at a dose range of 2 to 25 mg/kg (Prod Info PERJETA(TM) intravenous injection, 2012).