Pertuza420 mg/14 ml

Pertuza is a HER2-targeted monoclonal antibody approved only for use in combination regimens for HER2-positive breast cancer, based on confirmed HER2 overexpression/gene amplification by an FDA-approved test. It is not used as monotherapy.

Established (FDA-approved) indications

Pertuza is not approved for HER2-negative breast cancer or for cancers other than breast cancer, and is not established as effective outside of these specific combination regimens.

Each single-dose vial contains Pertuzumab 420 mg/14 mL (30 mg/mL) as a sterile, preservative-free, clear to slightly opalescent, colorless to pale brown concentrate for solution for intravenous infusion, for dilution before use.

Pertuza is a humanized monoclonal antibody (IgG1) that targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 (HER2/neu). It is used as part of combination regimens with trastuzumab and chemotherapy for HER2-positive breast cancer, and carries boxed warnings for embryo-fetal toxicity and left ventricular (cardiac) dysfunction.

Monoclonal antibody; HER2/neu receptor dimerization inhibitor; antineoplastic (targeted anti-HER2 therapy). Pertuza belongs to this class and is always used in combination, never as monotherapy.

Pertuzumab binds to subdomain II of the HER2 extracellular domain, a binding site distinct from that of trastuzumab (which binds subdomain IV). This blocks HER2 from pairing (heterodimerizing) with other HER family members, particularly HER3, thereby inhibiting ligand-dependent intracellular signaling through the PI3K/Akt pathway and other downstream cascades that drive tumor cell proliferation and survival. Because Pertuzumab and trastuzumab bind different, complementary epitopes on HER2, their combined use produces a more comprehensive blockade of HER2-mediated signaling than either antibody alone.

Pertuza is for intravenous infusion only and must never be given as an intravenous push or bolus. It is administered through a dedicated infusion line, diluted as directed, and must not be mixed or co-administered with other medicinal products in the same line or bag. In a treatment visit, trastuzumab is typically infused first, followed by Pertuza, and then the chemotherapy component (for example, docetaxel), with an observation period after the Pertuza infusion, especially the first dose, to monitor for infusion-related reactions.

No formal pharmacokinetic drug-drug interaction studies have been conducted for Pertuza, as it is a monoclonal antibody not metabolized through cytochrome P450 pathways. Clinically significant interactions relate mainly to combined toxicity:

• Anthracyclines (for example, doxorubicin): concurrent or closely sequential use with Pertuza-trastuzumab therapy increases the risk of cardiotoxicity (decreased LVEF or heart failure); anthracyclines are generally avoided during the combination phase (see Precautions and Warnings).
• Other antineoplastic agents (for example, docetaxel): used intentionally in combination per approved regimens; overlapping toxicities such as neutropenia and diarrhea should be monitored.
• Trastuzumab: intended concurrent use with a complementary mechanism; no adverse pharmacokinetic interaction has been identified between the two antibodies.

Pertuza must not be physically mixed or diluted with other drugs in the same infusion bag or line.

The most common side effects, occurring in more than 30% of patients receiving Pertuza-based combination regimens, include:

• Diarrhea
• Alopecia (hair loss)
• Nausea
• Neutropenia (low white blood cell count)
• Fatigue
• Rash
• Peripheral neuropathy
• Vomiting and headache

Serious adverse effects

• Infusion-related reactions, including hypersensitivity or anaphylaxis (see Precautions and Warnings)
• Left ventricular dysfunction, decreased LVEF, or congestive heart failure (see Precautions and Warnings)
• Febrile neutropenia
• Severe diarrhea that may require hospitalization and fluid or electrolyte management

Pertuza carries a boxed warning for embryo-fetal toxicity: exposure during pregnancy can cause fetal harm, including embryo-fetal death and birth defects. Pregnancy status should be verified before starting Pertuza. Females of reproductive potential should use effective contraception during treatment with Pertuza and for at least 7 months after the final dose. Pertuza should be used during pregnancy only if there is no suitable alternative and only under close specialist supervision, since the potential risk to the fetus is well established; any pregnancy occurring during treatment should be reported to a physician immediately. It is not known whether Pertuza passes into human breast milk; because of the potential for serious adverse reactions in a breastfed infant, breastfeeding is not recommended during treatment and for 7 months after the last dose. Always consult a physician regarding pregnancy planning, contraception, and breastfeeding before and during treatment with Pertuza.

Left ventricular dysfunction (boxed warning)

Pertuza, used in combination with trastuzumab, can cause subclinical and clinical cardiac failure, manifesting as decreased LVEF and congestive heart failure. Left ventricular function should be assessed before starting treatment and monitored at regular intervals during treatment; the risk is further increased when anthracycline-containing chemotherapy is also used. Treatment is withheld or discontinued according to established LVEF criteria.

Embryo-fetal toxicity

See Pregnancy and Lactation for full details; pregnancy testing and effective contraception are required.

Infusion-related reactions and hypersensitivity

Patients should be observed closely during and for a period after each Pertuza infusion, particularly the first dose, for signs of infusion-related reaction or hypersensitivity/anaphylaxis. Facilities and personnel for managing such reactions should be available.

Diarrhea

Diarrhea associated with Pertuza-based regimens can be severe; patients should be monitored and managed promptly with antidiarrheal treatment and fluid/electrolyte replacement as needed, with dose interruption in severe cases.

HER2 testing and appropriate use

Pertuza should be used only in patients with confirmed HER2 overexpression or gene amplification by a validated test, and only as part of the specific combination regimens for which it is approved; it should never be used for HER2-negative breast cancer and never as monotherapy.

There is no established antidote for Pertuza overdose, and clinical experience with overdose is limited. In case of suspected overdose with Pertuza, the patient should be monitored closely for signs of adverse reactions, particularly infusion-related reactions and cardiac dysfunction, and given appropriate supportive care. Seek immediate medical attention or contact emergency services if an overdose of Pertuza is suspected.

Store Pertuza vials refrigerated at 2 degrees C to 8 degrees C (36 degrees F to 46 degrees F) in the original carton to protect from light. Do not freeze. Do not shake the vial. Once diluted for infusion, use according to the diluted-solution storage instructions provided by the pharmacy or manufacturer. Keep out of reach of children.

Pediatric use

Safety and efficacy of Pertuza in pediatric patients have not been established.

Geriatric use

Available data do not suggest a significant difference in the safety or efficacy of Pertuza between patients 65 years and older and younger patients, though data in patients over 75 are limited; monitor closely for tolerability.

Renal impairment

No dose adjustment of Pertuza is considered necessary in patients with mild to moderate renal impairment; data in severe renal impairment are limited.

Hepatic impairment

Pertuza has not been formally studied in hepatic impairment; as a monoclonal antibody, it is not expected to require hepatic dose adjustment, but use with appropriate monitoring.

The duration of Pertuza treatment depends on the indication. In the neoadjuvant setting, it is typically given for a limited number of cycles, as part of a several-month pre-surgical regimen, together with chemotherapy before surgery. In the adjuvant setting, Pertuza is continued together with trastuzumab, with or following chemotherapy, to complete a total of one year (up to 18 cycles) of HER2-targeted therapy. In the metastatic setting, Pertuza is continued every 3 weeks until disease progression or unacceptable toxicity occurs.

Monoclonal antibody (humanized IgG1); HER2/neu receptor dimerization inhibitor; targeted antineoplastic agent.

Pertuzumab is a HER2 dimerization inhibitor. It binds subdomain II of the HER2 extracellular domain, the primary site for HER2 pairing with other HER family receptors, especially HER3, and thereby blocks ligand-activated HER2:HER3 heterodimer formation. This inhibits downstream signaling through the PI3K/Akt pathway, reducing tumor cell proliferation and survival signals. Because Pertuzumab targets an epitope distinct from trastuzumab, combining the two produces complementary, more complete blockade of HER2 pathway signaling.

Safety and efficacy of Pertuza in pediatric patients under 18 years of age have not been established, and breast cancer is exceptionally rare in this age group. Pertuza is not recommended for use in children outside of a formal clinical trial setting.