And Trastuzumab

Uses

Hyaluronidase recombinant is a tissue permeability modifier used as an adjuvant-

• In subcutaneous fluid administration for achieving hydration
• To increase the dispersion and absorption of other injected drugs
• In subcutaneous urography for improving resorption of radiopaque agents

Pertuzumab is a HER2/neu receptor antagonist used for:

Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Use in combination with trastuzumab and chemotherapy as:

• Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.
• Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence

Adjuvant Breast Cancer: Trastuzumab is used for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer

• As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• As part of a treatment regimen with docetaxel and carboplatin
• As a single agent following multi-modality anthracycline based therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Trastuzumab

Metastatic Breast Cancer: Trastuzumab is used for:

• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for Trastuzumab

Metastatic Gastric Cancer: Trastuzumab is used, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for Trastuzumab

And Trastuzumab is also used to associated treatment for these conditions: Parenteral rehydration therapy, Parenteral drug administration, Subcutaneous urographyEarly Breast Cancer, Inflammatory Breast Cancer (IBC), Locally Advanced Breast Cancer (LABC), Metastatic Breast CancerBreast Cancer, Early Breast Cancer, Inflammatory Breast Cancer (IBC), Locally Advanced Breast Cancer (LABC), Metastatic Adenocarcinoma of the Gastro-Esophageal Junction, Metastatic Adenocarcinoma of the Stomach, Metastatic Breast Cancer, Metastatic Gastric Adenocarcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma

How And Trastuzumab works

Hyaluronidase cleaves hyaluronic acid at the glucosaminidic bond between C1 of glucosamine and C4 of glucuronic acid. Hyaluronic acid is a key component of the extracellular matrix. Injection of hyaluronidase with other fluids, drugs, or radiopaque agents improves the ability of these other compounds to permeate the extracellular space more easily.

Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor that plays an integral role in cell proliferation, differentiation, and survival. HER2 becomes active following dimerization with another HER2 receptor, another member of the HER protein family (e.g. HER3), or with a ligand - this dimer then phosphorylates and activates numerous intracellular signaling proteins, initiating signal transduction via pathways that include the Ras/mitogen-activated protein kinase pathway, the phosphatidylinositol 3' kinase (PI3K)/Akt pathway, and then Janus kinases/signal transducer and activator transcription pathway. HER2 is also a known oncogene - it is overexpressed or gene-amplified (i.e. HER2-positive) in approximately 20% of breast cancers and these cancers carry a generally poorer prognosis than HER2-negative breast cancers.

Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2, thereby inhibiting ligand-initiated intracellular signaling via the MAP kinase and PI3K pathways. Inhibition of these pathways results in inhibition of cell growth and the initiation of apoptosis, respectively. Pertuzumab also appears to mediate antibody-dependent cell-mediated cytotoxicity.

Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers . The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains . Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression . Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation , and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation . Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2 . While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction.

Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor .

Dosage

And Trastuzumab dosage

Inject 150 units Hyaluronidase recombinant prior to subcutaneous fluid administration. It will facilitate absorption of 1,000 mL or more of solution. The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. The rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion

Increasing dispersion and absorption of injected drugs: Add 50-300 units (most typically 150 U) Hyaluronidase recombinant to the injection solution.

Subcutaneous Urography: Inject 75 units Hyaluronidase recombinant subcutaneously over each scapula, followed by injection of the contrast medium at the same sites

For intravenous infusion only. Do not administer as an intravenous push or bolus.

HER2 testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency.

The initial Pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute intravenous infusion.

MBC: Administer Pertuzumab, trastuzumab, and docetaxel by intravenous infusion every 3 weeks.

Neoadjuvant: Administer Pertuzumab, trastuzumab, and chemotherapy by intravenous infusion preoperatively every 3 weeks for 3 to 6 cycles.

Adjuvant: Administer Pertuzumab, trastuzumab, and chemotherapy by intravenous infusion postoperatively every 3 weeks for a total of 1 year (up to 18 cycles).

Intravenous (Adult)-

Early breast cancer: For treatment after chemotherapy, radiotherapy or surgery. Initially, 4 mg/kg via infusion over 90 min followed by 2 mg/kg via infusion over 30 min wkly for 1 yr or until disease recurrence, whichever occurs 1st. Alternatively, initial dose of 8 mg/kg via infusion over 90 min followed by 6 mg/kg via infusion over 30-90 min at 3-wkly interval for 1 yr or until disease recurrence, whichever occurs 1st.

Metastatic breast cancer: As monotherapy or combination therapy (with an aromatase inhibitor or taxane): Initially, 4 mg/kg via infusion over 90 min followed by 2 mg/kg via infusion over 30 min at wkly interval until progression of disease. As trastuzumab emtansine: 3.6 mg/kg as infusion 3 wkly (21-day cycle). Admin initial dose for 90 min. Subsequent doses may be administered as 30 min infusions.

Gastric cancer: For metastatic: Initially, 8 mg/kg via infusion over 90 min followed by 6 mg/kg via infusion over 30-90 min at 3-wkly interval until progression of disease.

Reconstitute with 20 mL of bacteriostatic sterile water for inj into a soln containing 21 mg/mL of trastuzumab. Swirl gently; do not shake. Dilute further prior to admin with appropriate vol of reconstituted trastuzumab soln in 250 mL of NaCl 0.9% inj.

Side Effects

The following adverse reactions have been identified during post-approval use of hyaluronidase products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequently reported adverse reactions have been mild local injection site reactions such as erythema and pain. Hyaluronidase has been reported to enhance the adverse reactions associated with co-administered drug products. Edema has been reported most frequently in association with subcutaneous fluid administration. Allergic reactions (urticaria or angioedema) have been reported in less than 0.1% of patients receiving hyaluronidase. Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.

Metastatic Breast Cancer:

• The most common adverse reactions (> 30%) with Pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia,neutropenia, nausea, fatigue, rash, and peripheral neuropathy.

Neoadjuvant Treatment of Breast Cancer:

• The most common adverse reactions (> 30%) with Pertuzumab in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia.
• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia.
• The most common adverse reactions (>30%) with Pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH) were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia.
• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and paclitaxel when given for 4 cycles following 4 cycles of ddAC were nausea, diarrhea, alopecia, fatigue, constipation and headache.
• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and docetaxel when given for 4 cycles following 4 cycles of FEC were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia.

Adjuvant Treatment of Breast Cancer:

• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and chemotherapy were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy and vomiting.

Fever, headache, fatigue, nausea, vomiting, diarrhoea, infections, increased cough, dyspnoea, rash, neutropenia, anaemia, and myalgia; cardiac dysfunction, CHF.

Toxicity

Data regarding overdose of hyaluronidase is not readily available. In the even of an overdose, treat patients with symptomatic and supportive measures.

There are no data regarding overdose of pertuzumab. Single doses higher than 25 mg/kg have not been tested. Symptoms of overdose are likely to be consistent with pertuzumab's adverse effect profile, and may therefore involve significant diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and/or peripheral neuropathy. Pertuzumab has been associated with the development of left ventricular dysfunction (i.e. cardiotoxicity) that may be exacerbated in instances of overdose.

There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines.

Precaution

Spread of Localized Infection: Hyaluronidase should not be injected into or around an infected or acutely inflamed area because of the danger of spreading a localized infection. Hyaluronidase should not be used to reduce the swelling of bites or stings.

Ocular Damage: Hyaluronidase should not be applied directly to the cornea. It is not for topical use.

Enzyme Inactivation with Intravenous Administration: Hyaluronidase recombinant should not be administered intravenously. Its effects relative to dispersion and absorption of other drugs are not produced when it is administered intravenously because the enzyme is rapidly inactivated.

Infusion-Related Reactions: Monitor for signs and symptoms. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms. If a severe hypersensitivity reaction/anaphylaxis occurs, discontinue the infusion immediately and administer appropriate medical therapies

Patient with pre-existing CV and pulmonary disease; extensive pulmonary tumour involvement. Pregnancy and lactation.

Interaction

It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding Hyaluronidase recombinant to a solution containing another drug.

No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel, paclitaxel, or carboplatin.

May increase cardiotoxicity of antineoplastic agents. May increase neutropenic effect of immunosuppressants. May increase serum level with paclitaxel.

Volume of Distribution

Data regarding the volume of distribution of hyaluronidase are not readily available.

The average steady-state volume of distribution following intravenous administration is 3.53 - 7.5 L.

Elimination Route

Data regarding the absorption of hyaluronidase are not readily available.

Intravenously administered pertuzumab, given as a loading dose of 840mg followed by a maintenance dose of 420mg every 3 weeks, reaches steady-state concentration following the first maintenance dose. In its subcutaneous formulation, in combination with [hylauronidase], the absolute bioavailability of pertuzumab is approximately 0.7 and the median T_max is 4 days. This subcutaneous formulation leverages the benefits of co-administration with hyaluronidase - this enzyme breaks down hylauronic acid, thereby decreasing the viscosity of the extracellular matrix (ECM) and allowing for greater bioavailability with subcutaneous administration.

Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 mcg/mL.

Half Life

Hyaluronidase has a half life of two minutes, but a duration of action of 24-48 hours due to its high potency.

The median half-life of pertuzumab was determined to be 18 days based on a population pharmacokinetic analysis.

The terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, respectively.

Clearance

Data regarding the clearance of hyaluronidase are not readily available.

The median clearance of pertuzumab was determined to be 0.24 L/day based on a population pharmacokinetic analysis.

The predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 L/day.

Elimination Route

After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further broken down and eliminated by the kidneys.

Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very low.

Pregnancy & Breastfeeding use

Pregnancy Category C. It is also not known whether Hyaluronidase recombinant can cause fetal harm when administered to a pregnant woman. Hyaluronidase recombinant should be given to a pregnant woman only if clearly needed.

Nursing Mothers: It is not known whether hyaluronidase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hyaluronidase is administered to a nursing woman

Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of Pertuzumab. There is no information regarding the presence of pertuzumab in human milk, the effects on the breastfed infant or the effects on milk production.

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Hyaluronidase recombinant is contraindicated in patients with known hypersensitivity to hyaluronidase or any of the excipients in Hyaluronidase recombinant. A preliminary skin test for hypersensitivity to Hyaluronidase recombinant can be performed. The skin test is made by an intradermal injection of approximately 0.02 mL (3 Units) of a 150 Unit/mL solution. A positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes and accompanied by localized itching. Transient vasodilation at the site of the test, i.e., erythema, is not a positive reaction. Discontinue Hyaluronidase recombinant if sensitization occurs.

Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

Severe dyspnoea at rest.

Special Warning

Pediatric Use: Clinical hydration requirements for children can be achieved through administration of subcutaneous fluids facilitated with Hyaluronidase recombinant.

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

Storage Condition

Store unopened in a refrigerator at 2° to 8°C. DO NOT FREEZE.

Store vials in a refrigerator at 2°C to 8°C until time of use. Keep vial in the outer carton in order to protect from light.

Store between 2-8° C.

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