Dosage & Administration
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Phesgo Prescribing Information
Cardiomyopathy
PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity were highest in patients receiving PHESGO with anthracycline-containing chemotherapy regimens. Evaluate cardiac function prior to and during treatment with PHESGO. Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Embryo-fetal Toxicity
Exposure to PHESGO can result in embryo-fetal death and birth defects, including oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1), (8.3)].
Pulmonary Toxicity
PHESGO administration can result in serious and fatal pulmonary toxicity. Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Monitor patients until symptoms completely resolve [see Warnings and Precautions (5.3)].
Early Breast Cancer (EBC)
PHESGO is indicated for use in combination with chemotherapy for
- the neoadjuvant treatment of adult 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 [see Dosage and Administration (2.2) and Clinical Studies (14.2)].
- the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.2)].
Select patients for therapy based on an FDA-approved companion diagnostic test [see Dosage and Administration (2.1)].
Metastatic Breast Cancer (MBC)
PHESGO is indicated for use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease [see Dosage and Administration (2.2) and Clinical Studies (14.1)].
Select patients for therapy based on an FDA-approved companion diagnostic test [see Dosage and Administration (2.1)].
Patient Selection
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
Important Dosage and Administration Information
PHESGO is for subcutaneous use only in the thigh. Do not administer intravenously.
PHESGO has different dosage and administration instructions than intravenous pertuzumab, intravenous trastuzumab, and subcutaneous trastuzumab when administered alone.
Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan.
PHESGO must always be administered by a healthcare professional.
In patients receiving an anthracycline-based regimen for early breast cancer, administer PHESGO following completion of the anthracycline.
In patients receiving PHESGO for early breast cancer with docetaxel or paclitaxel, administer docetaxel or paclitaxel after PHESGO.
In patients receiving PHESGO for metastatic breast cancer with docetaxel, administer docetaxel after PHESGO.
Observe patients for a minimum of 30 minutes after initial dose of PHESGO and 15 minutes after each maintenance dose of PHESGO for signs or hypersensitivity symptoms or administration-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use [see Warnings and Precautions (5.5)].
Recommended Doses and Schedules
The recommended dosage and administration schedule for PHESGO are shown in Table 1.
| Dose | Strength | Administration Instructions |
|---|---|---|
| Initial dose | 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase in 15 mL | Administer subcutaneously over approximately 8 minutes |
| (1,200 mg, 600 mg, and 30,000 units/15 mL) | ||
| Maintenance dose (administer every 3 weeks) | 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase in 10 mL (600 mg, 600 mg, and 20,000 units/10 mL) | Administer subcutaneously over approximately 5 minutes every 3 weeks |
No dose adjustments for PHESGO are required for patient body weight or for concomitant chemotherapy regimen.
Patients currently receiving intravenous pertuzumab and trastuzumab can transition to PHESGO. In patients receiving intravenous pertuzumab and trastuzumab with < 6 weeks since their last dose, administer PHESGO as a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every 3 weeks for subsequent administrations. In patients receiving intravenous pertuzumab and trastuzumab with ≥ 6 weeks since their last dose, administer PHESGO as an initial dose of 1,200 mg pertuzumab/600 mg trastuzumab, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations.
Neoadjuvant Treatment of Breast Cancer
Administer PHESGO every 3 weeks for 3 to 6 cycles as part of a treatment regimen for early breast cancer [see Clinical Studies (14.2)].
Refer to the prescribing information for pertuzumab, administered in combination with trastuzumab and chemotherapy, for recommended dose and dosage modifications.
Following surgery, patients should continue to receive PHESGO to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as a part of a complete regimen for early breast cancer.
Adjuvant Treatment of Breast Cancer
Administer PHESGO every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as part of a complete regimen for early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy. Start PHESGO on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.2)].
Metastatic Breast Cancer (MBC)
When administered with PHESGO, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated. Administer PHESGO until disease progression or unmanageable toxicity, whichever occurs first.
Dose Modification
Dose Modification for Delayed or Missed Doses
For delayed or missed doses of PHESGO, if the time between two sequential injections is less than 6 weeks, administer the maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL. Do not wait until the next planned dose.
If the time between two sequential injections is 6 weeks or more, re-administer the initial dose of 1,200 mg, 600 mg, and 30,000 units/15 mL, followed every 3 weeks thereafter by a maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL.
For chemotherapy dose modifications, see relevant prescribing information.
Cardiomyopathy [see Boxed Warning, Warnings and Precautions (5.1)]
Assess left ventricular ejection fraction (LVEF) prior to initiation of PHESGO and at regular intervals during treatment as indicated in Table 2.
The recommendations on dose modifications in the event of LVEF dysfunction are indicated in Table 2 [see Warnings and Precautions (5.1)].
| Pre-treatment LVEF: | Monitor LVEF every: | Withhold PHESGO for at least 3 weeks for an LVEF decrease to: | Resume PHESGO after 3 weeks if LVEF has recovered to: | |||
|---|---|---|---|---|---|---|
| ||||||
| Early Breast Cancer | ≥ 55% * | ~12 weeks (once during neoadjuvant therapy) | <50% with a fall of ≥10%-points below pre-treatment value | Either | ||
| ≥50% | <10% points below pre-treatment value | |||||
| Metastatic Breast Cancer | ≥ 50% | ~12 weeks | Either | Either | ||
| <40% | 40%-45% with a fall of ≥10%-points below pre-treatment value | >45% | 40%-45% with a fall of <10%-points below pre-treatment value | |||
If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO [see Warnings and Precautions (5.1)].
Hypersensitivity and Administration-Related Reactions
Discontinue the injection immediately if the patient experiences a serious hypersensitivity reaction (e.g. anaphylaxis) [see Warnings and Precautions (5.5)].
Preparation for Administration
To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is PHESGO and not intravenous pertuzumab, or intravenous trastuzumab, or subcutaneous trastuzumab.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if particulates or discoloration is present. Do not shake. Discard any unused portion remaining in the vial.
For both the initial and maintenance dose, each corresponding PHESGO vial is ready-to-use for one subcutaneous injection and should not be diluted.
A syringe, a transfer needle, and an injection needle are needed to withdraw PHESGO solution from the vial and inject it subcutaneously. PHESGO may be injected using 25G-27G (3/8"-5/8") hypodermic injection needles.
To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration followed by volume adjustment to 15 mL (initial dose) and 10 mL (maintenance dose). If the dose is not to be administered immediately, and the solution of PHESGO has been withdrawn from the vial into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe with the peel-off sticker and store the syringe in the refrigerator [2°C to 8°C (36°F to 46°F)] for up to 24 hours and at room temperature [20°C to 25°C (68°F to 77°F)] for up to 4 hours and avoid unnecessary storage.
PHESGO is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride and fluorinated ethylene polypropylene.
Administration
- Administer PHESGO 1,200 mg, 600 mg, 30,000 units/15 mL subcutaneously over approximately 8 minutes
- Administer PHESGO 600 mg, 600 mg, 20,000 units/10 mL subcutaneously over approximately 5 minutes
The subcutaneous injection site should be alternated between the left and right thigh only. New injections should be given at least 1 inch (2.5 cm) from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. Do not split the dose between two syringes or between two sites of administration. During the treatment course with PHESGO, other medications for subcutaneous administration should preferably be injected at different sites.
Injection: PHESGO is a clear to opalescent, and colorless to slightly brownish solution provided as:
- 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in a single-dose vial
- 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in a single-dose vial
Pregnancy
Pregnancy Pharmacovigilance Program
There is a pregnancy pharmacovigilance program for PHESGO. If PHESGO is administered during pregnancy, or if a patient becomes pregnant while receiving PHESGO or within 7 months following the last dose of PHESGO, health care providers and patients should immediately report PHESGO exposure to Genentech at 1-888-835-2555.
Risk Summary
PHESGO can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of intravenous trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see Data). In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures that were 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on Cmax (see Data). Apprise the patient of the potential risks to a fetus. There are clinical considerations if PHESGO is used during pregnancy or within 7 months prior to conception (see Clinical Considerations).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received PHESGO during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
Data
Human Data
In post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after amniotic index improved and oligohydramnios recurred.
Animal Data
PHESGO for subcutaneous injection contains pertuzumab, trastuzumab, and hyaluronidase [see Description (11)].
Pertuzumab:
Pregnant cynomolgus monkeys were treated on Gestational Day (GD) 19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85%. At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.
Trastuzumab:
In studies where intravenous trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.
Hyaluronidase:
In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is >2,400 and 3,600, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is >400 and 600, based on loading and maintenance doses, respectively, times higher than the human dose.
In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is >1,200 and 1,800, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.
Lactation
Risk Summary
There is no information regarding the presence of pertuzumab, trastuzumab or hyaluronidase in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest that human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating cynomolgus monkeys but not associated with neonatal toxicity (see Data). Consider the developmental and health benefits of breast feeding along with the mother's clinical need for PHESGO treatment and any potential adverse effects on the breastfed child from PHESGO or from the underlying maternal condition. This consideration should also take into account the elimination half-life of pertuzumab and the trastuzumab wash out period of 7 months [see Clinical Pharmacology (12.3)].
Data
In lactating cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of intravenous trastuzumab). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age.
Females and Males of Reproductive Potential
PHESGO can cause embryo-fetal harm when administered during pregnancy.
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to the initiation of PHESGO.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PHESGO [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
Pediatric Use
The safety and effectiveness of PHESGO in pediatric patients have not been established.
Geriatric Use
Of the total number of patients in the FeDeriCa trial (n=500) treated with PHESGO, 11% were 65 and over, while 1.6% were 75 and over. Clinical studies of PHESGO did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.
In the intravenous trastuzumab trials, the risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients, in both those receiving treatment for adjuvant therapy or metastatic disease. Other differences in safety or effectiveness were not observed between elderly patients and younger patients. In the intravenous pertuzumab in combination with trastuzumab trials, the risk of decreased appetite, anemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral and hypomagnesemia was increased in patients 65 years of age and older compared to patients less than 65 years of age.
PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients.