Trastuzumab; hyaluronidase-oysk is a combination of trastuzumab, a HER2/neu receptor antagonist, and hyaluronidase, an endoglycosidase indicated for the treatment of HER2-overexpressing breast cancer in adults. Use should be limited to patients with documented overexpression of the HER2 protein, using FDA-approved tests specific for breast cancer; gene amplification and HER2 protein overexpression are not as well correlated in gastric cancer as they are in breast cancer. Treatment with trastuzumab; hyaluronidase can cause heart failure, with the highest incidence in patients receiving concomitant therapy with anthracyclines; monitor left ventricular function in all patients. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Trastuzumab; hyaluronidase is for subcutaneous administration only; do not administer intravenously. Trastuzumab; hyaluronidase has different dosing and administration instructions than intravenous trastuzumab products.
-Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products.
-No dose adjustments for patient body weight or for different concomitant chemotherapy regimens are required.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use vial if particulates or discoloration is present.
-If a dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses.
Subcutaneous Administration
-Trastuzumab; hyaluronidase should be administered by a health care professional.
-Trastuzumab; hyaluronidase is a ready-to-use solution and does not need to be diluted.
-To prepare the dosing syringe, withdraw the solution of trastuzumab; hyaluronidase from the vial into the syringe. Replace the transfer needle with a syringe closing cap and label the syringe with the peel-off sticker.
-Discard any unused portion remaining in the vial.
-To avoid needle clogging, attach the injection needle to the syringe immediately prior to administration followed by volume adjustment to 5 mL. Trastuzumab; hyaluronidase is compatible with polypropylene and polycarbonate syringe material as well as stainless steel transfer and injection needles.
-Alternate injection sites between the left and right thigh. Administer over 2 to 5 minutes.
-New injections should be at least 2.5 cm from the previous site on healthy skin. Do not inject into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.
-Inject other medicinal products for subcutaneous administration at different sites if possible.
Storage
-If a syringe containing trastuzumab; hyaluronidase is not used immediately, it may be stored in the refrigerator for up to 24 hours and subsequently at room temperature for up to 4 hours. Protect from light. Do not shake or freeze.
Subclinical and clinical heart failure can occur as a result of treatment with trastuzumab; hyaluronidase. There is a 4- to 6-fold increase in the incidence of symptomatic cardiac dysfunction in patients receiving trastuzumab (monotherapy or in combination with chemotherapy) compared with those not receiving trastuzumab; the incidence and severity were highest in patients receiving concomitant anthracycline-containing chemotherapy regimens. The incidence of symptomatic cardiac dysfunction was similar for subcutaneous trastuzumab; hyaluronidase and intravenous trastuzumab. In a randomized, open-label study (the HannaH trial) comparing subcutaneous trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or doxorubicin/cyclophosphamide (AC)) (n = 297) to intravenous trastuzumab plus chemotherapy (n = 298), left ventricular dysfunction (3.4% vs. 4%) was among the most frequent cardiac adverse reactions. Heart failure and congestive heart failure (CHF) were also reported in 1% of patients treated with trastuzumab; hyaluronidase compared with less than 1% of patients treated with trastuzumab; a significant decrease in left ventricular ejection fraction of 10% or more (to an LVEF of less than 50%) was comparable between arms (3.8% vs. 4.2%). Fixed dosing of trastuzumab; hyaluronidase did not increase the risk of cardiac events or left ventricular dysfunction in patients with lower body weights (less than 59 kg). In another multicenter, 2-cohort, nonrandomized, open-label clinical trial (the SafeHER trial), a cardiac disorder was reported in 17% of patients treated with trastuzumab; hyaluronidase (n = 1,864), of which decreased ejection fraction (4.5%) was the most common; less than 1% of patients reported heart failure during the treatment period and one patient reported CHF during the follow-up period. Overall, 6% of patients treated with trastuzumab; hyaluronidase had an LVEF less than 50% with a decrease of 10% or more from baseline. In 3 clinical trials of patients receiving adjuvant therapy with intravenous trastuzumab (monotherapy or in combination with chemotherapy) (NSABP B31, HERA, and BCIRG006), between 1.4% and 15% of patients treated with intravenous trastuzumab discontinued treatment due to clinical evidence of myocardial dysfunction or a significant decline in LVEF. In the HERA study (1 year of intravenous trastuzumab), severe CHF occurred in 0.8% of patients and mild symptomatic or asymptomatic left ventricular dysfunction occurred in 4.6% of patients. Among patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who developed CHF, one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up; approximately 24% of patients were asymptomatic and had recovery to a normal LVEF (50% or more) on continued medical management at the time of last follow-up. In 3 clinical trials of patients with metastatic breast cancer, cardiac dysfunction was reported in 7% to 28% (grade 3 or 4, 4% to 19%) of patients receiving IV trastuzumab.
Edema was reported in 12% to 14% (grade 3 or 4, less than 1%) of patients treated with subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared with 5% to 15% of patients who received intravenous trastuzumab with or without chemotherapy (n = 884) in 3 open-label studies. Peripheral edema was reported in 10% to 22% of patients with metastatic breast cancer treated with trastuzumab monotherapy or in combination with paclitaxel or doxorubicin/cyclophosphamide (AC).
Hypertension was reported in 8% (grade 3 or 4, 2% to 2.4%) of patients treated with neoadjuvant or adjuvant subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared with 5% (grade 3 or 4, less than 1%) of patients receiving intravenous trastuzumab with or without chemotherapy (n = 298) in 2 open-label trials.
Arrhythmia or arrhythmia exacerbation was reported in 5% of patients receiving neoadjuvant or adjuvant treatment with both subcutaneous trastuzumab; hyaluronidase plus chemotherapy (n = 297) and intravenous trastuzumab plus chemotherapy (n = 298) in a randomized, open-label trial (grade 3 or 4, 0% vs. less than 1%). Sinus tachycardia was also reported in 5% to 12% of patients with metastatic breast cancer receiving intravenous trastuzumab with or without chemotherapy (n = 586) in another randomized, open-label trial.
Flushing was reported in 12% to 14% (grade 3 or 4, less than 1%) of patients receiving neoadjuvant or adjuvant treatment with subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared with 13% (grade 3 or 4, less than 1%) of those receiving intravenous trastuzumab with or without chemotherapy in 2 open-label trials. Hot flashes were also reported in 10% of patients receiving trastuzumab; hyaluronidase in these trials.
Treatment with trastuzumab; hyaluronidase can result in serious and fatal pulmonary toxicity including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusion, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome (ARDS), and pulmonary fibrosis. Symptoms usually occur during or within 24 hours of administration. Cough was reported in 11% to 12% (grade 3 or 4, less than 1%) of patients receiving neoadjuvant or adjuvant treatment with subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared with 8% of those receiving intravenous trastuzumab with or without chemotherapy (n = 298) in 2 open-label clinical trials; mild (grade 1 or 2) dyspnea was reported in 7% to 11% (grade 3 or 4, less than 1%) versus 8% of patients, respectively. In patients with metastatic breast cancer treated with intravenous trastuzumab, increased cough was reported in 26% of patients receiving trastuzumab alone (n = 352) and 41% to 43% when administered in combination with chemotherapy (n = 234). Dyspnea occurred in 22% to 27% of patients receiving trastuzumab alone or in combination with paclitaxel (n = 443) and in 42% of those receiving trastuzumab in combination with doxorubicin/cyclophosphamide (AC) (n = 143).
Serious hypersensitivity reactions or anaphylaxis have been reported in 4.2% to 9% (grade 3 or 4, 1% or less) of patients receiving neoadjuvant or adjuvant treatment with subcutaneous trastuzumab; hyaluronidase in 2 open-label trials (n = 2,161). In one non-randomized, open-label clinical trial (n = 1,864), administration-related reactions occurred in 39% of patients treated with trastuzumab; hyaluronidase either as monotherapy or with sequential or concurrent chemotherapy (grade 3 or 4, 1%); the most frequently reported grade 3 or higher administration-related reactions were dyspnea (less than 1%), cough (less than 1%), and hypersensitivity (less than 1%). Serious and fatal reactions have also been reported after treatment with intravenous trastuzumab products (all grade, 3% to 8%; grade 3 or 4, 1.3%). Closely monitor patients for systemic hypersensitivity reactions, especially during the first administration. Consider premedication with an analgesic, antipyretic, or antihistamine prior to readministration of trastuzumab; hyaluronidase for patients experiencing reversible grade 1 or 2 hypersensitivity reactions. Discontinue trastuzumab; hyaluronidase for angioedema or acute respiratory distress syndrome (ARDS); monitor patients until symptoms completely resolve. Permanently discontinue trastuzumab; hyaluronidase in patients who experience anaphylaxis or severe hypersensitivity reactions.
Injection site reaction has been reported in 10% to 20% of patients treated with subcutaneous trastuzumab; hyaluronidase with or without chemotherapy in 2 open-label clinical trials (n = 2,161), including injection site joint pain, bruising, dermatitis, discoloration, discomfort, erythema, extravasation, fibrosis, hematoma, bleeding, hypersensitivity, induration, inflammation, irritation, macule, mass, nodule, edema, pallor, paresthesia, pruritus, rash, ulcer, vesicles, and warmth; injection-site pain (grade 1 or 2, 6% to 11%; grade 3, 1 patient) and erythema (all grade, 7% to 9%; grade 3 or 4, less than 1%) were the most common reactions. Rash (all grade, 16% to 26%; grade 3 or 4, less than 1%) and pruritus (grade 1 or 2, 6% to 9%) were also reported with trastuzumab; hyaluronidase in these trials; rash has also been reported in 17% to 38% of patients treated with intravenous trastuzumab with or without chemotherapy. An incision site complication occurred in 11% of patients receiving subcutaneous trastuzumab; hyaluronidase (n = 297) compared with 8% (grade 3 or 4, less than 1%) of those receiving intravenous trastuzumab (n = 298) in a randomized, open-label trial.
Alopecia was reported in 63% (grade 3 or 4, 1.3%) of patients receiving neoadjuvant or adjuvant treatment with subcutaneous trastuzumab; hyaluronidase in combination with chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297), compared with 63% (grade 3 or 4, 1.7%) of those receiving intravenous trastuzumab plus chemotherapy (n = 298) in a randomized, open-label clinical trial. Alopecia was also reported in 9% (grade 3 or 4, less than 1%) of patients receiving subcutaneous trastuzumab; hyaluronidase as monotherapy or in combination with unspecified sequential or concurrent chemotherapy in another single-arm, open-label trial (n = 1,864). Nail disorder (all grade, 10% to 14% vs. 14%; grade 3 or 4, less than 1% vs. less than 1%) and skin discoloration (grade 1 or 2, 9% vs. 8%) occurred with a similar frequency in patients treated with trastuzumab; hyaluronidase compared with intravenous trastuzumab in these trials. Radiation skin injury was reported in 14% of patients who received trastuzumab; hyaluronidase in one of these trials. Herpes simplex (all grade 2% to 12%) and acne (2% to 11%) have also been reported with intravenous trastuzumab monotherapy (n = 352) and in combination with chemotherapy (n = 235) in another open-label study.
Subcutaneous administration of trastuzumab; hyaluronidase may exacerbate chemotherapy-induced neutropenia. In randomized, controlled clinical trials with intravenous trastuzumab, the per-patient incidences of grade 3 or 4 neutropenia and febrile neutropenia were higher in patients receiving trastuzumab plus myelosuppressive chemotherapy compared to those receiving chemotherapy alone; the incidence of septic death was similar. In a randomized, open-label study comparing subcutaneous trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) to intravenous trastuzumab plus chemotherapy (n = 298), neutropenia (all grade, 44% vs. 47%; grade 3 or 4, 30% to 34%), anemia (all grade, 12% vs. 14%; grade 3 or 4, less than 1% vs. 1%), and leukopenia (all grade, 11% vs. 16%; grade 3 or 4, 5% vs. 8%) were among the most common adverse reactions; febrile neutropenia (6%) and granulocytopenia (grade 3 or 4, 1%) were also reported in patients receiving subcutaneous trastuzumab; hyaluronidase with chemotherapy. Anemia was also reported in 8% (grade 3 or 4, less than 1%) of patients receiving subcutaneous trastuzumab; hyaluronidase monotherapy or with sequential or concurrent chemotherapy in a single-arm, open-label trial; neutropenia (all grade, 6%; grade 3 or 4, 4%), febrile neutropenia (2%), and leukopenia (1%) were among the most common grade 3 or 4 adverse reactions in that trial. Anemia and leukopenia were reported in 4% and 3% of patients treated with intravenous trastuzumab monotherapy (n = 352), in 14% and 24%, respectively, when trastuzumab was administered with paclitaxel (n = 91), and in 36% and 52%, respectively, when trastuzumab was administered with doxorubicin/cyclophosphamide (AC) (n = 143) in another randomized, open-label study. Immune thrombocytopenia has been reported with trastuzumab; hyaluronidase treatment in postmarketing experience.
Oligohydramnios resulting in teratogenesis (e.g., pulmonary hypoplasia and skeletal abnormalities) and neonatal death has been reported in pregnant women in postmarketing experience with intravenous trastuzumab, alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios.
The incidence of gastrointestinal adverse reactions with subcutaneous administration of trastuzumab; hyaluronidase is similar to intravenous administration of trastuzumab. In a randomized, open-label trial where neoadjuvant or adjuvant trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) was compared to trastuzumab plus chemotherapy (n = 298), nausea (all grade, 49% vs. 49%; grade 3 or 4, 1.3% vs. 1.3%), diarrhea (all grade, 34% vs. 37%; grade 3 or 4, 2.7% vs. 2.7%), vomiting (all grade, 23% vs. 23%; grade 3 or 4, 1% vs. 1.7%), stomatitis (all grade, 21% vs. 18%; grade 3 or 4, less than 1% vs. less than 1%), abdominal pain (all grade, 14% vs. 14%; grade 3 or 4, 0% vs. less than 1%), dyspepsia (grade 1 or 2, 11% vs. 10%), and mucosal inflammation (all grade, 6% to 10% vs. 13%; grade 3 or 4, less than 1% vs. 0%) were reported; constipation (14%) was also reported in patients who received trastuzumab; hyaluronidase with chemotherapy. In another single-arm, open-label trial, diarrhea (all grade, 21%; grade 3 or 4, 1%), nausea (all grade, 15%; grade 3 or 4, less than 1%), abdominal pain (all grade, 10%; grade 3 or 4, less than 1%, constipation (all grade, 9%; grade 3 or 4, less than 1%), stomatitis (all grade, 8%; grade 3 or 4, less than 1%), and vomiting (all grade, 7%; grade 3 or 4, less than 1%) were reported in patients who received trastuzumab; hyaluronidase either as monotherapy or sequentially or concurrently with unspecified chemotherapy. Gastrointestinal adverse reactions have also been reported with intravenous trastuzumab monotherapy (n = 352) and in combination with paclitaxel (n = 91) or doxorubicin/cyclophosphamide (AC) (n = 143), including nausea (33% vs. 51% vs. 76%), diarrhea (25% vs. 45% vs. 45%), vomiting (23% vs. 37% vs. 53%), abdominal pain (22% vs. 34% vs. 23%), and nausea/vomiting (8% vs. 14% vs. 18%).
The incidence of dysgeusia (grade 1 or 2, 10% vs. 8%) and anorexia (all grade, 20% vs. 20%; grade 3 or 4, less than 1% vs. less than 1%) was similar between patients receiving neoadjuvant or adjuvant trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) and those who received trastuzumab plus chemotherapy (n = 298) in a randomized, open-label trial. Anorexia has also been reported in 14% of patients with metastatic breast cancer receiving intravenous trastuzumab and in 24% to 31% of those receiving intravenous trastuzumab with chemotherapy.
The incidence of musculoskeletal adverse reactions with neoadjuvant or adjuvant use of subcutaneous administration of trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) in 2 open-label trials was similar to intravenous administration of trastuzumab with or without chemotherapy (n = 298), including myalgia (all grade, 17% to 21% vs. 19%; grade 3 or 4, less than 1% vs. less than 1%), arthralgia (all grade, 18% to 21% vs. 21%; grade 3 or 4, less than 1% vs. less than 1%), back pain (all grade, 8% to 11% vs. 9%; grade 3 or 4, 1% or less vs. 1%), pain in extremities (all grade, 10% to 11% vs. 9%; grade 3 or 4, less than 1% vs. less than 1%), and generalized pain (all grade, 5% to 8% vs. 5% to 9%; grade 3 or 4, less than 1% vs. less than 1%). Bone pain was also reported in 6% (grade 3 or 4, less than 1%) of patients receiving neoadjuvant or adjuvant subcutaneous trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) compared to 3.4% of those receiving intravenous trastuzumab plus chemotherapy (n = 298) in a randomized, open-label trial. Musculoskeletal adverse reactions were more common in general in patients with metastatic breast cancer receiving intravenous trastuzumab with or without chemotherapy (n = 586) including pain (47% to 61%), back pain (22% to 34%), and accidental injury (6% to 13%). Bone pain (24% vs. 7%) and arthralgia (37% vs. 6% to 8%) were more common in patients with metastatic breast cancer receiving intravenous trastuzumab plus paclitaxel (n = 91) compared with trastuzumab monotherapy or in combination with doxorubicin/cyclophosphamide (AC) (n = 495).
Fever (all grade, 11% to 13% vs. 12%; grade 3 or 4, 1% or less vs. 1%), upper respiratory infection (all grade, 19% to 24% vs. 27%; grade 3 or 4, 1% or less vs. less than 1%), and urinary tract infection (all grade, 4% to 6% vs. 8%; grade 3 or 4, less than 1% vs. less than 1%) occurred with a similar frequency in patients receiving neoadjuvant or adjuvant subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared with intravenous trastuzumab with or without chemotherapy (n = 298) in 2 open-label clinical trials. Grade 3 cellulitis was reported in 1% of patients receiving trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) in a randomized, open-label trial. Mild (grade 1 or 2) viral infection was also reported in 5% of patients receiving subcutaneous trastuzumab; hyaluronidase in a single-arm, open-label trial (n = 1,864). In a randomized, open-label trial of patients with metastatic breast cancer receiving intravenous trastuzumab, fever (36% vs. 49% to 56%), infection (20% vs. 47%), rhinitis (14% vs. 22%), pharyngitis (12% fs. 22% to 30%), sinusitis (9% vs. 13% to 21%), and urinary tract infection (5% vs. 13% to 18%) occurred less often with trastuzumab monotherapy compared to in combination with chemotherapy. Chills (32% to 41%) and flu syndrome (10% to 12%) occurred with a similar frequency with intravenous trastuzumab monotherapy and in combination with chemotherapy.
Peripheral neuropathy occurred in 14% to 20% (grade 3 or 4, less than 1%) of patients receiving neoadjuvant or adjuvant subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 2,161) in 2 open-label trials, compared to 15% of those receiving intravenous trastuzumab with or without chemotherapy (n = 298). Paresthesias were also reported in 6% (grade 3 or 4, less than 1%) of patients receiving trastuzumab; hyaluronidase monotherapy or with sequential or concurrent chemotherapy in a single-arm, open-label trial (n = 1,864). Nervous system adverse reactions have also been reported in patients with metastatic breast cancer receiving intravenous trastuzumab monotherapy (n = 352), in combination with paclitaxel (n = 91), or in combination with doxorubicin/cyclophosphamide (AC) (n = 143) in a randomized, open-label trial, including paresthesias (9% vs. 48% vs. 17%), peripheral neuritis (2% vs. 23% vs. 2%), and neuropathy (1% vs. 13% vs. 4%).
Fatigue was reported in 33% to 49% (grade 3 or 4, less than 1%) of patients receiving neoadjuvant or adjuvant subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared to 49% (grade 3 or 4, 2%) of patients receiving intravenous trastuzumab with or without chemotherapy (n = 298) in 2 open-label trials. Asthenia was also reported in 42% to 62% of patients with metastatic breast cancer receiving intravenous trastuzumab with or without chemotherapy (n = 586).
Headache (all grade, 13% to 17% vs. 15%; grade 3 or 4, less than 1% vs. less than 1%) and dizziness (all grade, 6% to 10% vs. 9%; grade 3 or 4, less than 1% vs. 1%) were reported with a similar frequency in patients receiving neoadjuvant or adjuvant subcutaneous trastuzumab; hyaluronidase with or without chemotherapy (n = 2,161) compared to intravenous trastuzumab with or without chemotheapy (n = 298) in 2 open-label trials. Insomnia was also reported in 7% (grade 3 or 4, less than 1%) of patients receiving neoadjuvant or adjuvant trastuzumab; hyaluronidase in a single-arm, open-label trial (n = 1,864). In a randomized, open-label trial of patients with metastatic breast cancer receiving intravenous trastuzumab monotherapy (n = 352) or in combination with chemotherapy (n = 234), headache (26% vs. 36% to 44%), insomnia (14% vs. 25% to 29%), dizziness (13% vs. 22% to 24%), and depression (6% vs. 12% to 20%) were also reported.
Glomerulopathy (e.g., membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis) has been reported in postmarketing experience with trastuzumab.
Grade 3 or 4 oligomenorrhea (2%) and amenorrhea (1%) were reported in patients receiving neoadjuvant or adjuvant treatment with trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) in a randomized, open-label trial.
Mild epistaxis (grade 1 or 2, 6% vs. 6%) and nasal irritation/inflammation (grade 1 or 2, 5% to 6% vs. 7%) were reported with a similar frequency in patients receiving neoadjuvant or adjuvant treatment with subcutaneous trastuzumab; hyaluronidase (n = 2,161) compared to intravenous trastuzumab (n = 298) in 2 open-label trials.
An abnormal liver function analysis including elevated hepatic enzymes was reported in 6% (grade 3 or 4, 1%) of patients receiving subcutaneous trastuzumab; hyaluronidase plus chemotherapy (docetaxel followed by fluorouracil or epirubicin/cyclophosphamide) (n = 297) compared with 9% (grade 3 or 4, 1.7%) of those receiving intravenous trastuzumab in a randomized, open-label trial.
Cases of tumor lysis syndrome (TLS) have been reported in postmarketing experience with patients treated with trastuzumab. Patients with significant tumor burden (e.g., bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure; consider additional monitoring and/or treatment as clinically indicated
In a randomized, open-label clinical trial,treatment-induced/enhanced anti-trastuzumab antibodies (antibody formation) were detected in 10% of patients treated with intravenous trastuzumab (n = 296) compared with 16% of those who received subcutaneous trastuzumab; hyaluronidase (n = 295). Also, neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 20 patients in the intravenous trastuzumab arm and in 3 of 47 patients in the trastuzumab; hyaluronidase arm. None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Results may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Comparison of the incidence of antibodies to trastuzumab; hyaluronidase with the incidence of antibodies to other products may be misleading.
Subclinical and clinical heart failure can occur as a result of treatment with trastuzumab; hyaluronidase. There is a 4- to 6-fold increase in the incidence of symptomatic cardiac dysfunction in patients receiving trastuzumab (monotherapy or in combination with chemotherapy) compared with those not receiving trastuzumab. The incidence and severity were highest in patients receiving concomitant anthracycline-containing chemotherapy regimens; patients who receive anthracycline after stopping trastuzumab; hyaluronidase may also be at increased risk of cardiac dysfunction. The incidence of symptomatic cardiac dysfunction was similar for subcutaneous trastuzumab; hyaluronidase and intravenous trastuzumab. Use trastuzumab; hyaluronidase with caution in patients with a history of cardiac disease, heart failure, cardiomyopathy, ventricular dysfunction, hypertension, or cardiac arrhythmias, as trastuzumab; hyaluronidase can cause these issues as well as cardiac death; an asymptomatic decline in the left ventricular ejection fraction (LVEF) is also possible. The risk of cardiac dysfunction was increased in geriatric patients compared to younger patients in clinical trials. Obtain a baseline measurement of LVEF by echocardiogram or MUGA immediately prior to initiation of trastuzumab; hyaluronidase, every 3 months during treatment, upon completion of therapy, and every 6 months for at least 2 years after adjuvant therapy. An interruption or discontinuation of therapy may be necessary for a decline in LVEF; the safety of continuing or resuming trastuzumab; hyaluronidase in patients with treatment-induced left ventricular cardiac dysfunction has not been adequately studied.
Use trastuzumab; hyaluronidase with caution in patients with preexisting chronic lung disease (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Treatment with trastuzumab; hyaluronidase can result in serious and fatal pulmonary toxicity, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis, which may be more severe in patients with symptomatic intrinsic lung disease or with more extensive tumor involvement of the lungs that results in dyspnea at rest. Symptoms usually occur during or within 24 hours of trastuzumab; hyaluronidase administration. Discontinue trastuzumab; hyaluronidase for interstitial pneumonitis or acute respiratory distress syndrome; monitor patients until symptoms completely resolve.
Serious hypersensitivity reactions or anaphylaxis have been reported with trastuzumab; hyaluronidase treatment. Patients who have dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or fatal reaction. Closely monitor patients for systemic hypersensitivity reactions, especially during the first administration. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Consider premedication with an analgesic, antipyretic, or antihistamine prior to readministration of trastuzumab; hyaluronidase for patients experiencing reversible grade 1 or 2 hypersensitivity reactions. Discontinue trastuzumab; hyaluronidase for angioedema or acute respiratory distress syndrome (ARDS); monitor patients until symptoms completely resolve. Permanently discontinue trastuzumab; hyaluronidase in patients who experience anaphylaxis or severe hypersensitivity reactions.
Chemotherapy-induced neutropenia and febrile neutropenia may be exacerbated by the addition of subcutaneous trastuzumab; hyaluronidase. The incidence of grade 3 or 4 neutropenia and febrile neutropenia were higher in patients receiving intravenous trastuzumab plus myelosuppressive chemotherapy compared to those receiving chemotherapy alone in randomized, controlled clinical trials; the incidence of septic death was similar.
Trastuzumab; hyaluronidase has different dosage and administration instructions than intravenous trastuzumab products, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan. Ensure correct formulation selection and dose before preparation and administration.
Serious fetal harm can occur if trastuzumab; hyaluronidase is administered during pregnancy or within 7 months prior to conception. Counsel women to avoid pregnancy during trastuzumab; hyaluronidase therapy and for 7 months after the last dose. If a woman becomes pregnant while receiving or within 7 months of receiving trastuzumab; hyaluronidase, inform her of the fetal risks, monitor for oligohydramnios, and immediately report to the pregnancy pharmacovigilance program at Genentech (1-888-835-2555). If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and is consistent with community standards of care. Oligohydramnios and oligohydramnios sequence (manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death) have occurred in pregnant women who received trastuzumab alone or in combination with chemotherapy. In some women, the amniotic fluid index increased after trastuzumab cessation. In one case, treatment was resumed with trastuzumab after the amniotic fluid index improved, resulting in a recurrence of oligohydramnios. Based on animals studies with hyaluronidase, there is no evidence of teratogenicity or other adverse effects on sexual maturation, learning and memory, or fertility of the offspring.
Counsel patients about the reproductive risk and contraception requirements during and after treatment with trastuzumab; hyaluronidase. Trastuzumab can be teratogenic if taken by the mother during pregnancy or within 7 months prior to conception. Females should avoid pregnancy and use effective contraception during and for at least 7 months after treatment with trastuzumab; hyaluronidase. Females of reproductive potential should undergo pregnancy testing prior to treatment initiation. Women who become pregnant while receiving trastuzumab; hyaluronidase or within 7 months of the last dose should be apprised of the potential hazard to the fetus; healthcare providers and patients should immediately report trastuzumab exposure to Genentech (1-888-835-2555).
It is not known whether trastuzumab is excreted into human milk. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with trastuzumab; hyaluronidase and for 7 months after the last dose.
For the treatment of HER2-positive breast cancer:
NOTE: Patients should be selected based on an FDA-approved companion diagnostic for trastuzumab showing the presence of HER2 protein overexpression or HER2 gene amplification in tumor specimens. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics. Tests should be specific for breast cancers due to differences in breast vs. gastric histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
-for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (greater than 2 cm diameter or node-positive) in combination with pertuzumab and chemotherapy*:
NOTE: Pertuzumab is FDA-approved in combination with trastuzumab; hyaluronidase and chemotherapy for this indication.
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes on day 1, every 3 weeks, in combination with pertuzumab (840 mg IV over 60 minutes [of cycle 1 only], followed 3 weeks later by 420 mg IV over 30 to 60 minutes repeated every 3 weeks), for a total of 3 to 6 cycles as part of one of the following treatment regimens: Four preoperative cycles of pertuzumab in combination with trastuzumab; hyaluronidase and docetaxel with 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC); Three or four preopoerative cycles of FEC alone followed by 3 or 4 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; hyaluronidase; Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab; hyaluronidase (TCH); Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative doses of pertuzumab in combination with paclitaxel and trastuzumab; hyaluronidase. After surgery, give IV pertuzumab and trastuzumab; hyaluronidase every 3 weeks to complete 1 year of therapy (up to 18 cycles). Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given PRIOR to the taxane infusion in patients receiving a taxane-containing regimen. In patients receiving an anthracycline-containing regimen, pertuzumab and trastuzumab; hyaluronidase should be given following completion of the anthracycline. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued.
-for adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer as monotherapy, following multimodality anthracycline-based chemotherapy:
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes once every 3 weeks for 52 weeks or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose is required. Do not substitute trastuzumab; hyaluronidase with ado-trastuzumab emtansine or trastuzumab. In a randomized clinical trial of patients with HER2-positive breast cancer, one year of adjuvant trastuzumab after the completion chemotherapy and radiation (if applicable) resulted in significantly improved disease-free survival compared with observation; overall survival was not significantly improved. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.
-for adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer in combination with docetaxel, after completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH):
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, in combination with docetaxel (100 mg/m2 IV) beginning on day 1 for a total of 4 cycles (12 weeks). Continue 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously for a total of 52 weeks of trastuzumab therapy or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. Begin docetaxel plus trastuzumab; hyaluronidase after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); do NOT administer trastuzumab; hyaluronidase concurrently with doxorubicin and cyclophosphamide. In a randomized clinical trial of patients with HER2-positive breast cancer, adjuvant treatment with docetaxel plus trastuzumab after completion of AC chemotherapy significantly improved disease-free survival compared with docetaxel alone. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.
-for adjuvant treatment of HER2-positive, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer in combination with paclitaxel, after completion of doxorubicin and cyclophosphamide chemotherapy (AC-TH):
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, in combination with paclitaxel (either 80 mg/m2 IV weekly or 175 mg/m2 IV every 3 weeks) beginning on day 1 for a total of 12 weeks. Continue 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously for a total of 52 weeks of trastuzumab therapy or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. Begin paclitaxel plus trastuzumab; hyaluronidase after the completion of 4 cycles of AC chemotherapy (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 21 days); do NOT administer trastuzumab; hyaluronidase concurrently with doxorubicin and cyclophosphamide. In an efficacy analysis of two randomized clinical trials of patients with HER2-positive breast cancer (n = 3,752), the adjuvant combination of paclitaxel plus trastuzumab after the completion of AC chemotherapy significantly improved both disease-free survival and overall survival compared with paclitaxel alone. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.
-for adjuvant treatment of HER2-positive, node-positive or node negative (ER/PR negative or with one high-risk feature) breast cancer, in combination with carboplatin and docetaxel (TCH):
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, in combination with docetaxel (75 mg/m2 IV) followed by carboplatin (AUC 6 IV over 30 to 60 minutes) every 3 weeks beginning on day 1 for a total of 6 cycles (18 weeks). On week 19, continue 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously for a total of 52 weeks of trastuzumab therapy or until disease recurrence, whichever occurs first; extending treatment beyond 1 year is not recommended. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. In a randomized clinical trial of patients with HER2-positive breast cancer, one year of adjuvant trastuzumab after the completion chemotherapy and radiation (if applicable) resulted in significantly improved disease-free survival compared with observation; overall survival was not significantly improved. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.
-for the adjuvant treatment of early breast cancer in patients at high risk of recurrence, in combination with pertuzumab and standard anthracycline- and/or taxane-based chemotherapy*:
NOTE: Pertuzumab is FDA-approved in combination with trastuzumab; hyaluronidase and standard anthracycline- and/or taxane-based chemotherapy for this indication.
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes on day 1 every 3 weeks, in combination with pertuzumab (840 mg IV over 60 minutes [of cycle 1 only], followed 3 weeks later by 420 mg IV over 30 to 60 minutes repeated every 3 weeks), for for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity. Give with standard anthracycline- and/or taxane-based chemotherapy for early breast cancer. Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given before the taxane in taxane-containing regimens. Give pertuzumab and trastuzumab; hyaluronidase after the completion of the anthracycline dose in anthracycline-containing regimens. Observe closely for infusion-related reactions after the first pertuzumab infusion for 60 minutes and for 30 minutes after subsequent infusions; do not start other therapy until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued.
-for the first-line treatment of HER2-positive metastatic breast cancer, in combination with paclitaxel:
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes, in combination with paclitaxel (175 mg/m2 IV over 3 hours) on day 1, every 3 weeks for at least 6 cycles or until disease progression. No loading dose of trastuzumab; hyaluronidase-oysk is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. In a multicenter, randomized, open-label clinical trial of patients with previously untreated metastatic breast cancer, treatment with trastuzumab plus paclitaxel significantly improved the median time to progression (6.7 vs. 2.5 months), overall response rate (38% vs. 15%), and duration of response (8.3 vs. 4.3 months) compared with paclitaxel alone; overall survival was not significantly improved. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.
-for the treatment of HER2-positive metastatic breast cancer in patients who have failed one or more chemotherapy regimens for metastatic disease, as monotherapy:
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes on day 1, every 3 weeks until disease progression. No loading dose of trastuzumab; hyaluronidase is required. Do not substitute trastuzumab; hyaluronidase for or with other trastuzumab-based products. Monotherapy with trastuzumab resulted in an overall response rate of 14% (complete response (CR), 2%; partial response, 12%) in a multicenter, noncomparative study in patients with metastatic breast cancer and relapse after 1 or more prior chemotherapy regimens; CR only occurred in patients with disease limited to the skin and lymph nodes. The response rate for patients with tumors that tested as CTA 3+ was 18%, while the response rate was 6% for tumors that tested as CTA 2+. Treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on pharmacokinetic and efficacy outcomes in a randomized clinical trial.
-for the treatment of HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, in combination with pertuzumab and docetaxel*:
NOTE: Pertuzumab is FDA-approved in combination with trastuzumab; hyaluronidase and docetaxel for this indication.
Subcutaneous dosage:
Adults: 600 mg trastuzumab and 10,000 units hyaluronidase (5 mL) subcutaneously over approximately 2 to 5 minutes in combination with pertuzumab (840 mg IV over 60 minutes [of cycle 1 only], followed 3 weeks later by 420 mg IV over 30 to 60 minutes repeated every 3 weeks) and docetaxel (75 mg/m2 IV) on day 1; in the clinical trial, docetaxel was continued for at least a total of 6 cycles and pertuzumab/trastuzumab were administered until disease progression or unacceptable toxicity. Pertuzumab and trastuzumab; hyaluronidase can be given in any order; however, both agents should be given PRIOR TO the docetaxel infusion. Observe closely for infusion-related reactions for 60 minutes after the first pertuzumab infusion and for 30 minutes after subsequent infusions; do not start other infusions until after this observation period. Do not administer pertuzumab without trastuzumab; hyaluronidase; withhold or discontinue pertuzumab therapy if trastuzumab; hyaluronidase is withheld or discontinued. In a multicenter, double-blind, placebo-controlled trial of patients with HER2-positive metastatic breast cancer (CLEOPATRA), treatment with pertuzumab, trastuzumab, and docetaxel significantly improved progression-free survival (18.5 months vs. 12.4 months) compared with trastuzumab and docetaxel alone. Overall survival was also significantly improved in the pertuzumab arm (56.5 months vs. 40.8 months).
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Cardiomyopathy
-Absolute decrease in left ventricular ejection fraction (LVEF) of 16% or more from baseline, or LVEF lower than institutional limits of normal and an absolute decrease from baseline of 10% or more: Hold trastuzumab; hyaluronidase therapy for at least 4 weeks; repeat LVEF measurement at 4-week intervals. If the LVEF returns to normal limits within 4 to 8 weeks and the absolute decrease from baseline is 15% or less, treatment may be resumed. The safety of continuation or resumption of treatment with trastuzumab; hyaluronidase in patients with treatment-induced left ventricular cardiac dysfunction has not been studied. Permanently discontinue trastuzumab; hyaluronidase for a persistent LVEF decline lasting greater than 8 weeks or for cardiomyopathy requiring an interruption of therapy on more than 3 occasions.
Pulmonary Toxicity
-Discontinue trastuzumab; hyaluronidase for anaphylaxis, interstitial pneumonitis, or acute respiratory distress syndrome (ARDS).
Maximum Dosage Limits:
-Adults
600 mg trastuzumab and 10,000 units of hyaluronidase (5 mL) subcutaneously once every 3 weeks.
-Geriatric
600 mg trastuzumab and 10,000 units of hyaluronidase (5 mL) subcutaneously once every 3 weeks.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Aspirin: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect. (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Caffeine; Pyrilamine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Chlorpheniramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Diphenhydramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Acrivastine; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Amide local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Aminosalicylate sodium, Aminosalicylic acid: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Anthracyclines: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Articaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Aspirin, ASA: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Caffeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Carisoprodol; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Dipyridamole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Omeprazole: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Aspirin, ASA; Oxycodone: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Bismuth Subsalicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Brompheniramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Brompheniramine; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Brompheniramine; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Bupivacaine Liposomal: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Bupivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Bupivacaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Bupivacaine; Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Bupivacaine; Meloxicam: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Carbinoxamine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlophedianol; Dexbrompheniramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorcyclizine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chloroprocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Chlorpheniramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Codeine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Dextromethorphan: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Hydrocodone: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Chlorpheniramine; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Choline Salicylate; Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Clemastine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Cocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Conjugated Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Corticotropin, ACTH: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Cortisone: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Cyclophosphamide: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity.
Cyproheptadine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Daunorubicin Liposomal; Cytarabine Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Daunorubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dexbrompheniramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dexbrompheniramine; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dexchlorpheniramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dienogest; Estradiol valerate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Dimenhydrinate: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Diphenhydramine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Diphenhydramine; Ibuprofen: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Diphenhydramine; Naproxen: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Diphenhydramine; Phenylephrine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Doxorubicin Liposomal: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Doxorubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Doxylamine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Doxylamine; Pyridoxine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Drospirenone; Estetrol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Drospirenone; Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Drospirenone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Elagolix; Estradiol; Norethindrone acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Epirubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Ester local anesthetics: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Esterified Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estradiol; Levonorgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estradiol; Norethindrone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estradiol; Norgestimate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estradiol; Progesterone: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estrogens: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Estropipate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Ethinyl Estradiol; Norgestrel: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Etonogestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hydroxyzine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Idarubicin: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Levonorgestrel; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Lidocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Lidocaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Lidocaine; Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Magnesium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Meclizine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Mepivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Methenamine; Sodium Salicylate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Norethindrone; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Norgestimate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Prilocaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Prilocaine; Epinephrine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Pseudoephedrine; Triprolidine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Relugolix; Estradiol; Norethindrone acetate: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Ropivacaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Salicylates: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Salsalate: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sedating H1-blockers: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Tetracaine: (Moderate) Hyaluronidase, when used in combination with local anesthetics, hastens the onset of analgesia and reduces the swelling caused by local infiltration; this interaction is beneficial and is the reason hyaluronidase is used adjunctively in local infiltrative anesthesia techniques. However, the wider spread of the local anesthetic solution may increase the systemic absorption of the local anesthetic, which shortens the duration of anesthetic action and tends to increase the potential risk for systemic side effects.
Triprolidine: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER2. The HER2 or c-erbB2 gene is an oncogene that encodes for the HER2 transmembrane receptor protein (185 Kd) and is structurally related to the epidermal growth factor receptor. Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) preferentially acts on cancer cells that overexpress HER2 compared with cancer cells that do not overexpress HER2. The overexpression of HER2 in tumor cells is closely associated with increased angiogenesis and expression of vascular epidermal growth factor (VEGF); when the VEGF pathway is inhibited, tumor growth is suppressed. In cells treated with trastuzumab, the HER2 receptor is downregulated, cyclin-dependent kinase inhibitor p27 accumulates, and cell cycle arrest occurs. Trastuzumab also inhibits the constitutive HER2 cleavage/shedding mediated by metalloproteases, which may correlate with the clinical activity of trastuzumab.
Hyaluronidase is a endoglycosidase used to increase dispersion and absorption of coadministered drugs when administered subcutaneously. In the administered doses, hyaluronidase in trastuzumab; hyaluronidase acts transiently and locally. It increases permeability of the subcutaneous tissue by depolymerizing hyaluronan, which is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days; the effects of hyaluronidase are reversible and permeability of subcutaneous tissue is restored within 24 to 48 hours. Hyaluronidase has been shown to increase the absorption rate of a trastuzumab product into systemic circulation when given in the subcutis of Gottingen Minipigs.
Trastuzumab; hyaluronidase is administered subcutaneously. Based on a population pharmacokinetic model, the volume of distribution (Vd) of trastuzumab after subcutaneous administration of trastuzumab; hyaluronidase was 2.9 Liters. The linear elimination clearance was 0.11 Liters/day. The non-linear elimination Vmax was 11.9 mg/day and the non-linear elimination Km was 33.9 mg/Liter.
Affected cytochrome P450 isoenzymes and drug transporters: None
Formal drug interaction studies have not been performed with trastuzumab in humans. Clinically significant interactions between trastuzumab and concomitant medications have not been observed in clinical trials.
-Route-Specific Pharmacokinetics
Subcutaneous Route
The absolute bioavailability of trastuzumab after subcutaneous administration of trastuzumab; hyaluronidase was 0.77. The first-order absorption rate of subcutaneous trastuzumab; hyaluronidase was 0.4 days, with a time to maximal concentration (Tmax) of 3 days. The Cmax after subcutaneous administration of trastuzumab; hyaluronidase was 79.3 mcg/mL after the first cycle and 149 mcg/mL after the 7th cycle, compared with 178 mcg/mL and 179 mcg/mL for intravenous trastuzumab, respectively. The AUC was 1,065 mcg/mL x day for trastuzumab; hyaluronidase in the first cycle and 2,337 mg/mL x day in the 7th cycle; the AUC for trastuzumab was 1,373 mcg/mL x day and 1,794 mcg/mL x day, respectively. In a multicenter, randomized, open-label clinical trial (the HannaH study; n = 596), treatment with subcutaneous trastuzumab; hyaluronidase with chemotherapy was noninferior to intravenous trastuzumab based on coprimary pharmacokinetic (trastuzumab Cmin) and efficacy (pCR rate at definitive surgery) outcomes. In this study, the Cmin pre-dose Cycle 8 was 78.7 mcg/mL for subcutaneous trastuzumab; hyaluronidase compared to 57.8 mcg/mL for intravenous trastuzumab; the geometric mean ratio was 1.3 (90% CI, 1.2 to 1.4). The mean Cmax was 32% lower, and the mean AUC following the Cycle 7 dose and the Cycle 12 dose was 10% and 20% higher, respectively, with subcutaneous trastuzumab; hyaluronidase compared to intravenous trastuzumab. Trastuzumab is estimated to reach concentrations that are less than 1 mcg/mL by 7 months in at least 95% of patients. The rate of pCR prior to surgery in the HannaH study was 45.4% in the subcutaneous trastuzumab and hyaluronidase arm compared with 40.7% in the intravenous trastuzumab arm (95% CI for difference in pCR, -4 to 13.4); there was no difference in event-free survival or overall survival after a median follow-up of over 70 months. No new safety signals were identified for trastuzumab and hyaluronidase in another nonrandomized, open-label clinical trial (the SafeHER study; n = 1,864).
-Special Populations
Obesity
Body weight showed a statistically significant influence on the pharmacokinetics of trastuzumab after subcutaneous administration of trastuzumab; hyaluronidase. However, no dose adjustments are needed as the exposure changes are not considered clinically relevant. The mean steady-state AUC of trastuzumab was about 80% higher in patients with a body weight less than 51 kg after subcutaneous administration of trastuzumab; hyaluronidase than after intravenous trastuzumab. The AUC was 20% lower in the highest body weight group (greater than 90 kg) after subcutaneous trastuzumab than after intravenous trastuzumab treatment.