Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf (Monograph)

Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: Immunoglobulin G1, anti-(human neu (receptor)) (human-mouse monoclonal 2C4 heavy chain), disulfide with human-mouse monoclonal 2C4 κ-chain, dimer
CAS number: 380610-27-5

Medically reviewed by Drugs.com on Dec 21, 2022. Written by ASHP.

Introduction

Antineoplastic agent; fixed combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (pertuzumab/trastuzumab/hyaluronidase-zzxf); pertuzumab is a recombinant humanized anti-human epidermal growth factor receptor type 2 (anti-HER2/ERBB2) monoclonal antibody, trastuzumab is a recombinant DNA-derived humanized anti-HER2 monoclonal antibody, and hyaluronidase-zzxf is a recombinant endoglycosidase that enhances dispersion and absorption of pertuzumab and trastuzumab.

Uses for Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf

Breast Cancer

In combination with chemotherapy for the neoadjuvant treatment of adults with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen.

In combination with chemotherapy for the adjuvant treatment of adults with HER2-positive early-stage breast cancer at high risk of recurrence.

In combination with docetaxel for the treatment of adults with HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

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

Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Dosage and Administration

General

Pretreatment Screening

• Select patients for pertuzumab/trastuzumab/hyaluronidase-zzxf therapy based on HER2 protein overexpression or HER2 gene amplification in tumor specimens using an FDA-approved test specific for breast cancer by laboratories with demonstrated proficiency.

• Verify pregnancy status in females of reproductive potential prior to initiating therapy.

• Perform baseline cardiac evaluation including history, physical examination, and assessment of LVEF (i.e., echocardiogram and/or MUGA scan) prior to initiating therapy.

Patient Monitoring

• Monitor patients for hypersensitivity symptoms or administration-related reactions during and for a minimum of 30 minutes after administration of the initial dose of pertuzumab/trastuzumab/hyaluronidase-zzxf, and during and for 15 minutes after administration of each maintenance dose.

• Assess LVEF at regular intervals (e.g., every 3 months) during treatment. Following completion of therapy, continue to monitor for cardiomyopathy and assess LVEF every 6 months for at least 2 years as a component of adjuvant therapy.

Premedication and Prophylaxis

• In patients experiencing reversible grade 1 or grade 2 hypersensitivity reactions with pertuzumab/trastuzumab/hyaluronidase-zzxf, consider premedication with an analgesic, antipyretic, or an antihistamine prior to re-administering the combination drug.

Dispensing and Administration Precautions

• Pertuzumab/trastuzumab/hyaluronidase-zzxf must always be administered by a healthcare professional.

• Dosage and administration instructions for pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo) differ from those of IV pertuzumab (Perjeta), IV trastuzumab (Herceptin), and sub-Q trastuzumab (Herceptin Hylecta) when administered alone. Do not substitute pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo) for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan.

• To prevent medication errors, check vial labels to ensure that the drug being prepared and administered is pertuzumab/trastuzumab/hyaluronidase-zzxf and not IV pertuzumab, IV trastuzumab, or sub-Q trastuzumab.

• Drugs and emergency equipment for treatment of hypersensitivity reactions should be readily available during administration of pertuzumab/trastuzumab/hyaluronidase-zzxf.

• Procedures for proper handling (including wearing protective gloves and a protective suit) and disposal of antineoplastic agents should be followed when preparing and administering pertuzumab, trastuzumab, and hyaluronidase.

Administration

Sub-Q Administration

Administer by sub-Q injection only; do not administer IV or by IM injection.

Available in single-use vials containing the fixed combination of 1200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase-zzxf in 15 mL of solution (for initial dose) or the fixed combination of 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase-zzxf in 10 mL of solution (for maintenance doses). A single dose of pertuzumab/trastuzumab/hyaluronidase-zzxf requires administration of entire contents of one vial. Do not dilute the drug.

Vials contain no preservatives and are intended for single-use only; discard any unused portions. Solution should appear clear to opalescent and colorless to light brown; do not use if cloudy, discolored, or contains particles.

Prior to administration, withdraw entire contents of drug from vial using a syringe and transfer needle. Remove transfer needle and replace with a 25- to 27-gauge, (3/8)–(5/8)-inch hypodermic needle; adjust volume of drug solution in syringe to 15 mL for the initial dose or 10 mL for maintenance doses.

Administer sub-Q injection immediately into thigh. If not administered immediately, replace transfer needle with a syringe cap and label syringe; may store for up to 24 hours under refrigeration or up to 4 hours at room temperature.

Alternate injection sites between the left and right thigh, ≥1 inch (2.5 cm) from previous injection site; avoid any area that is tender, red, bruised, or hard. A single dose should not be split into 2 syringes or administered into two different administration sites.

During treatment course with pertuzumab/trastuzumab/hyaluronidase-zzxf, administer other sub-Q medications preferably at different sites.

Pertuzumab/trastuzumab/hyaluronidase-zzxf is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride. and fluorinated ethylene polypropylene.

Rate of Administration

Initial dose: Administer over approximately 8 minutes.

Subsequent doses: Administer over approximately 5 minutes.

Dosage

Consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with pertuzumab/trastuzumab/hyaluronidase.

If a dose of pertuzumab/trastuzumab/hyaluronidase-zzxf is missed or delayed, and the time between 2 sequential injections is <6 weeks, administer the maintenance dose as soon as possible; do not wait until the next planned dose. If the time between 2 sequential injections is ≥6 weeks, re-administer the initial dose, followed every 3 weeks thereafter by a maintenance dose.

Patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf in combination with anthracycline-based chemotherapy: Administer pertuzumab/trastuzumab/hyaluronidase-zzxf after administration of the anthracycline is completed.

Patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf with taxane-based chemotherapy (docetaxel or paclitaxel): Administer taxane-based chemotherapy after administration of pertuzumab/trastuzumab/hyaluronidase-zzxf. Administer initial pertuzumab/trastuzumab/hyaluronidase-zzxf dose on day 1 of the first taxane-based chemotherapy cycle.

Patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf for metastatic breast cancer with docetaxel: Administer docetaxel after pertuzumab/trastuzumab/hyaluronidase-zzxf.

Dosage adjustment is not necessary for concomitant chemotherapy.

Adults

Breast Cancer

Neoadjuvant Therapy for HER2-positive Early-stage Breast Cancer

Sub-Q

Administer as part of a treatment regimen.

Recommended initial dose of the fixed combination is 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase in 15 mL (administered by sub-Q injection over approximately 8 minutes), followed by maintenance doses of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase in 10 mL (administered by sub-Q injection over approximately 5 minutes) every 3 weeks for 3–6 cycles prior to surgery.

In the FeDeriCa trial, pertuzumab/trastuzumab/hyaluronidase-zzxf was administered as part of the following neoadjuvant treatment regimens: 4 preoperative cycles of dose-dense doxorubicin and cyclophosphamide alone followed by 4 preoperative cycles of pertuzumab/trastuzumab/hyaluronidase in combination with paclitaxel or docetaxel.

Following surgery, continue pertuzumab/trastuzumab/hyaluronidase-zzxf therapy to complete 1 year of therapy (up to 18 cycles) or until disease progression or unacceptable toxicity occurs.

Adjuvant Therapy for HER2-positive Early-stage Breast Cancer

Sub-Q

Administer as part of a complete regimen, including standard anthracycline- and/or taxane-based chemotherapy.

Recommended initial dose of the fixed combination is 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase in 15 mL (administered by sub-Q injection over approximately 8 minutes). Begin pertuzumab/trastuzumab/hyaluronidase-zzxf therapy on day 1 of the first taxane-containing cycle.

Follow with maintenance doses of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase in 10 mL (administered by sub-Q injection over approximately 5 minutes) every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or intolerable toxicity occurs.

Metastatic Breast Cancer

Sub-Q

Recommended initial dose of the fixed combination is 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase in 15 mL (administered by sub-Q injection over approximately 8 minutes) in combination with docetaxel 75 mg/m² (administered as an IV infusion).

Follow with maintenance doses of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase in 10 mL (administered by sub-Q injection over approximately 5 minutes) in combination with docetaxel 75 mg/m² (administered by IV infusion); dosage of docetaxel may be increased to 100 mg/m² if initial dosage is well tolerated. Continue therapy until disease progression or unacceptable toxicity occurs.

Patients Transitioning From IV Pertuzumab and IV Trastuzumab Therapy to Pertuzumab/trastuzumab/hyaluronidase-zzxf

Patients previously receiving IV pertuzumab and IV trastuzumab (<6 weeks since last dose): Administer the fixed combination as a maintenance dosage of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase every 3 weeks.

Patients previously receiving IV pertuzumab and IV trastuzumab (≥6 weeks since last dose): Administer the fixed combination as an initial dose of 1200 mg pertuzumab/600 mg trastuzumab/30,000 units hyaluronidase followed by a maintenance dosage of 600 mg pertuzumab/600 mg trastuzumab/20,000 units hyaluronidase every 3 weeks.

Dosage Modification for Toxicity and Contraindications to Continued Therapy

Dosage reductions not recommended; if toxicities occur, reduce injection rate or temporarily or permanently discontinue therapy.

Consult prescribing information for concomitant chemotherapy (anthracycline, docetaxel, paclitaxel) for detailed information on dosage modifications for these drugs.

Cardiovascular Toxicity

Early-stage Breast Cancer

If left ventricular ejection fraction (LVEF) decreases to <50% with an absolute decrease from baseline of ≥10%, withhold therapy for at least 3 weeks.

If LVEF has recovered to ≥50% or to an absolute decrease from baseline of <10%, resume therapy. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, or if patient is symptomatic, permanently discontinue therapy.

In patients receiving anthracycline-based chemotherapy, pertuzumab/trastuzumab/hyaluronidase-zzxf therapy should be initiated only if LVEF after completion of anthracyclines is within normal limits (≥50%).

Metastatic Breast Cancer

If LVEF decreases to <40% or to 40–45% with an absolute decrease from baseline of ≥10%, withhold therapy for at least 3 weeks.

If LVEF has recovered to >45% or to 40–45% with an absolute decrease from baseline of <10%, resume therapy. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, or if patient is symptomatic, permanently discontinue therapy.

Hypersensitivity and Administration-related Reactions

If a significant injection-related reaction occurs, reduce or pause injection rate and initiate appropriate medical therapy. If a serious hypersensitivity reaction occurs, immediately discontinue injection and permanently discontinue therapy.

Special Populations

Dosage adjustment is not necessary based on body weight or baseline albumin concentration.

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Related/similar drugs

Enhertu, Trodelvy, Arimidex, Femara, Xeloda, Herceptin, Ibrance

Cautions for Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf

Contraindications

• Known hypersensitivity to pertuzumab, trastuzumab, or hyaluronidase-zzxf, or any ingredient in the formulation.

Warnings/Precautions

Warnings

Cardiomyopathy

Serious and potentially fatal cardiovascular effects, including hypertension, arrhythmias, left ventricular cardiac dysfunction, subclinical and disabling cardiac failure, cardiomyopathy, and cardiac death reported. (See Boxed Warning.)

Increased incidence of LVEF decline reported in patients receiving IV pertuzumab and IV trastuzumab in combination with docetaxel. Risk of cardiac dysfunction may be increased in patients who receive anthracycline therapy after stopping pertuzumab/trastuzumab/hyaluronidase-zzxf.

Perform baseline cardiac evaluation (e.g., history, physical examination, LVEF assessment [echocardiogram and/or MUGA scan]) prior to initiating therapy. Assess LVEF at regular intervals (e.g., every 3 months) during treatment. Monitor for cardiomyopathy and assess LVEF every 6 months for at least 2 years as a component of adjuvant therapy after discontinuance of pertuzumab/trastuzumab/hyaluronidase-zzxf.

If substantial decreases in LVEF occur, may need to temporarily or permanently discontinue therapy. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue therapy.

Safety not established in patients with early breast cancer or metastatic breast cancer with baseline LVEF values <55 or 50%, respectively, prior history of CHF, or conditions that could impair left ventricular function (e.g., uncontrolled hypertension, recent MI, serious cardiac arrhythmia requiring treatment, or a cumulative prior anthracycline exposure to >360 mg/m² of doxorubicin or its equivalent).

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. (See Boxed Warning.) Embryotoxicity and fetotoxicity demonstrated. Oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death reported with use of IV trastuzumab during pregnancy. Oligohydramnios, delayed fetal kidney development, and embryo-fetal death observed in pregnant monkeys receiving pertuzumab at dosages higher than recommended.

Consider possibility that trastuzumab may persist in maternal tissues for up to 7 months after last dose.

Perform pregnancy test prior to initiation of therapy. Advise females of reproductive potential to use effective contraceptive methods during and for 7 months after discontinuance of drug.

If used during pregnancy or within 7 months of conception, apprise of potential fetal hazard. (See Pregnancy under Cautions.)

Monitor for oligohydramnios in patients who received pertuzumab/trastuzumab/hyaluronidase-zzxf during pregnancy or within 7 months prior to conception; perform appropriate fetal testing if oligohydramnios occurs.

Pulmonary Toxicity

Risk of serious, sometimes fatal, pulmonary toxicity. (See Boxed Warning.) Severe adverse pulmonary effects, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis, reported in patients receiving IV trastuzumab. Patients with symptomatic intrinsic lung disease or extensive tumor involvement of the lungs causing dyspnea at rest may experience more severe pulmonary toxicity.

Permanently discontinue therapy if anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome develops. Monitor patients carefully until signs and symptoms resolve completely.

Other Warnings and Precautions

Hypersensitivity and Administration-related Reactions

Severe administration-related reactions, including hypersensitivity, anaphylaxis, and fatal events, have been associated with IV pertuzumab and trastuzumab. Increased risk for severe or fatal administration-related reaction in patients with advanced malignancies and comorbidities who experience dyspnea at rest.

Most common reactions reported were injection site reactions and injection site pain.

Closely observe patients during and for 30 minutes after first injection, and during and for 15 minutes after subsequent injections. If an injection-related reaction occurs, slow down or pause injection and administer appropriate treatment. Evaluate and closely monitor patient until signs and symptoms completely resolve.

If a severe injection-related reaction or anaphylaxis occurs, permanently discontinue therapy.

Administer in a setting where emergency equipment and appropriate medical support are available for management of hypersensitivity reactions.

In patients experiencing reversible grade 1 or grade 2 hypersensitivity reactions, consider premedication with an analgesic, antipyretic, or an antihistamine prior to re-administering the combination drug.

Contraindicated in patients with known hypersensitivity to the drug or any ingredients in the formulation.

Neutropenia

Possible exacerbation of chemotherapy-induced neutropenia.

Immunogenicity

Potential for immunogenicity. Development of anti-pertuzumab, anti-trastuzumab, and anti-recombinant human hyaluronidase antibodies reported; neutralizing antibodies to pertuzumab or trastuzumab also detected. Clinical relevance of such antibodies not known.

Specific Populations

Pregnancy

May case fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If used during pregnancy or if patient becomes pregnant while receiving therapy or within 7 months after discontinuance of therapy, apprise of potential fetal hazard. Pregnancy pharmacovigilance program available for patients and providers through Genentech (888-835-2555).

Lactation

Not known whether pertuzumab/trastuzumab/hyaluronidase-zzxf is distributed into milk or if the drug has any effects on the breastfed infant or on milk production.

Consider benefits of breast-feeding and the importance of the drug to the woman as well as potential adverse effects on the breast-fed infant from the drug or underlying maternal condition. Take into account the elimination half-life of pertuzumab and the trastuzumab wash out period of 7 months.

Females and Males of Reproductive Potential

Risk of embryofetal harm. Verify pregnancy status in females of reproductive potential and advise such females to use effective contraceptive methods while receiving the drug and for 7 months after discontinuance of therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient data in patients ≥65 years of age to determine whether they respond differently from younger adults. In a population pharmacokinetic analysis, no substantial differences in pharmacokinetics were observed between geriatric and younger adults.

In studies with IV trastuzumab, risk of cardiac dysfunction increased in geriatric patients compared with younger patients. In studies with IV pertuzumab in combination with trastuzumab, decreased appetite, anemia, decreased weight, asthenia, dysgeusia, peripheral neuropathy, and hypomagnesemia occurred more frequently in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Effects of hepatic impairment on pharmacokinetics of pertuzumab and trastuzumab not known.

Renal Impairment

Pharmacokinetics of pertuzumab and trastuzumab not altered in patients with mild or moderate (Cl_cr ≥30 mL/minute) renal impairment. Effect of severe renal impairment (Cl_cr <30 mL/minute) on pharmacokinetics not established.

Common Adverse Effects

Neoadjuvant and adjuvant treatment of breast cancer in patients receiving pertuzumab/trastuzumab/hyaluronidase-zzxf (>30%): Alopecia, nausea, diarrhea, anemia, asthenia.

Metastatic breast cancer in patients receiving IV pertuzumab in combination with trastuzumab and docetaxel (>30%): Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy.

Drug Interactions

Anthracyclines

Increased risk of cardiotoxic effects after pertuzumab/trastuzumab/hyaluronidase-zzxf therapy is discontinued. Avoid concomitant therapy for up to 7 months after last dose of pertuzumab/trastuzumab/hyaluronidase-zzxf; if concomitant therapy necessary, monitor cardiac function closely.

Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration, absolute bioavailability of pertuzumab and trastuzumab is approximately 70 and 80%, respectively. Peak plasma concentrations of pertuzumab and trastuzumab are observed at 4 days.

Duration

Hyaluronidase: Effects are reversible; permeability of subcutaneous tissue restored in 24–48 hours.

Plasma Concentrations

Following sub-Q administration, AUC and peak plasma concentrations of pertuzumab at cycle 7 were approximately 34% lower and 5% higher, respectively, compared to that following IV administration of pertuzumab. AUC and peak plasma concentrations of trastuzumab at cycle 7 were approximately 31% lower and 9% higher, respectively, compared to that following IV administration of trastuzumab.

Special Populations

Pharmacokinetics not affected by age, sex, or ethnicity (Asian versus non-Asian).

Baseline serum albumin concentration or lean body weight do not have clinically important effects on systemic exposure to pertuzumab or trastuzumab.

Renal impairment (Cl_cr ≥30 mL/minute): No effects on pertuzumab/trastuzumab/hyaluronidase pharmacokinetics. Pharmacokinetics not evaluated in patients with severe renal impairment (Cl_cr <30 mL/minute).

Pharmacokinetics not evaluated in patients with hepatic impairment.

Elimination

Half-life

Pertuzumab: Approximately 24 days.

Stability

Storage

Parenteral

Injection for Sub-Q Use

2–8°C in the original carton to protect from light; do not freeze or shake.

Syringes containing drug solution: If not used immediately, may store at room temperature for up to 4 hours or in refrigerator at 2–8°C for up to 24 hours. Do not shake.

Actions

• Pertuzumab and trastuzumab: Antineoplastic agents; anti-HER2/ERBB2s recombinant humanized monoclonal antibodies (IgG1 kappa immunoglobulins).

• Hyaluronidase-zzxf: Recombinant endoglycosidase; acts locally to temporarily increase permeability of sub-Q tissue by depolymerizing hyaluronan (a polysaccharide found in extracellular matrix of sub-Q tissue); increases dispersion and absorption of pertuzumab and trastuzumab.

• Pertuzumab binds specifically to extracellular dimerization domain (subdomain II) of HER2 protein, blocking heterodimerization of HER2 with other ligand-bound members of the HER family (i.e., epidermal growth factor receptor [EGFR]/HER1, HER3, HER4). Blockade of HER2 heterodimerization (particularly with HER3) results in inhibition of ligand-activated intracellular signaling through 2 major signal pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt), potentially causing cell growth arrest and apoptosis, respectively.

• Trastuzumab binds to extracellular domain (subdomain IV) of HER2 protein, blocking ligand-independent, HER2 mediated cell proliferation and inhibiting intracellular signaling through PI3K signaling pathway in human tumor cells that overexpress HER2/neu protein.

• Pertuzumab- and trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) also demonstrated and occurs preferentially in cells that overexpress the HER2 protein.

• Combination of pertuzumab and trastuzumab substantially augments antitumor activity in HER2-overexpressing xenograft models.

Advice to Patients

• Risk of cardiotoxicity. Advise patients to contact a health care professional immediately if new onset or worsening shortness of breath, cough, swelling of the ankles and/or legs, swelling of the face, palpitations, weight gain >5 pounds in 24 hours, dizziness, or loss of consciousness occurs.

• Risk of fetal harm (e.g., embryo-fetal death, birth defects). Advise women of childbearing potential to use effective contraceptive methods during and for 7 months after discontinuance of pertuzumab/trastuzumab/hyaluronidase. Encourage women who have been exposed to pertuzumab/trastuzumab/hyaluronidase during pregnancy or within 7 months following the last dose of the drug to report their pregnancy to Genentech at 1-888-835-2555.

• Advise women to inform their clinicians if they are or plan to breast-feed.

• Risk of injection-related or hypersensitivity reactions. Advise patients to contact their clinician immediately if dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain occurs.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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