(kar MUS teen)
- bis(chloroethyl) nitrosourea
- Carmustine Polymer Wafer
- Carmustine Sustained-Release Implant Wafer
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
BiCNU: 100 mg (1 ea) [contains alcohol, usp]
Gliadel Wafer: 7.7 mg (8 ea) [contains polifeprosan 20]
Brand Names: U.S.
- Gliadel Wafer
- Antineoplastic Agent, Alkylating Agent
- Antineoplastic Agent, Alkylating Agent (Nitrosourea)
Interferes with the normal function of DNA and RNA by alkylation and cross-linking the strands of DNA and RNA, and by possible protein modification; may also inhibit enzyme processes by carbamylation of amino acids in protein
IV: 3.3 L/kg; readily crosses blood-brain barrier producing CSF levels >50% of blood plasma levels; highly lipid soluble
Rapidly hepatic; forms active metabolites
IV: Urine (~60% to 70%) within 96 hours; lungs (~10% as CO2)
IV: Biphasic: Initial: 1.4 minutes; Secondary: 22 minutes (active metabolites: Plasma half-life of 67 hours)
Use: Labeled Indications
Injection: Palliative treatment of brain tumors including glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors
Wafer (implant): Treatment of newly-diagnosed high-grade malignant glioma (as an adjunct to surgery and radiation); treatment of recurrent glioblastoma multiforme (as adjunct to surgery)
Hodgkin lymphoma, relapsed/refractory: Injection: Palliative treatment (secondary) of Hodgkin lymphoma (in combination with other antineoplastics) that has relapsed with or was refractory to primary therapy
Multiple myeloma: Injection: Palliative treatment of multiple myeloma (in combination with prednisone)
Non-Hodgkin lymphomas, relapsed/refractory: Injection: Palliative treatment (secondary) of non-Hodgkin lymphoma (in combination with other antineoplastics) that has relapsed with or was refractory to primary therapy
Treatment of mycosis fungoides (topical); stem cell or bone marrow transplant, autologous (injection)
IV: Hypersensitivity to carmustine or any component of the formulation
Implant: There are no contraindications listed in the manufacturer’s labeling.
Note: Carmustine (IV) is associated with a moderate to high emetic potential (dose-related); antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011).
Brain tumors, Hodgkin lymphoma, multiple myeloma, non-Hodgkin lymphoma (per manufacturer labeling): IV: 150 to 200 mg/m2 every 6 weeks or 75 to 100 mg/m2/day for 2 days every 6 weeks
Glioblastoma multiforme (recurrent), glioma (malignant, newly-diagnosed high-grade): Implantation (wafer): 8 wafers (7.7 mg each) implanted intracranially into in the resection cavity (total dose 61.6 mg); should the size and shape not accommodate 8 wafers, the maximum number of wafers feasible (up to 8) should be placed
Brain tumor, primary (off-label doses): IV:
80 mg/m2/day for 3 days every 8 weeks for 6 cycles (Brandes, 2004)
200 mg/m2 every 8 weeks [maximum cumulative dose: 1500 mg/m2] (Selker, 2002)
Hodgkin lymphoma, relapsed or refractory (off-label dose): IV: Mini-BEAM regimen: 60 mg/m2 day 1 every 4 to 6 weeks (in combination with etoposide, cytarabine, and melphalan) (Colwill, 1995; Martin, 2001)
Multiple myeloma, relapsed, refractory (off-label dose): IV: VBMCP regimen: 20 mg/m2 day 1 every 35 days (in combination with vincristine, melphalan, cyclophosphamide, and prednisone) (Kyle, 2006; Oken, 1997)
Mycosis fungoides, early stage (off-label use; Zackheim, 2003): Topical:
Ointment (10 mg/100 grams petrolatum): Apply (with gloves) once daily to affected areas
Solution (0.2% solution in alcohol; dilute 5 mL in 60 mL water): Apply (with gloves) once daily to affected areas
Stem cell or bone marrow transplant, autologous (off-label use): IV:
BEAM regimen: 300 mg/m2 6 days prior to transplant (in combination with etoposide, cytarabine, and melphalan) (Chopra, 1993; Linch, 2010)
CBV regimen: 600 mg/m2 3 days prior to transplant (in combination with cyclophosphamide and etoposide) (Reece, 1991)
Refer to adult dosing.
Dosing: Renal Impairment
IV: There are no dosage adjustments provided in the manufacturer’s labeling. The following dosage adjustments have been reported (Kintzel, 1995):
CrCl 46 to 60 mL/minute: Administer 80% of dose
CrCl 31 to 45 mL/minute: Administer 75% of dose
CrCl ≤30 mL/minute: Consider use of alternative drug.
Wafer implant: There are no dosage adjustments provided in the manufacturer’s labeling.
Dosing: Hepatic Impairment
IV: Dosage adjustment may be necessary; however, no specific guidelines are available.
Wafer implant: There are no dosage adjustments provided in the manufacturer’s labeling.
Dosing: Adjustment for Toxicity
Hematologic toxicity: Based on nadir counts with previous dose (manufacturer’s labeling). IV:
If leukocytes ≥3,000/mm3 and platelets ≥75,000/mm3: Administer 100% of dose
If leukocytes 2,000 to 2,999/mm3 or platelets 25,000 to 74,999/mm3: Administer 70% of dose
If leukocytes <2,000/mm3 or platelets <25,000/mm3: Administer 50% of dose
American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).
American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in carmustine dosing for hematopoietic stem cell transplant conditioning regimens in adult patients weighing ≤120% of their ideal body weight (IBW). In patients weighing >120% IBW, utilize adjusted body weight 25% (ABW25) to calculate BSA (Bubalo, 2014).
ABW25: Adjusted wt (kg) = Ideal body weight (kg) + 0.25 [actual wt (kg) - ideal body weight (kg)]
Injection: Reconstitute initially with 3 mL of supplied diluent (dehydrated alcohol injection, USP); then further dilute with SWFI (27 mL), this provides a concentration of 3.3 mg/mL in ethanol 10%; protect from light; further dilute for infusion with D5W using a non-PVC container (eg, glass or polyolefin).
Implant: Each wafer is packaged within 2 nested aluminum foil pouches; the inner pouch is sterile and is designed to maintain sterility and protect from moisture; the outer wrap is not sterile. Deliver to the operating room in the unopened outer aluminum foil pouch. Do not open until the wafers are ready to be implanted. Follow manufacturer’s instructions for opening the pouch, being careful not to apply pressure to the wafer.
Carmustine (IV) is associated with a moderate to high emetic potential (dose-related); antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011).
Injection: Irritant (alcohol-based diluent). Significant absorption to PVC containers; should be prepared in either glass or polyolefin containers. Infuse over at least 2 hours (infusions <2 hours may lead to injection site pain or burning); infuse through a free-flowing saline or dextrose infusion, or administer through a central catheter to alleviate venous pain/irritation.
High-dose carmustine (transplant dose; off-label use): Infuse over a least 2 hours to avoid excessive flushing, agitation, and hypotension; was infused over 1 hour in some trials (Chopra, 1993). High-dose carmustine may be fatal if not followed by stem cell rescue. Monitor vital signs frequently during infusion; patients should be supine during infusion and may require the Trendelenburg position, fluid support, and vasopressor support.
Implant: Double glove before handling; outer gloves should be discarded as chemotherapy waste after handling wafers. Any wafer or remnant that is removed upon repeat surgery should be discarded as chemotherapy waste. The outer surface of the external foil pouch is not sterile. Open pouch gently; avoid pressure on the wafers to prevent breakage. Wafers that are broken in half may be used, however, wafers broken into more than 2 pieces should be discarded in a biohazard container. Slight overlapping of wafers during placement is acceptable. Oxidized regenerated cellulose (Surgicel) may be placed over the wafer to secure; irrigate cavity prior to closure.
Topical (off-label use): Apply solution with brush or gauze pads; ointment and solution should be applied while wearing gloves to involved areas only; avoid contact with eyes or mouth (Zackheim, 2003).
See Trissel’s IV Compatibility Database
Injection: Store intact vials and provided diluent under refrigeration at 2°C to 8°C (36°F to 46°F). Carmustine has a low melting point (30.5°C to 32°C [86.9°F to 89.6°F]); exposure to temperature at or above the melting point will cause the drug to liquefy and appear as an oil film on the vials. If drug liquefies, discard the vials as this is a sign of decomposition.
Reconstituted solutions are stable for 24 hours refrigerated (2°C to 8°C) and protected from light. Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation.
Solutions diluted to a concentration of 0.2 mg/mL in D5W are stable for 8 hours at room temperature (25°C) in glass and protected from light. Although the manufacturer recommends only glass containers be used, stability of a 1 mg/mL solution in D5W has also been demonstrated for up to 6 hours (with a 6% to 7% loss of potency) in polyolefin containers (Trissel, 2006).
Wafer: Store at or below -20°C (-4°F). Unopened outer foil pouches may be kept at room temperature for up to 6 hours at a time for up to 3 cycles within a 30-day period.
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Cimetidine: May enhance the myelosuppressive effect of Carmustine. Management: Consider alternatives to cimetidine in patients receiving carmustine. If the combination cannot be avoided, monitor for enhanced carmustine myelotoxicity. Consider therapy modification
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification
Melphalan: May enhance the adverse/toxic effect of Carmustine. Specifically, melphalan may sensitize patients to carmustine lung toxicity. Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination
IV: Frequency not defined:
Cardiovascular: Cardiac arrhythmia (with high doses), chest pain, flushing (with rapid infusion), hypotension, tachycardia
Central nervous system: Dizziness, headache
Dermatologic: Burning sensation of skin (after skin contact), hyperpigmentation (after skin contact)
Gastrointestinal: Nausea (common; dose related), vomiting (common; dose related)
Hematologic & oncologic: Leukopenia (common; onset: 5 to 6 weeks; recovery: After 1 to 2 weeks), thrombocytopenia (common: onset: ~4 weeks; recovery: After 1 to 2 weeks), anemia, febrile neutropenia, malignant neoplasm (secondary; acute leukemia, bone marrow dysplasias)
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases
Hypersensitivity: Hypersensitivity reaction
Infection: Infection (with high doses)
Local: Burning sensation at injection site, erythema at injection site, pain at injection site, swelling at injection site, tissue necrosis at injection site, venous thrombosis at injection site (rare)
Ophthalmic: Neuroretinitis, suffusion of the conjunctiva (with rapid infusion)
Renal: Azotemia (progressive; with long-term therapy), nephron atrophy (with long-term therapy), nephrotoxicity, renal failure (with long-term therapy)
Respiratory: Interstitial pneumonitis (with high doses), lung hypoplasia, pulmonary fibrosis (occurring up to 17 years after treatment), pulmonary infiltrates
Central nervous system: Seizure (37%; new or worsening: 20%), cerebral edema (4% to 23%), depression (16%)
Dermatologic: Skin rash (5% to 12%)
Gastrointestinal: Nausea (22%), vomiting (21%), constipation (19%)
Genitourinary: Urinary tract infection (21%)
Neuromuscular & skeletal: Weakness (22%)
Miscellaneous: Wound healing impairment (14% to 16%), fever (12%)
1% to 10%:
Cardiovascular: Chest pain (5%)
Central nervous system: Intracranial hypertension (9%), cerebral hemorrhage (6%), meningitis (4%)
Gastrointestinal: Abdominal pain (8%)
Infection: Abscess (local 6%)
Neuromuscular & skeletal: Back pain (7%)
<1% (Limited to important or life-threatening): Sepsis
Concerns related to adverse effects:
• Bone marrow suppression: Injection: [US Boxed Warning]: Bone marrow suppression, primarily thrombocytopenia (which may lead to bleeding) and leukopenia (which may lead to infection), is the most common and severe toxicity. Hematologic toxicity is generally is delayed; monitor blood counts for at least 6 weeks following treatment. The manufacturer suggests not administering more frequently than every 6 weeks for approved doses/uses. Myelosuppression is cumulative; consider nadir blood counts from prior dose for dosage adjustment. Patients must have platelet counts >100,000/mm3 and leukocytes >4,000/mm3 for a repeat dose. Myelosuppression generally occurs 4 to 6 weeks after administration; thrombocytopenia occurs at ~4 weeks and persists for 1 to 2 weeks; leukopenia occurs at 5 to 6 weeks and persists for 1 to 2 weeks. Anemia may occur (less common and less severe than leukopenia or thrombocytopenia).
• Gastrointestinal toxicity: Injection: Carmustine is associated with a moderate to high emetic potential (dose-related); antiemetics are recommended to prevent nausea and vomiting (Basch, 2011; Dupuis, 2011).
• Hepatic: Injection: Reversible increases in transaminases, bilirubin, and alkaline phosphatase have been reported (rare). Monitor liver function tests periodically during treatment.
• Infusion site reactions: Injection: Injection site burning and local tissue reactions, including swelling, pain, erythema, and necrosis have been reported. Monitor infusion site closely for infiltration or injection site reactions.
• Intracranial hypertension: Wafer implant: Brain edema has been reported in patients with newly diagnosed glioma, including one report of intracranial mass effect unresponsive to corticosteroids that led to brain herniation. Monitor closely for intracranial hypertension related to brain edema, inflammation, or necrosis of brain tissue surrounding resection. Re-operation to remove wafers (or remnants) may be necessary for refractory cases.
• Meningitis: Wafer implant: Cases of meningitis have occurred in patients with recurrent glioma receiving wafer implants. Two cases were bacterial (one patient required removal of implants 4 days after implantation and the other developed meningitis following reoperation for recurrent tumor). Another case was determined to be chemical meningitis and resolved with corticosteroids. Monitor postoperatively for signs/symptoms of meningitis and CNS infection.
• Ocular toxicity: Off-label administration (intraarterial intracarotid route) has been associated with ocular toxicity.
• Pulmonary toxicity: Injection: [US Boxed Warnings]: Dose-related pulmonary toxicity may occur; patients receiving cumulative doses >1,400 mg/m2 are at higher risk. Delayed onset of pulmonary fibrosis may occur years after treatment (may be fatal), particularly in children. Pulmonary toxicity has occurred in children up to 17 years after treatment;this occurred in ages 1 to 16 for the treatment of intracranial tumors; cumulative doses ranged from 770 to 1,800 mg/m2 (in combination with cranial radiotherapy). Pulmonary toxicity is characterized by pulmonary infiltrates and/or fibrosis and has been reported from 9 days to 43 months after nitrosourea treatment (including carmustine). Although pulmonary toxicity generally occurs in patients who have received prolonged treatment, pulmonary fibrosis has been reported with cumulative doses <1,400 mg/m2. In addition to high cumulative doses, other risk factors for pulmonary toxicity include history of lung disease and baseline predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) <70%. Baseline and periodic pulmonary function tests are recommended. For high-dose treatment (transplant; off-label dose), acute lung injury may occur ~1 to 3 months post transplant; advise patients to contact their transplant physician for dyspnea, cough, or fever; interstitial pneumonia may be managed with a course of corticosteroids.
• Renal: Injection: Renal failure, progressive azotemia, and decreased kidney size have been reported in patients who have received large cumulative doses or prolonged treatment. Renal toxicity has also been reported in patients who have received lower cumulative doses. Monitor renal function tests periodically during treatment.
• Secondary malignancies: Injection: Long-term use is associated with the development of secondary malignancies (acute leukemias and bone marrow dysplasias).
• Seizures: Wafer implant: Seizures occurred in patients who received carmustine wafer implants, including new or worsening seizures and treatment-emergent seizures. Just over half of treatment-emergent seizures occurred within 5 days of surgery; the median onset of first new or worsened post-operative seizure was 4 days. Optimal anti-seizure therapy should be initiated prior to surgery. Monitor for seizures.
• Wound healing impairment: Wafer Implant: Impaired neurosurgical wound healing, including would dehiscence, delayed healing, and subdural, subgleal or wound effusions may occur with carmustine wafer implant treatment; cerebrospinal fluid leaks have also been reported. Monitor post-operatively for impaired neurosurgical wound healing.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Elderly: Injection: Consider initiating treatment at the lower end of the dose range.
• Pediatric: Injection: Children are at higher risk of delayed pulmonary toxicity.
Dosage form specific issues:
• Injection: Diluent contains ethanol.
• Wafer: Monitor closely for known craniotomy-related complications (seizure, intracranial infection, abnormal wound healing, brain edema). Wafer migration may occur; avoid communication between the resection cavity and the ventricular system to prevent wafer migration; communications larger than the wafer should be closed prior to implantation; wafer migration into the ventricular system may cause obstructive hydrocephalus. Monitor for signs/symptoms of obstructive hydrocephalus.
• Experienced physician: Injection: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Injection: CBC with differential and platelet count (weekly for at least 6 weeks after a dose), pulmonary function tests (FVC, DLCO; at baseline and frequently during treatment), liver function (periodically), renal function tests (periodically); monitor blood pressure and vital signs during administration, monitor infusion site for possible infiltration
Wafer: Monitor postoperatively for seizures, impaired neurosurgical wound healing, and signs/symptoms of meningitis, CNS infection, and obstructive hydrocephalus; monitor closely for intracranial hypertension related to brain edema, inflammation, or necrosis of brain tissue surrounding resection.
Pregnancy Risk Factor
Adverse events have been observed in animal reproduction studies. Carmustine may cause fetal harm if administered to a pregnant woman. Women of childbearing potential should use effective contraception to avoid becoming pregnant while on treatment. May impair fertility. Advise males of potential risk of infertility and to seek fertility/family planning counseling prior to receiving carmustine wafer implants.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience constipation, abdominal pain, or back pain. Have patient report immediately to prescriber signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of infection, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), angina, seizures, severe headache, severe nausea, vomiting, vision changes, neck rigidity, wound healing impairment, depression, severe loss of strength and energy, chills, painful urination, tachycardia, severe dizziness, passing out, or injection site redness, edema, burning, pain, or severe irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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