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Axicabtagene Ciloleucel

Pronunciation

(ax i CAB tay jeen sye LO loo sel)

Index Terms

  • Anti-CD19/CD28/CD3zeta CAR Gammaretroviral Vector-transduced Autologous T Lymphocytes KTE-C19
  • Autologous Anti-CD19 CAR-positive T lymphocytes KTE-C19
  • Axi-Cel
  • KTE-C19
  • KTE-C19 CAR
  • Yescarta

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intravenous [preservative free]:

Yescarta: (1 ea) [contains albumin human, dimethyl sulfoxide]

Brand Names: U.S.

  • Yescarta

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD19
  • Antineoplastic Agent, CAR-T Immunotherapy
  • CAR-T Cell Immunotherapy
  • Cellular Immunotherapy, Autologous
  • Chimeric Antigen Receptor T-Cell Immunotherapy

Pharmacology

Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy in which a patient's T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to CD28 and CD3 zeta. CD3 zeta is a critical component for initiating T-cell activation and antitumor activity. After binding to CD19-expressing cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades, which results in T cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines, leading to destruction of CD19-expressing cells. Axicabtagene ciloleucel is prepared from the patient's peripheral blood cells obtained via leukapheresis.

Onset of Action

Median time to response: 1 month (range: 0.8 to 6 months) (Neelapu 2017)

Time to Peak

Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 14 days after infusion

Duration of Action

Anti-CD19 CAR T cells displayed an initial rapid expansion followed by a decline to near baseline levels by 3 months post axicabtagene ciloleucel infusion

Use: Labeled Indications

Large B-cell lymphoma, relapsed or refractory: Treatment of relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma

Limitations of use: Not indicated for the treatment of patients with primary CNS lymphoma

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

For autologous use only; confirm patient identity matches cassette and infusion bag prior to infusion.

Large B-cell lymphoma (relapsed or refractory): Note: A treatment course consists of lymphodepleting chemotherapy (with fludarabine and cyclophosphamide) on the fifth, fourth, and third day prior to axicabtagene ciloleucel infusion (confirm availability of autogolous axicabtagene ciloleucel prior to initiating lymphodepleting chemotherapy). Ensure tocilizumab and emergency equipment are available prior to axicabtagene ciloleucel infusion and during recovery period.

Premedicate with acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or orally ~60 minutes prior to axicabtagene ciloleucel infusion. Avoid prophylactic systemic corticosteroids because they may interfere with the axicabtagene ciloleucel activity.

IV: Target dose: 2 × 106 CAR-positive viable T cells per kg body weight (Neelapu 2017); maximum dose: 2 × 108 CAR-positive viable T cells.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Cytokine release syndrome (CRS): Note: Patients with ≥ grade 2 CRS should be monitored with continuous cardiac telemetry and pulse oximetry. Consider obtaining an echocardiogram in patients with severe CRS; severe or life-threatening CRS may require intensive care supportive therapy.

Grade 1 (fever, nausea, fatigue, headache, myalgia, malaise): Treat symptoms as appropriate; tocilizumab and/or corticosteroids are not indicated.

Grade 2 (oxygen requirement <40% FiO2 or hypotension responsive to fluids or low-dose of one vasopressor or grade 2 organ toxicity): Administer tocilizumab 8 mg/kg IV; maximum: 800 mg/dose (see Tocilizumab monograph); may repeat every 8 hours as needed (maximum: 3 doses in a 24-hour period, maximum total of 4 doses). If no improvement within 24 hours after initiating tocilizumab, administer methylprednisolone 1 mg/kg IV twice daily or equivalent dexamethasone (eg, 10 mg IV every 6 hours); continue corticosteroid until toxicity is ≤ grade 1, then taper over 3 days.

Grade 3 (oxygen requirement ≥40% FiO2 or hypotension requiring high-dose or multiple vasopressors or grade 3 organ toxicity or grade 4 transaminitis): Administer tocilizumab 8 mg/kg IV; maximum: 800 mg/dose (see Tocilizumab monograph); may repeat every 8 hours as needed (maximum: 3 doses in a 24-hour period, maximum total of 4 doses). In addition to tocilizumab, administer methylprednisolone 1 mg/kg IV twice daily or equivalent dexamethasone (eg, 10 mg IV every 6 hours); continue corticosteroid until toxicity is ≤ grade 1, then taper over 3 days.

Grade 4 (life-threatening; requirements for ventilator support, continuous veno-venous hemodialysis [CVVHD] or grade 4 organ toxicity [excluding transaminitis]): Administer tocilizumab 8 mg/kg IV; maximum: 800 mg/dose (see Tocilizumab monograph); may repeat every 8 hours as needed (maximum: 3 doses in a 24-hour period, maximum total of 4 doses). In addition to tocilizumab, administer methylprednisolone 1,000 mg IV daily for 3 days; if improves, then manage corticosteroid therapy as above.

Neurologic toxicity: Note: Patients with ≥ grade 2 neurologic toxicity should be monitored with continuous cardiac telemetry and pulse oximetry. Severe or life-threatening neurologic toxicity may require intensive care supportive therapy. Consider non-sedating anti-seizure medication (eg, levetiracetam) for seizure prophylaxis for any ≥ grade 2 neurologic toxicity.

Neurologic toxicity with concurrent CRS:

Grade 2: Administer tocilizumab 8 mg/kg IV; maximum: 800 mg/dose (see Tocilizumab monograph); may repeat every 8 hours as needed (maximum: 3 doses in a 24-hour period, maximum total of 4 doses). If no improvement within 24 hours after initiating tocilizumab, administer dexamethasone 10 mg IV every 6 hours (if not already receiving other corticosteroids); continue corticosteroid until toxicity is ≤ grade 1, then taper over 3 days.

Grade 3: Administer tocilizumab 8 mg/kg IV; maximum: 800 mg/dose (see Tocilizumab monograph); may repeat every 8 hours as needed (maximum: 3 doses in a 24-hour period, maximum total of 4 doses). In addition to tocilizumab, administer dexamethasone 10 mg IV every 6 hours (administer the first dose with the first dose of tocilizumab); continue corticosteroid until toxicity is ≤ grade 1, then taper over 3 days.

Grade 4: Administer tocilizumab 8 mg/kg IV; maximum: 800 mg/dose (see Tocilizumab monograph); may repeat every 8 hours as needed (maximum: 3 doses in a 24-hour period, maximum total of 4 doses). In addition to tocilizumab, administer methylprednisolone 1,000 mg IV daily for 3 days (administer the first dose with the first dose of tocilizumab); if improves, then manage corticosteroid therapy as above.

Neurologic toxicity without concurrent CRS:

Grade 2 or grade 3: Administer dexamethasone 10 mg IV every 6 hours; continue corticosteroid until toxicity is ≤ grade 1, then taper over 3 days.

Grade 4: Administer methylprednisolone 1,000 mg IV daily for 3 days; if improves, then manage corticosteroid therapy as above.

Reconstitution

Do not remove the product bag from the cassette if the information on the patient-specific label does not match the intended patient. Inspect patient-specific infusion bag for breaks or cracks prior to thawing (if bag is compromised, contact manufacturer). Place infusion bag inside a second sterile bag in case of leaks and to protect ports from contamination. Thaw at 37°C using a water bath or dry thaw method until there is no visible ice in the infusion bag. Do not wash, spin down, and/or re-suspend axicabtagene ciloleucel in new media prior to infusion. Gently mix contents of the thawed infusion bag to disperse cellular material clumps; inspect for visible cell clumps; if visible cell clumps remain, gently mix the contents of the bag (small clumps of cellular material should disperse with gentle manual mixing). Do not infuse if clumps are not dispersed, if the infusion bag is damaged or leaking, or if it otherwise appears to be compromised (contact manufacturer). Axicabtagene ciloleucel contains human blood cells that are genetically modified with replication incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal.

Administration

IV: For IV use only. Administer in a health care facility. Coordinate the timing of administration with thawing (may be stored for up to 3 hours at room temperature after thawing); infusion start time may need to be adjusted based on thawing.

Prime the tubing with NS prior to infusion. Infuse entire contents of bag within 30 minutes either by gravity or a peristaltic pump (infusion bag volume is ~68 mL). A central line is preferred for infusion. Gently agitate the bag during infusion to prevent cell clumping. After completion of the infusion, rinse the tubing with NS at the same infusion rate to ensure cell product delivery. Do not use a lymphocyte depleting filter.

Prior to administration: Ensure tocilizumab and emergency equipment are available prior to infusion and during recovery period. Premedicate with acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or orally ~60 minutes prior to axicabtagene ciloleucel infusion. Avoid prophylactic systemic corticosteroids, as they may interfere with the axicabtagene ciloleucel activity. Confirm patient identity and match to patient identifiers on the infusion cassette and bag. Inspect the contents of the thawed infusion bag for visible cell clumps; if visible cell clumps remain, gently mix the contents of the bag (small clumps of cellular material should disperse with gentle manual mixing). Do not infuse if clumps are not dispersed, if the infusion bag is damaged or leaking, or if it otherwise appears to be compromised. Apply universal precautions for product handling.

Storage

Store frozen suspension in the vapor phase of liquid nitrogen (≤ -150°C). After thawing, may be stored for up to 3 hours at room temperature of 20°C to 25°C.

Drug Interactions

Corticosteroids (Systemic): May diminish the therapeutic effect of Axicabtagene Ciloleucel. Management: Avoid use of corticosteroids as premedication before axicabtagene ciloleucel. Corticosteroids may, however, be required for treatment of cytokine release syndrome or neurologic toxicity. Consider therapy modification

Vaccines (Live): Axicabtagene Ciloleucel may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of infection may be increased. Axicabtagene Ciloleucel may diminish the therapeutic effect of Vaccines (Live). Management: Avoid live virus vaccines for at least 6 weeks prior to initiation of lymphodepleting therapy, during axicabtagene ciloleucel infusion, and after treatment until full immune recovery is achieved. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Hypotension (57%), tachycardia (57%), cardiac arrhythmia (23%), edema (19%), hypertension (15%), thrombosis (10%), cardiac failure (6%), capillary leak syndrome (3%)

Central nervous system: Brain disease (57%; lasted up to 173 days), fatigue (46%), headache (44% to 45%), chills (40%), dizziness (21%), motor dysfunction (19%), aphasia (18%), delirium (17%)

Endocrine & metabolic: Hypophosphatemia (grade 3 or 4: 50%), hyponatremia (grade 3 or 4: 19%), weight loss (16%), increased uric acid (grade 3 or 4: 13%), dehydration (11%)

Gastrointestinal: Decreased appetite (44%), diarrhea (38%), nausea (34%), vomiting (26%), constipation (23%), abdominal pain (14%), xerostomia (11%)

Hematologic & oncologic: Lymphocytopenia (grade 3 or 4: 100%), leukopenia (grade 3 or 4: 96%), neutropenia (grade 3 or 4: 93%), anemia (grade 3 or 4: 66%), thrombocytopenia (grade 3 or 4: 58%), febrile neutropenia (36%), hypogammaglobulinemia (15%)

Hepatic: Increased direct serum bilirubin (grade 3 or 4: 13%)

Hypersensitivity: Cytokine release syndrome (94%)

Infection: Infection (26%), viral infection (16%), bacterial infection (13%)

Neuromuscular & skeletal: Tremor (31%), limb pain (17%), back pain (15%), myalgia (14%)

Renal: Renal insufficiency (12%)

Respiratory: Hypoxia (32%), cough (30%), dyspnea (19%), pleural effusion (13%)

Miscellaneous: Fever (86%)

1% to 10%:

Central nervous system: Anxiety (9%), insomnia (9%), ataxia (6%), seizure (4%), cognitive dysfunction (comprehending mathematics: 2%), myoclonus (2%)

Dermatologic: Skin rash (9%)

Endocrine & metabolic: Hypokalemia (grade 3 or 4: 10%)

Genitourinary: Urinary tract infection (>2%)

Hematologic & oncologic: Blood coagulation disorder (2%), natural killer cell count increased (hemophagocytic lymphohistiocytosis/macrophage activation syndrome: 1%)

Hepatic: Increased serum ALT (grade 3 or 4: 10%)

Hypersensitivity: Hypersensitivity reaction (1%)

Infection: Fungal infection (5%), clostridium infection (>2%)

Neuromuscular & skeletal: Arthralgia (10%)

Respiratory: Pulmonary edema (9%), pulmonary infection (>2%)

Frequency not defined: Central nervous system: Cerebral edema, leukoencephalopathy, seizure

ALERT: U.S. Boxed Warning

Cytokine release syndrome:

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel. Do not administer axicabtagene ciloleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Neurological toxicities:

Neurological toxicities, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with axicabtagene ciloleucel. Provide supportive care and/or corticosteroids as needed.

REMS program:

Axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS.

Warnings/Precautions

Concerns related to adverse effects:

• Cytokine release syndrome: [US Boxed Warning]: Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel. Do not administer axicabtagene ciloleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Grade 3 or 4 CRS reactions have occurred. The median time to onset of CRS was 2 days (range: 1 to 12 days); the median duration of CRS was 7 days (range: 2 to 58 days). Key manifestations of CRS include fever, hypotension, tachycardia, hypoxia, and chills. Cardiac arrhythmias (eg, atrial fibrillation, ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) may be associated with CRS (may be serious). Ensure that tocilizumab is available (a minimum of 2 doses) on site prior to axicabtagene ciloleucel infusion. Monitor for signs or symptoms of CRS for at least 4 weeks after treatment (daily for 7 days following the infusion). Patients should seek immediate medical attention if signs or symptoms of CRS occur at any time. Evaluate patients immediately at the first sign of CRS; hospitalize and begin supportive care, tocilizumab, and/or corticosteroids as indicated.

• Cytopenias: Prolonged cytopenias may occur several weeks after lymphodepleting chemotherapy and axicabtagene ciloleucel infusion. Unresolved (by day 30 following axicabtagene ciloleucel treatment) grade 3 and 4 cytopenias included neutropenia, thrombocytopenia, and anemia. Monitor blood counts.

• Hepatitis B virus reactivation: Hepatitis B virus (HBV) reactivation (sometimes resulting in fulminant hepatitis, hepatic failure, and death) can occur in patients treated with medications directed against B cells. Hepatitis has been reported in patients who are hepatitis B surface antigen (HBsAg) positive, and in patients who are HBsAg-negative but are hepatitis B core antibody (anti-HBc) positive. HBV reactivation has occurred in patients who appear to have resolved hepatitis B infection (HBsAg-negative, anti-HBc-positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg-negative and anti-HBc-positive. Reactivation of HBV replication is often followed by hepatitis (increased transaminase levels). Increased bilirubin levels, liver failure, and death can occur in severe cases. Screen for HBV, HCV, and HIV in accordance with clinical guidelines prior to collection of cells for manufacturing.

• Hypersensitivity: Allergic reactions may occur with axicabtagene ciloleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may occur due to the dimethyl sulfoxide (DMSO) or residual gentamicin in axicabtagene ciloleucel.

• Hypogammaglobulinemia: Hypogammaglobulinemia and B-cell aplasia may occur in patients receiving axicabtagene ciloleucel. Monitor immunoglobulin levels after axicabtagene ciloleucel treatment. Manage hypogammaglobulinemia with infection precautions, antibiotic prophylaxis, and immunoglobulin treatment (per standard replacement guidelines).

• Infection: Serious infections (including life-threatening infections) occurred in patients after axicabtagene ciloleucel infusion, including grades 3 and higher infections in close to one-quarter of patients. Viral and bacterial infections were reported as well as infections due to unknown pathogens. Begin prophylaxis according to local guidelines prior to axicabtagene ciloleucel infusion. Monitor for signs and symptoms of infection before and following treatment and manage appropriately; do not administer to patients with clinically significant active systemic infections. Neutropenic fever has been observed after axicabtagene ciloleucel infusion and may occur concurrently with CRS. If neutropenic fever occurs, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as clinically indicated.

• Neurological toxicities: [US Boxed Warning]: Neurological toxicities, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel, including concurrently with CRS or after CRS resolution. Monitor for neurological toxicities after treatment with axicabtagene ciloleucel. Provide supportive care and/or corticosteroids as needed. Most neurological toxicities occurred within 8 weeks following axicabtagene ciloleucel infusion; the median time to onset was 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities have been observed in close to one-third of patients. The most common neurological toxicities were encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety. Prolonged encephalopathy (lasting up to 173 days) was observed. Fatal and serious cases of cerebral edema have occurred; other serious events included leukoencephalopathy and seizures. Monitor for signs or symptoms of neurologic toxicities for at least 4 weeks after treatment (daily for 7 days following the infusion). Treat promptly if neurologic toxicities occur. Due to the potential for neurologic events, including altered mental status or seizures, patients receiving axicabtagene ciloleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following administration; during this initial period, advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery.

• Secondary malignancy: Patients treated with axicabtagene ciloleucel may develop secondary malignancies or leukemia recurrence. Monitor permanently for secondary malignancies. If a secondary malignancy occurs, contact the manufacturer (1-844-454-KITE) to obtain patient sampling instructions for testing.

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.

• Immunizations: Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel treatment, and until immune recovery following treatment. The safety of immunization with live viral vaccines during or following axicabtagene ciloleucel treatment has not been studied.

Other warnings/precautions:

• Appropriate use: For autologous use only. Confirm patient identity and match to patient identifiers on the cassette and infusion bag prior to infusion. Administer in a health care facility; patients should remain within proximity of the facility for at least 4 weeks after infusion.

• REMS program: [US Boxed Warning]: Axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS. Information is available at www.YescartaREMS.com or 1-844-454-5483.

Monitoring Parameters

Screen for HBV, HCV, and HIV (prior to collection of cells for manufacturing). Monitor immunoglobulin levels and blood counts (after treatment). Pregnancy testing is recommended prior to therapy (in sexually active women of reproductive potential).

Monitor for signs/symptoms of CRS and neurological toxicities for at least 4 weeks after treatment (monitor daily for the first 7 days after infusion at the health care facility; patients with ≥ grade 2 CRS should be monitored with continuous cardiac telemetry and pulse oximetry), monitor for hypersensitivity reactions and for signs/symptoms of infection. Monitor (life-long) for secondary malignancies.

Pregnancy Considerations

Animal reproduction studies have not been conducted. Treatment with axicabtagene ciloleucel is not recommended during pregnancy. If placental transfer were to occur, fetal toxicity, including B-cell lymphocytopenia, may occur.

Pregnancy testing is recommended prior to therapy in sexually active women of reproductive potential. Refer to the cyclophosphamide and fludarabine monographs for information related to use of effective contraception in patients using these medications for lymphodepleting chemotherapy. The duration of contraception needed following axicabtagene ciloleucel administration is not known. Potential pregnancies (following treatment) should be discussed with the prescriber.

Patient Education

• 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 lack of appetite, nausea, vomiting, diarrhea, constipation, abdominal pain, dry mouth, weight loss, painful extremities, muscle pain, joint pain, muscle spasm, muscle weakness, or back pain. Have patient report immediately to prescriber signs of cytokine release syndrome (chills, dizziness, loss of strength and energy, fever, headache, passing out, rash, angioedema, difficulty breathing, nausea, vomiting, or wheezing), agitation, confusion, anxiety, vision changes, dizziness, passing out, hallucinations, headache, seizures, tremors, difficulty speaking, behavioral changes, mood changes, signs of infection, 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 fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), shortness of breath, excessive weight gain, swelling in arms or legs, severe loss of strength and energy, tachycardia, abnormal heartbeat, severe fatigue, difficulty focusing, edema, signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), or angina (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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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