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AzaTHIOprine

Pronunciation

Pronunciation

(ay za THYE oh preen)

Index Terms

  • Azathioprine Sodium

Dosage Forms

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

Solution Reconstituted, Injection:

Generic: 100 mg (1 ea)

Tablet, Oral:

Azasan: 75 mg, 100 mg [scored]

Imuran: 50 mg [scored]

Generic: 50 mg

Brand Names: U.S.

  • Azasan
  • Imuran

Pharmacologic Category

  • Immunosuppressant Agent

Pharmacology

Azathioprine is an imidazolyl derivative of mercaptopurine; metabolites are incorporated into replicating DNA and halt replication; also block the pathway for purine synthesis (Taylor, 2005). The 6-thioguanine nucleotide metabolites appear to mediate the majority of azathioprine’s immunosuppressive and toxic effects.

Absorption

Oral: Well absorbed

Metabolism

Hepatic; metabolized to 6-mercaptopurine via glutathione S-transferase (GST) reduction. Further metabolized (in the liver and GI tract) via three major pathways: Hypoxanthine guanine phosphoribosyltransferase (to active metabolites: 6-thioguanine-nucleotides, or 6-TGNs), xanthine oxidase (to inactive metabolite: 6-thiouric acid), and thiopurine methyltransferase (TPMT) (to inactive metabolite: 6-methylmercaptopurine)

Excretion

Urine (primarily as metabolites)

Onset of Action

Immune thrombocytopenia: Initial response: 30 to 90 days; Peak response: 30 to 120 days (Neunert 2011)

Time to Peak

Oral: 1 to 2 hours (including metabolites)

Half-Life Elimination

Azathioprine and mercaptopurine: Variable: ~2 hours (Taylor, 2005)

Protein Binding

~30%

Special Populations: Renal Function Impairment

Clearance (azathioprine and metabolites) may be delayed in oliguric patients, particularly in those with tubular necrosis in the immediate post-transplant phase (cadaveric transplant).

Use: Labeled Indications

Renal transplantation: Adjunctive therapy in prevention of rejection of kidney transplants

Rheumatoid arthritis: Treatment of active rheumatoid arthritis (RA), to reduce signs and symptoms

Use: Unlabeled

Adjunct in prevention of rejection of solid organ (nonrenal) transplants; remission maintenance or reduction of steroid use in Crohn disease (CD) and in ulcerative colitis (UC); dermatomyositis/polymyositis; erythema multiforme; pemphigus vulgaris, lupus nephritis (maintenance), chronic refractory immune thrombocytopenia (ITP), relapsed/remitting multiple sclerosis

Contraindications

Hypersensitivity to azathioprine or any component of the formulation; pregnancy (in patients with rheumatoid arthritis); patients with rheumatoid arthritis and a history of treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan) may have a prohibitive risk of malignancy with azathioprine treatment

Dosing: Adult

Note: Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity receiving conventional azathioprine doses are at risk for developing severe, life-threatening myelotoxicity. Dosage reductions are recommended for patients with reduced TPMT activity; consider discontinuing in patients with abnormal blood counts that do not respond to dose reduction.

Renal transplantation (treatment usually started the day of transplant, however, has been initiated [rarely] 1 to 3 days prior to transplant):

Oral: Initial: 3 to 5 mg/kg once daily (usually given as a single daily dose), then 1 to 3 mg/kg once daily maintenance

IV: [Canadian product]: Initial: 3 to 5 mg/kg daily; Maintenance: dose reduction to 1 to 3 mg/kg daily is usually possible. Note: IV is indicated only in patients unable to tolerate oral medications (dosing should be transitioned from IV to oral as soon as tolerated).

Rheumatoid arthritis:

Oral:

Initial: 1 mg/kg/day (50 to 100 mg) given once daily or divided twice daily for 6 to 8 weeks; may increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks

Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly (monitor for delayed toxicities)

IV [Canadian product]: Note: IV is indicated only in patients unable to tolerate oral medications (dosing should be transitioned from IV to oral as soon as tolerated):

Initial: ~1 mg/kg/day (50 to 100 mg) given once daily or divided twice daily for 6 to 8 weeks; may increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks

Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly (monitor for delayed toxicities)

Crohn disease, remission maintenance or reduction of steroid use (off-label use): Oral: 2 to 3 mg/kg/day (Lichtenstein, 2009)

Dermatomyositis/polymyositis, adjunctive management (off-label use): Oral: 50 mg/day in conjunction with prednisone; increase by 50 mg/week to total dose of 2 to 3 mg/kg/day (Briemberg, 2003); Note: Onset of beneficial effects may take 3 to 6 months; however, may be preferred over methotrexate in patients with pulmonary or hepatic toxicity.

Immune thrombocytopenia, chronic (refractory or relapsed) (off-label use): Oral: 1 to 2 mg/kg/day; maximum dose: 150 mg/day (Provan 2010). Initial response is observed at 30 to 90 days; may take up to 6 months for peak response (Neunert 2011; Provan 2010)

Lupus nephritis, maintenance (off-label use): Oral: Initial: 2 mg/kg/day; may reduce to 1.5 mg/kg/day after 1 month (if proteinuria <1 g/day and serum creatinine stable) (Moroni, 2006) or target dose: 2 mg/kg/day (Hahn, 2012; Houssiau, 2010)

Ulcerative colitis, remission maintenance or reduction of steroid use (off-label use): Oral: 1.5 to 2.5 mg/kg/day (Kornbluth, 2010)

Dosage adjustment for concomitant use with allopurinol: Reduce azathioprine dose to one-third or one-fourth the usual dose when used concurrently with allopurinol. Patients with low or absent TPMT activity may require further dose reductions or discontinuation.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no specific dosage adjustments provided in the manufacturer’s labeling; however, oliguric patients, particularly those with tubular necrosis in the immediate post-transplant period (cadaveric transplant) may have delayed clearance and typically receive lower doses. The following adjustments have been recommended (Aronoff, 2007):

CrCl >50 mL/minute: No adjustment recommended.

CrCl 10-50 mL/minute: Administer 75% of normal dose.

CrCl <10 mL/minute: Administer 50% of normal dose.

Hemodialysis (dialyzable; ~45% removed in 8 hours): Administer 50% of normal dose; supplement: 0.25 mg/kg

CRRT: Administer 75% of normal dose

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Rapid WBC count decrease, persistently low WBC count, or serious infection: Reduce dose or temporarily withhold treatment.

Severe toxicity (hematologic or other) in renal transplantation: May require discontinuation.

Hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease): Permanently discontinue.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Powder for injection [Canadian product]: Reconstitute each vial with 5 to 10 mL sterile water for injection (adding 5 mL will result in a 10 mg/mL solution); gently swirl to dissolve. May further dilute in NS for infusion.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). When compounding an oral liquid or suspension, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

A 50 mg/mL oral suspension may be prepared with tablets. Crush one-hundred-twenty 50 mg tablets in a mortar and reduce to a fine powder. Add 40 mL of either cherry syrup (diluted 1:4 with Simple Syrup, USP); a 1:1 mixture of Ora-Sweet® and Ora-Plus; or a 1:1 mixture of Ora-Sweet SF and Ora-Plus®, and mix to a uniform paste. Mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well", "refrigerate", and “protect from light”. Stable for 60 days refrigerated.

Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.8862208

Administration

Oral: Administering tablets after meals or in divided doses may decrease adverse GI events.

IV [Canadian product]: Infusion is usually administered over 30 to 60 minutes, although may be infused over 5 minutes up to over 8 hours.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014).

Compatibility

Stable in D5W, NS.

Storage

Tablet: Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture.

Powder for injection [Canadian product]: Store intact vials at 15°C to 25°C (59°F to 77°F). Protect from light. Use immediately after preparation; discard unused portion.

Drug Interactions

5-ASA Derivatives: May decrease the metabolism of Thiopurine Analogs. Monitor therapy

ACE Inhibitors: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Allopurinol: May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides. Management: Reduce the azathioprine dose to one third to one quarter of the usual dose if used concomitantly with allopurinol, and monitor closely for systemic toxicity (particularly hematologic toxicity, nausea, and vomiting). Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Cyclophosphamide: AzaTHIOprine may enhance the hepatotoxic effect of Cyclophosphamide. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Febuxostat: May increase the serum concentration of AzaTHIOprine. Avoid combination

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

Mercaptopurine: AzaTHIOprine may enhance the myelosuppressive effect of Mercaptopurine. Avoid combination

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

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Ribavirin (Oral Inhalation): May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients extra closely for signs/symptoms of myelosuppression. Consider therapy modification

Ribavirin (Systemic): May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients closely for signs/symptoms of myelosuppression. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Sulfamethoxazole: May enhance the myelosuppressive effect of AzaTHIOprine. 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

Trimethoprim: May enhance the myelosuppressive effect of AzaTHIOprine. 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): AzaTHIOprine may enhance the adverse/toxic effect of Vaccines (Live). AzaTHIOprine may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose azathioprine (3 mg/kg/day or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns and is not a contraindication for administration of zoster vaccine. Higher doses of azathioprine should be avoided. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): AzaTHIOprine may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

TPMT phenotyping results will not be accurate following recent blood transfusions.

Adverse Reactions

Frequency not always defined; dependent upon dose, duration, indication, and concomitant therapy.

Central nervous system: Malaise

Gastrointestinal: Nausea and vomiting (rheumatoid arthritis: 12%), diarrhea

Hematologic & oncologic: Leukopenia (renal transplant: >50%; rheumatoid arthritis: 28%), neoplasia (renal transplant 3% [other than lymphoma], 0.5% [lymphoma]), thrombocytopenia

Hepatic: Hepatotoxicity, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases

Infection: Increased susceptibility to infection (renal transplant 20%; rheumatoid arthritis <1%; includes bacterial, fungal, protozoal, viral, opportunistic, and reactivation of latent infections)

Neuromuscular & skeletal: Myalgia

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Abdominal pain, acute myelocytic leukemia, alopecia, anemia, arthralgia, bone marrow depression, hemorrhage, hepatic veno-occlusive disease, hepatosplenic T-cell lymphomas, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hypersensitivity, hypotension, interstitial pneumonitis (reversible), JC virus infection, macrocytic anemia, malignant lymphoma, malignant neoplasm of skin, negative nitrogen balance, pancreatitis, pancytopenia, progressive multifocal leukoencephalopathy, skin rash, steatorrhea, Sweet's syndrome (acute febrile neutrophilic dermatosis)

ALERT: U.S. Boxed Warning

Malignancy:

Chronic immunosuppression with azathioprine, a purine antimetabolite, increases risk of malignancy in humans. Reports of malignancy include posttransplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Health care providers using this drug should be very familiar with this risk, as well as with the mutagenic potential to both men and women, and with possible hematologic toxicities. Inform patients of the risk of malignancy with azathioprine.

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal toxicity: Severe nausea, vomiting, diarrhea, rash, fever, malaise, myalgia, hypotension, and liver enzyme abnormalities may occur within the first several weeks of treatment and are generally reversible upon discontinuation.

• Hematologic toxicity: Dose-related hematologic toxicities (leukopenia, thrombocytopenia, and anemias, including macrocytic anemia or pancytopenia) may occur; may be severe and/or delayed. Thiopurine methyltransferase (TPMT) genotyping or phenotyping may help to identify patients who are at an increased risk for developing azathioprine toxicity. Patients with intermediate TPMT activity may be at increased risk for hematologic toxicity at conventional azathioprine doses; patients with low or absent TPMT activity are at risk for severe, life-threatening myelotoxicity. Myelosuppression may be more severe with renal transplants undergoing rejection. Monitor CBC with differential and platelets weekly during the first month, then twice a month for 2 months, then monthly (or more frequently if clinically indicated). May require treatment interruption or dose reduction. Leukopenia does not correlate with therapeutic effect and the dose should not be increased intentionally to lower the white blood cell count.

• Hepatotoxicity: Hepatotoxicity (transaminase, bilirubin, and alkaline phosphatase elevations) may occur, usually in renal transplant patients. Usually occurs within 6 months of transplant and is normally reversible with discontinuation. Monitor liver function periodically. Rarely, hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported; discontinue if hepatic SOS is suspected.

• Infections: Chronic immunosuppression increases the risk of serious, sometimes fatal, infections (bacterial, viral, fungal, protozoal, and opportunistic), including reactivation of latent infections.

• Malignancy: [US Boxed Warning]: Chronic immunosuppression with azathioprine (a purine antimetabolite), increases the risk of malignancy. Malignancies reported have included post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Health care providers using this drug should be very familiar with this risk, as well as with the mutagenic potential to both men and women, and with possible hematologic toxicities. Patients should be informed of the risk for malignancy development. HSTCL is a rare white blood cell cancer that is usually fatal and has predominantly occurred in adolescents and young adults treated for Crohn disease or ulcerative colitis and receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. Most cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents, although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy. Renal transplant patients are also at increased risk for malignancy (eg, skin cancer, lymphoma); limit sun and ultraviolet light exposure and use appropriate sun protection.

• Progressive multifocal leukoencephalopathy: Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including azathioprine (some cases have been fatal). Risk factors for PML include treatment with immunosuppressants and immune system impairment. Consider a diagnosis of PML in any patient presenting with new-onset neurological manifestations; consultation with a neurologist as clinically indicated may be warranted. Consider decreasing the degree of immunosuppression with respect to the risk of organ rejection in transplant patients.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage reductions may be necessary.

• TPMT deficiency: Patients with genetic deficiency of TPMT are more sensitive to myelosuppressive effects. Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity are at risk for developing severe and life-threatening hematologic toxicity. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity. Consider TPMT testing in patients with abnormally low CBC unresponsive to dose reduction. TPMT testing does not substitute for CBC monitoring.

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.

• Mercaptopurine: Azathioprine is metabolized to mercaptopurine; concomitant use may result in profound myelosuppression and should be avoided.

• TPMT or xanthine oxidase inhibitors: Patients on concurrent therapy with drugs which may inhibit TPMT (eg, olsalazine) or xanthine oxidase (eg, allopurinol) may be sensitive to myelosuppressive effects. Dose adjustment of azathioprine may be recommended when used concurrently with allopurinol; patients with low or absent TPMT activity may require further dose reductions or discontinuation.

• Vaccines: Immune response to vaccines may be diminished.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be prescribed by physicians familiar with the risks, including hematologic toxicities and mutagenic potential.

Monitoring Parameters

CBC with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly; monitor more frequently with dosage modifications), total bilirubin, liver function tests, creatinine clearance, TPMT genotyping or phenotyping (consider TPMT testing in patients with abnormally low CBC unresponsive to dose reduction); monitor for symptoms of infection

For use as immunomodulatory therapy in CD or UC, monitor CBC with differential weekly for 1 month, then biweekly for 1 month, followed by monitoring every 1 to 2 months throughout the course of therapy; monitor more frequently if symptomatic. LFTs should be assessed every 3 months. Monitor for signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Azathioprine crosses the placenta in humans; congenital anomalies, immunosuppression, hematologic toxicities (lymphopenia, pancytopenia), and intrauterine growth retardation have been reported. Azathioprine should not be used to treat rheumatoid arthritis during pregnancy. Women of childbearing potential should avoid becoming pregnant during treatment.

The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 877-955-6877.

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?)

• Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), angina, severe nausea, vomiting, loss of strength and energy, bruising, bleeding, severe dizziness, passing out, diarrhea, muscle pain, night sweats, excessive weight loss, mole changes, skin growths, or signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes) (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 healthcare 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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