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Cryptococcal meningitis in HIV-infected patients: Treatment of cryptococcal meningitis in HIV-infected patients.
Fungal infections, empiric therapy: Empiric treatment in febrile neutropenic patients with presumed fungal infection.
Fungal infections, systemic therapy: Treatment of systemic infections caused by Aspergillus sp, Candida sp, and/or Cryptococcus sp in patients refractory to conventional amphotericin B deoxycholate therapy or when renal impairment or unacceptable toxicity precludes the use of the deoxycholate formulation.
Leishmaniasis (visceral): Treatment of visceral leishmaniasis.
Hypersensitivity to amphotericin B deoxycholate or any component of the formulation
Note: Lipid-based amphotericin formulations (AmBisome) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]) or with other lipid-based amphotericin formulations (amphotericin B lipid complex [Abelcet], amphotericin B cholesteryl sulfate complex [Amphotec]). Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.
Usual dosage range: IV: 3 to 6 mg/kg/day
Note: Premedication: For patients who experience nonanaphylactic immediate infusion-related reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal anti-inflammatory agent ‚ ± diphenhydramine; or acetaminophen with diphenhydramine; or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.
Indication-specific dosing: IV:
Aspergillus(systemic infection): 3 to 5 mg/kg/day
Aspergillosis (invasive) in HIV-infected patients (alternative to preferred therapy) (off-label use): 5 mg/kg/day until infection resolution and CD4 count >200 cells/mm3 (HHS [OI adult 2015])
Candidiasis:
Empiric therapy: 3 to 5 mg/kg/day (Pappas 2009)
Endocarditis: 3 to 5 mg/kg/day (with or without flucytosine) for 6 weeks after valve replacement; Note: If isolates susceptible and/or clearance demonstrated, guidelines recommend step-down to fluconazole; also for long-term suppression therapy if valve replacement is not possible (Pappas 2009)
General invasive disease: 3 to 5 mg/kg/day with oral flucytosine (off-label combination; Pappas 2009)
Meningitis: 3 to 5 mg/kg/day with or without oral flucytosine (off-label combination; Pappas 2009)
Osteoarticular: 3 to 5 mg/kg/day for several weeks, followed by fluconazole for 6 to 12 months (osteomyelitis) or 6 weeks (septic arthritis) (Pappas 2009)
Systemic infection: Manufacturer 's labeling: 3 to 5 mg/kg/day
Coccidioidomycosis in HIV-infected patients with severe, non-meningeal infection (ie, diffuse pulmonary or severely ill with extrathoracic, disseminated disease) (off-label use): 4 to 6 mg/kg/day until clinical improvement, then initiate triazole therapy (eg, fluconazole or itraconazole) (HHS [OI adult 2015])
Cryptococcus(systemic infection): 3 to 5 mg/kg/day
Cryptococcal meningitis in HIV-infected patients:
Manufacturer 's labeling: 6 mg/kg/day
Alternate recommendations: 3 to 4 mg/kg/day in combination with oral flucytosine (HHS [OI adult 2015])
Fungal sinusitis: Limited data in immunocompromised patients have shown efficacy with 3 to 10 mg/kg/day (Barron 2005; Pagano 2004; Rokicka 2006). Note: An azole antifungal is recommended if causative organism is Aspergillus spp or Pseudallescheria boydii (Scedosporium sp).
Histoplasmosis in HIV-infected patients (off-label use; HHS [OI adult 2015]):
Moderately severe to severe disseminated disease: Induction therapy: 3 mg/kg/day for at least 2 weeks, followed by oral itraconazole for maintenance therapy
Histoplasma meningitis: Induction therapy: 5 mg/kg/day for 4 to 6 weeks, followed by oral itraconazole for maintenance therapy
Leishmaniasis (cutaneous) in HIV-infected patients (off-label use): 2 to 4 mg/kg/day for 10 days or an interrupted schedule (eg, 4 mg/kg on days 1 through 5, and then on days 10, 17, 24, 31, 38). Total dose administered should be 20 to 60 mg/kg (HHS [OI adult 2015])
Leishmaniasis (visceral):
Immunocompetent: 3 mg/kg/day on days 1 through 5, and 3 mg/kg/day on days 14 and 21; a repeat course may be given in patients who do not achieve parasitic clearance
Immunocompromised: 4 mg/kg/day on days 1 through 5, and 4 mg/kg/day on days 10, 17, 24, 31, and 38
Leishmaniasis (visceral) in HIV-infected patients (off-label use; HHS [OI adult 2015]):
Treatment: 2 to 4 mg/kg/day or an interrupted schedule (eg, 4 mg/kg on days 1 through 5, and then on days 10, 17, 24, 31, and 38). Total dose administered: 20 to 60 mg/kg
Chronic maintenance therapy (for patients with a CD4 count <200 cells/mm3): 4 mg/kg every 2 to 4 weeks
Meningitis (secondary to contaminated [eg, Exserohilum rostratum] steroid products), severe or in patients not improving with voriconazole monotherapy (off-label use) (CDC 2013; Kauffman 2012): IV: 5 to 6 mg/kg/day in combination with voriconazole for ≥3 months; a higher dose (7.5 mg/kg/day) may be considered in patients who are not improving. Note: Consult an infectious disease specialist and current CDC guidelines for specific treatment recommendations.
Osteoarticular infection (secondary to contaminated [eg,Exserohilum rostratum] steroid products), severe or in patients with clinical instability (off-label use) (CDC 2013; Kauffman 2012): IV: 5 mg/kg/day in combination with voriconazole for ≥3 months. Note: Consult an infectious disease specialist and current CDC guidelines for specific treatment recommendations.
Penicillium marneffeiinfection in HIV-infected patients (off-label use): 3 to 5 mg/kg/day for 2 weeks, followed by oral itraconazole for 10 weeks, followed by chronic maintenance therapy (HHS [OI adult 2015])
Refer to adult dosing.
Note: Lipid-based amphotericin formulations (AmBisome) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]) or with other lipid-based amphotericin formulations (amphotericin B lipid complex [Abelcet], amphotericin B cholesteryl sulfate complex [Amphotec]). Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.
Usual dosage range: Infants, Children, and Adolescents: IV: 3 to 6 mg/kg/day
Note:Premedication: For patients who experience nonanaphylactic immediate infusion-related reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal anti-inflammatory agent ‚ ± diphenhydramine; or acetaminophen with diphenhydramine; or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.
Indication-specific dosing:
Infants, Children, and Adolescents: IV:
Empiric therapy: 3 mg/kg/day
Cryptococcal meningitis in HIV-exposed/infected patients:
Infants and Children: 6 mg/kg/dose once daily; may coadminister with flucytosine (HHS [OI pediatric 2013]; off-label combination)
Adolescents: Refer to adult dosing.
Systemic fungal infections (Aspergillus, Candida, Cryptococcus); non-HIV-exposed/-infected: 3 to 5 mg/kg/day
Systemic fungal infections (HIV-exposed/-infected [HHS (OI pediatric 2013; OI adult 2015)]; off-label use):
Infants and Children:
Candidiasis, invasive: 5 mg/kg/dose once daily
Coccidioidomycosis (severe illness with respiratory compromise due to diffuse pulmonary or disseminated non-meningitic disease): 5 mg/kg/dose once daily until clinical improvement, then initiate triazole therapy (eg, fluconazole or itraconazole); dosage may be increased to 10 mg/kg/dose once daily for life-threatening infection.
Cryptococcus, disseminated (non-CNS): 3 to 5 mg/kg/dose once daily (may consider addition of oral flucytosine)
Histoplasmosis:
CNS infection: 5 mg/kg/dose once daily
Disseminated: 3 to 5 mg/kg/day once daily
Adolescents: Refer to adult dosing.
Leishmaniasis (cutaneous) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.
Leishmaniasis (visceral):
Immunocompetent: 3 mg/kg/day on days 1 to 5, and 3 mg/kg/day on days 14 and 21; a repeat course may be given in patients who do not achieve parasitic clearance
Immunocompromised: 4 mg/kg/day on days 1 to 5, and 4 mg/kg/day on days 10, 17, 24, 31, and 38
Leishmaniasis (visceral) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.
Penicillium marneffeiinfection in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.
There are no dosage adjustments provided in the manufacturer 's labeling; has been successfully administered to patients with preexisting renal impairment.
End-stage renal disease (ESRD) on intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Poorly dialyzed; no dosage adjustment necessary (Heintz 2009)
CVVH/CVVHD/CVVHDF: No dosage adjustment necessary (Heintz 2009)
There are no dosage adjustments provided in the manufacturer 's labeling (has not been studied).
Reconstitute with 12 mL SWFI to a concentration of 4 mg/mL. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation. Shake the vial vigorously for 30 seconds, until dispersed into a translucent yellow suspension.
Filtration and dilution: Withdraw appropriate amount of reconstituted solution into a syringe, attach a 5-micron filter, and inject contents of syringe through filter needle into an appropriate amount of D5W. Dilute to a final concentration of 1-2 mg/mL (0.2-0.5 mg/mL for infants and small children).
Administer via intravenous infusion, over a period of approximately 2 hours. Infusion time may be reduced to approximately 1 hour in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased. Existing intravenous line should be flushed with D5W before and after infusion (if not feasible, administer through a separate line). An in-line membrane filter (not less than 1 micron) may be used.
For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic immediate infusion-related reactions, premedicate with the following drugs, 30 to 60 minutes prior to drug administration: A nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) ‚ ± diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.
If on parenteral nutrition, may need to adjust the amount of lipid infused. The lipid portion of amphotericin B (liposomal) formulation contains 0.27 kcal per 5 mg (Sacks 1997).
Store intact vials at ≤25 ‚ °C ( ≤77 ‚ °F). Reconstituted vials are stable at 2 ‚ °C to 8 ‚ °C (36 ‚ °F to 46 ‚ °F) for 24 hours. Do not freeze. Begin infusion within 6 hours of dilution with D5W. Extended storage information may be available; contact product manufacturer to obtain current recommendations.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Reconstituted, Intravenous:
AmBisome: 50 mg (1 ea) [contains cholesterol, distearoyl phosphatidylglycerol, hydrogenated soy phosphatidylcholine, sodium succinate hexahydrate, sucrose, tocopherol, dl-alpha]
Stable in D5W; incompatible with NS, 1/2NS, other saline-containing solutions, or preservatives.
Y-site administration: Incompatible with caspofungin.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Aminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Cardiac Glycosides: Amphotericin B may enhance the adverse/toxic effect of Cardiac Glycosides. Monitor therapy
Colistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Consider therapy modification
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy
CycloSPORINE (Systemic): Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Flucytosine: Amphotericin B may enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Monitor therapy
Foscarnet: May enhance the nephrotoxic effect of Amphotericin B. Avoid combination
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination
Sodium Stibogluconate [INT]: Amphotericin B may enhance the cardiotoxic effect of Sodium Stibogluconate [INT]. Consider therapy modification
Renal function (monitor frequently during therapy), electrolytes (especially potassium and magnesium), liver function tests, temperature, hematocrit, PT/PTT, CBC; monitor input and output; monitor for signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes, etc); monitor cardiac function if used concurrently with corticosteroids
Falsely-elevated serum phosphate may occur when using the PHOSm assay.
Percentage of adverse reactions is dependent upon population studied and may vary with respect to premedications and underlying illness. Incidence of decreased renal function and infusion-related events are lower than rates observed with amphotericin B deoxycholate.
>10%:
Cardiovascular: Hypertension (8% to 20%), tachycardia (9% to 19%), peripheral edema (15%), edema (12% to 14%), hypotension (7% to 14%), chest pain (8% to 12%), localized phlebitis (9% to 11%)
Central nervous system: Chills (29% to 48%), insomnia (17% to 22%), headache (9% to 20%), pain (14%), anxiety (7% to 14%), confusion (9% to 13%)
Dermatologic: Skin rash (5% to 25%), pruritus (11%)
Endocrine & metabolic: Hypokalemia (31% to 51%), hypomagnesemia (15% to 50%), hyperglycemia (8% to 23%), hypocalcemia (5% to 18%), hyponatremia (9% to 12%), hypervolemia (8% to 12%)
Gastrointestinal: Nausea (16% to 40%), vomiting (11% to 32%), diarrhea (11% to 30%), abdominal pain (7% to 20%), constipation (15%), anorexia (10% to 14%)
Genitourinary: Nephrotoxicity (14% to 47%), hematuria (14%)
Hematologic & oncologic: Anemia (27% to 48%), leukopenia (15% to 17%), thrombocytopenia (6% to 13%)
Hepatic: Increased serum alkaline phosphatase (7% to 22%), hyperbilirubinemia ( ≤18%), increased serum ALT (15%), increased serum AST (13%), abnormal hepatic function tests (not specified) (4% to 13%)
Hypersensitivity: Transfusion reaction (9% to 18%)
Infection: Sepsis (7% to 14%), infection (11% to 13%)
Neuromuscular & skeletal: Weakness (6% to 13%), back pain (12%)
Renal: Increased serum creatinine (18% to 40%), increased blood urea nitrogen (7% to 21%)
Respiratory: Dyspnea (18% to 23%), pulmonary disease (14% to 18%), cough (2% to 18%), epistaxis (9% to 15%), pleural effusion (13%), rhinitis (11%)
Miscellaneous: Infusion related reactions (4% to 21%; fever [7% to 24%], chills [6% to 24%], vomiting [4% to 16%], nausea [8% to 14%], dyspnea [5% to 10%], tachycardia [2% to 10%], hypertension [2% to 9%], vasodilation [5%], hypotension [4%], hyperventilation [1%], hypoxia [ ≤1%])
2% to 10%:
Cardiovascular: Atrial fibrillation, bradycardia, cardiac arrest, cardiac arrhythmia, cardiomegaly, facial edema, flushing, heart valve disease, orthostatic hypotension, vascular disorder, vasodilatation
Central nervous system: Dizziness (7% to 9%), abnormality in thinking, agitation, coma, depression, drowsiness, dysesthesia, dystonia, hallucination, malaise, nervousness, paresthesia, rigors, seizure
Dermatologic: Diaphoresis (7%), alopecia, cellulitis, dermal ulcer, dermatological reaction, maculopapular rash, skin discoloration, urticaria, vesiculobullous dermatitis, xeroderma
Endocrine & metabolic: Hypernatremia (4%), acidosis, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hypophosphatemia, increased lactate dehydrogenase, increased nonprotein nitrogen
Gastrointestinal: Gastrointestinal hemorrhage (10%), aphthous stomatitis, dyspepsia, dysphagia, enlargement of abdomen, eructation, fecal incontinence, flatulence, gingival hemorrhage, hematemesis, hemorrhoids, hiccups, increased serum amylase, intestinal obstruction, mucositis, rectal disease, stomatitis, xerostomia
Genitourinary: Dysuria, toxic nephrosis, urinary incontence, vaginal hemorrhage
Hematologic & oncologic: Blood coagulation disorder, bruise, decreased prothrombin time, hemophthalmos, hemorrhage, hypoproteinemia, increased prothrombin time, oral hemorrhage, petechia, purpura
Hepatic: Hepatic injury, hepatic veno-occlusive disease, hepatomegaly
Hypersensitivity: Delayed hypersensitivity, hypersensitivity reaction
Immunologic: Graft versus host disease
Infection: Herpes simplex infection
Local: Inflammation at injection site
Neuromuscular & skeletal: Arthralgia, myalgia, neck pain, ostealgia, tremor
Ophthalmic: Conjunctivitis, dry eyes
Renal: Acute renal failure, renal failure, renal function abnormality
Respiratory: Hypoxia (6% to 8%), asthma, atelectasis, dry nose, flu-like symptoms, hemoptysis, hyperventilation, pharyngitis, pneumonia, pulmonary edema, respiratory alkalosis, respiratory failure, respiratory insufficiency, sinusitis
Miscellaneous: Procedural complication (8% to 10%)
Postmarketing and/or case reports: Agranulocytosis, angioedema, cyanosis, hemorrhagic cystitis, hypoventilation, rhabdomyolysis
Concerns related to adverse effects:
- Anaphylaxis: Has been reported with amphotericin B-containing drugs; facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued; the patient should not receive further infusions. Administer under close clinical observation during initial dosing.
- Infusion reactions: Acute reactions (including fever and chills) may occur 1 to 3 hours after starting infusions; reactions are more common with the first few doses and generally diminish with subsequent doses. Immediately discontinue infusion if a severe anaphylactic reaction occurs; the patient should not receive further infusions.
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.
Other warnings/precautions:
- Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving simultaneous leukocyte transfusions and amphotericin B.
B
Adverse events were not observed in animal reproduction studies. Amphotericin crosses the placenta and enters the fetal circulation. Amphotericin B is recommended for the treatment of serious systemic fungal diseases in pregnant women; refer to current guidelines (King 1998).
Binds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death. Proposed mechanism suggests that amphotericin causes an oxidation-dependent stimulation of macrophages (Lyman 1992).
Vd: 0.1 to 0.16 L/kg
7 to 10 hours (following a single 24-hour dosing interval); Terminal half-life: 100 to 153 hours (following multiple dosing up to 49 days)
- 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 nausea, vomiting, diarrhea, constipation, lack of appetite, insomnia, back pain, abdominal pain, cough, anxiety, rhinorrhea, or sweating a lot. Have patient report immediately to prescriber signs of 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 kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), angina, tachycardia, black, tarry, or bloody stools, vomiting blood, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, severe headache, chills, pharyngitis, severe loss of strength and energy, bruising, or bleeding (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.