Repaglinide and Metformin

Dosage Forms

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

Tablet, Oral:

Generic:

1/500: Repaglinide 1 mg and metformin hydrochloride 500 mg [DSC]

2/500: Repaglinide 2 mg and metformin hydrochloride 500 mg [DSC]

Pharmacology

Mechanism of Action

Combination therapy; repaglinide and metformin act to improve glycemic control via two different mechanisms of action:

Repaglinide is a nonsulfonylurea hypoglycemic agent which stimulates insulin release by blocking ATP-dependent potassium channels, depolarizing the membrane and facilitating calcium entry through calcium channels; increased intracellular calcium stimulates insulin release from the pancreatic beta cells.

Metformin prevents hyperglycemia by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity via increased peripheral glucose uptake and utilization.

Use: Labeled Indications

Diabetes mellitus, type 2: Management of type 2 diabetes mellitus, as an adjunct to diet and exercise, in adults currently receiving or not adequately controlled on metformin and/or a glinide

Contraindications

Hypersensitivity to repaglinide, metformin, or any component of the formulation; severe renal impairment (GFR <30 mL/min/1.73 m²); acute or chronic metabolic acidosis (including diabetic ketoacidosis); concomitant administration of gemfibrozil.

Dosage and Administration

Dosing: Adult

Diabetes mellitus, type 2: Oral: Note: Daily doses should be divided and given 2 to 3 times daily with meals; Maximum single dose: Repaglinide 4 mg/metformin 1,000 mg; Maximum daily dose: Repaglinide 10 mg/metformin 2,500 mg/day

Patients currently taking repaglinide and metformin: Initial doses should be based on (but not exceeding) the patient's current doses of repaglinide and metformin; titrate as needed to the maximum daily dose to achieve targeted glycemic control

Patients inadequately controlled with metformin monotherapy: Initial dose: Repaglinide 1 mg/metformin 500 mg twice daily with meals. Titrate slowly to reduce the risk of repaglinide-induced hypoglycemia.

Patients inadequately controlled with glinide monotherapy: Initial dose: Metformin 500 mg twice daily plus repaglinide at a dose similar to (but not exceeding) the patient's current dose. Titrate slowly to reduce the risk of metformin-induced gastrointestinal adverse effects.

Dosage adjustment for concomitant therapy:

Concomitant use with clopidogrel: Initial dose: Repaglinide 0.5 mg before each meal (maximum dose: 4 mg/day). Note: Combination repaglinide/metformin dosage forms will not accommodate the reduced initial repaglinide dose. Individual agents are required.

Concomitant use with cyclosporine: Repaglinide dose should not exceed 6 mg/day.

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Administration

Oral: Administer up to 30 minutes before meals to avoid risk of hypoglycemia/GI upset; if a meal is skipped or patient is unable to take anything by mouth, do not administer dose.

Dietary Considerations

Should be taken up to 30 minutes before meals to prevent hypoglycemia and decrease the risk of GI upset; if the patient misses a meal or is unable to take anything by mouth, the fixed-dose repaglinide/metformin combination agent should not be administered. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy. Monitor for signs and symptoms of vitamin B₁₂ and/or folic acid deficiency; supplementation may be required.

Storage

Do not store above 25°C (77°F). Protect from moisture.

Drug Interactions

Abemaciclib: May increase the serum concentration of MetFORMIN. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Atazanavir: May increase the serum concentration of Repaglinide. Management: Use of repaglinide or other narrow therapeutic index CYP2C8 substrates with atazanavir without concurrent ritonavir is not recommended. If repaglinide is used with ritonavir-boosted atazanavir, no significant interaction is expected. Avoid combination

Bictegravir: May increase the serum concentration of MetFORMIN. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

Clopidogrel: May increase the serum concentration of Repaglinide. Management: Avoid use of clopidogrel and repaglinide if possible; if the combination must be used, limit total repaglinide daily dose to no more than 4 mg. This is contraindicated in some non-US labeling. Consider therapy modification

CycloSPORINE (Systemic): May increase the serum concentration of Repaglinide. Management: Limit the daily repaglinide dose to a maximum of 6 mg with concurrent use of cyclosporine, and monitor closely for increased repaglinide effects. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Repaglinide. Exceptions: Clopidogrel. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Avoid combination

CYP2C8 Inhibitors (Weak): May increase the serum concentration of Repaglinide. Exceptions: Ketoconazole (Systemic). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Consider the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Erythromycin (Systemic): May increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

HMG-CoA Reductase Inhibitors (Statins): May increase the serum concentration of Repaglinide. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Diatrizoate Sodium; Ethiodized Oil. Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

Letermovir: May increase the serum concentration of Repaglinide. Management: Monitor for increased repaglinide effects/toxicities (ie, hypoglycemia) if combined with letermovir. When letermovir is coadministered with cyclosporine, the use of repaglinide is not recommended. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Consider therapy modification

RifAMPin: May decrease the serum concentration of Repaglinide. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tafenoquine: May increase the serum concentration of MATE1 Substrates. Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Consider therapy modification

Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Consider therapy modification

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Consider therapy modification

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Adverse Reactions

The following information reflects the frequency of adverse effects experienced by patients who received the repaglinide/metformin fixed-dose combination product. Also see individual agents.

>10%:

Central nervous system: Headache (22%)

Endocrine & metabolic: Hypoglycemia (33%)

Gastrointestinal: Diarrhea (19%), nausea (15%)

Respiratory: Upper respiratory tract infection (11%)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Use in combination with NPH insulin is not indicated; across 7 studies, reports of myocardial ischemia (6 events) in patients using repaglinide plus insulin have caused concern. Further evaluation is required to assess the safety of this combination.
• Hypoglycemia: Severe hypoglycemia may occur with repaglinide; risk may be increased by changes in meal patterns, changes in physical activity levels, changes to coadministered medications, concomitant use with other antidiabetic agents. Symptoms may be less pronounced in patients with longstanding diabetes, diabetic neuropathy, recurrent hypoglycemia or taking concurrent medications blocking the sympathetic nervous system. Monitor blood glucose more frequently in patients at high risk of hypoglycemia or who may have reduced symptomatic awareness of hypoglycemia.
• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years of age, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.
• Vitamin B₁₂ concentrations: Long-term metformin use is associated with vitamin B₁₂ deficiency; monitor vitamin B₁₂ serum concentrations periodically with long-term therapy. Monitoring of B₁₂ serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2019).

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Use IR tablets after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Mingrone 2016). ER tablets may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Mechanick 2013; Melissas 2013). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC_0-∞ increased by 21%) and bioavailability (increased by 50%) (Padwal 2011). Lactate levels decrease after gastric bypass (RYGB)-induced weight loss irrespective of the use of metformin. Routinely lowering metformin dose after gastric bypass is not necessary as long as normal renal function is preserved (Deden 2018).

– Hypoglycemia: May increase the risk of hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period after surgery. Where possible, the selection of antidiabetic agents without the potential for hypoglycemia is advised.

• Heart failure: Metformin may be used in patients with stable heart failure; avoid use in unstable or hospitalized patients with heart failure (ADA 2019). Risk of lactic acidosis may be increased secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use of metformin in patients with heart failure may be associated with reduced mortality and reduction in hospital readmission for heart failure (Crowley 2017; Eurich 2013).
• Hepatic impairment: The manufacturer recommends to generally avoid use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Risk of hypoglycemia may be increased in patients with renal impairment. Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using eGFR; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. Use is contraindicated in patients with eGFR <30 mL/minute/1.73 m². Assess benefits/risks of continuing metformin therapy in patients whose eGFR falls below 45 mL/minute/1.73 m² during therapy; if used, metformin dosage reduction is recommended (ADA [Lipska 2011]; Inzucchi 2014). Repaglinide dose reduction may also be required. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.
• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

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.

Special populations:

• Elderly: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.
• Iodinated contrast: According to the manufacturer, it is recommended to temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m²; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m²; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR <30 mL/minute/1.73 m²]) or who are undergoing arterial catheter studies (ACR 2017).
• Patient education: Diabetes self-management education is essential to maximize the effectiveness of therapy.
• Surgical procedures: Metformin should be withheld the day of surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2019). Resume only after normal intake resumed and normal renal function is verified.

Monitoring Parameters

Regular assessment of fasting blood glucose, postprandial blood glucose, and hemoglobin A_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019]); initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices); renal function (eGFR) should be performed prior to initiation of therapy and at least annually (more often in patients at risk of developing renal impairment; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m²; every 3 months if eGFR 30 to <45 mL/minute/1.73 m² [Lipska 2011]); monitor vitamin B₁₂ serum concentrations periodically with long-term therapy; folate (if megaloblastic anemia is suspected).

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Metformin crosses the placenta (ADA 2020). Animal reproduction studies have not been conducted with this combination. See individual agents.

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 headache, passing gas, nausea, diarrhea, or common cold symptoms. Have patient report immediately to prescriber chills, sore throat, severe abdominal pain, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating), or signs of lactic acidosis (fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps) (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.