PrandiMet (Repaglinide and metformin) is an orally available anti-diabetic medicine that is used as an adjunct to diet and exercise for the treatment of adult patients with diabetes mellitus type 2.
PrandiMet (Repaglinide and metformin) Indications:
-
Diabetes mellitus Type 2:
- Used for management of type 2 diabetes mellitus, in adults currently receiving or not adequately controlled on metformin and/or a glinide, along with diet an excercise.
PrandiMet (Repaglinide and metformin) Dose in Adults
PrandiMet (Repaglinide and metformin) Dose in the treatment of type 2 Diabetes mellitus: Oral:
Note: Daily divided doses 2 to 3 times a day, taken along with food.
- 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 according to but not exceeding, the patient's current doses of repaglinide and metformin
- titrate as required 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 food.
- Titrate slowly to lessen the incidence of repaglinide induced hypoglycemia.
-
Patients inadequately controlled with glinide monotherapy:
- Initial dose: Metformin 500 mg twice daily plus repaglinide at a dose not more than the patient's current dose.
- Titrate slowly to reduce metformin-induced gastrointestinal side effects.
-
Dosage adjustment for concomitant therapy:
- Concomitant use with clopidogrel:
- Initial dose: Repaglinide 0.5 mg before every meal (maximum dose: 4 mg/day).
- Concomitant use with cyclosporine:
- Do not exceed 6mg/day of repaglinide
- Concomitant use with clopidogrel:
Use in Children:
Not indicated.
Pregnancy Risk Factor C
- Metformin crosses over to the placenta.
- Talk to individual agents.
Breastfeeding: Repaglinide or metformin
- Breast milk contains metformin; repaglinide does not exist.
- Due to the potential risk of hypoglycemia, breastfeeding is not advised.
PrandiMet (Repaglinide and metformin) Dose in Kidney Disease:
-
eGFR >45mL/minute/1.73m2
- There is no need to adjust the dosage
-
eGFR 30 - 45 mL/minute/1.73m2
- Pre-existing impairment
- Not recommended to initiate therapy
- Therapy: eGFR should be between 30 and 45mL/minute/1.73m2.
- Continued therapy is a good option.
- Metformin therapy should be continued. Reduce Metformin dosage by 50% (maximum Metformin 1,000 mg/day) while monitoring renal function every 3 months.
- Pre-existing impairment
-
eGFR 30mL/minute/1.73m2
- Contraindicated
PrandiMet (Repaglinide and metformin) Dose in Liver disease:
- Metformin should be avoided as liver disease can lead to lactic acidosis.
- Metformin continued use in diabetics with liver dysfunction (cirrhosis) has been successful.
- However, it may have a survival benefit for certain patients.
- Patients at high risk of lactic acidosis (eg renal impairment, alcohol abuse) should be treated with caution. Avoid hepatic impairment.
Side Effects of PrandiMet (Repaglinide and metformin):
-
Central nervous system:
- Headache
-
Endocrine & metabolic:
- Hypoglycemia
-
Gastrointestinal:
- Diarrhea
- Nausea
-
Respiratory:
- Upper respiratory tract infection
Contraindications to PrandiMet (Repaglinide and metformin):
- Hypersensitivity to metformin, repaglinide or any other component of the formulation
- Grave renal impairment (GFR 30mL/min/1.73m2)
- Chronic or acute metabolic acidosis (including diabetic ketoacidosis)
- Gemfibrozil may be administered simultaneously.
Warnings and precautions
-
Cardiovascular effects
- Combination with NPH insulin is not recommended. Six events of myocardial ischemia in patients treated with repaglinide plus Insulin were reported in seven studies.
- To determine the safety of this combination, further evaluation is necessary.
-
Hypoglycemia
- Repaglinide may cause severe hypoglycemia. This risk can be increased by changing your meal times, exercise levels, taking coadministered medications or using it in conjunction with other anti-hypoglycemic agents.
- Patients with diabetes, long-term hypoglycemia, and diabetic neuropathy may experience symptoms that are less severe.
- Patients at high risk for hypoglycemia and those with reduced symptoms of hypoglycemia should be monitored more often.
-
Lactic acidosis: [US Boxed Warning]
- Metformin-associated lactosis has been linked to death, hypothermia and hypotension in post-marketing cases.
- The symptoms include malaise, myalgias and respiratory distress as well as nonspecific symptoms such as abdominal pain, somnolence, stomach pain, or nausea. There are also elevated blood lactate levels (>5 mg/L) and anion gap acidosis. Metformin plasma levels are generally greater than 5 mg/mL.
- Patients with renal impairment, concomitant intake of certain drugs (eg carbonic anhydrase inhibiters such as topiramate), >=65, having a radiologic scan with contrast, surgery, and other procedures, hypoxic conditions (eg acute heart failure), excessive alcohol consumption, and hepatic impairment are all risk factors for lactic acidosis.
- If you suspect lactic acidosis, discontinue use immediately. It is best to get hemodialysis as soon as possible.
- Patients with diabetes who are receiving metformin should suspect lactic acidosis if they have signs of acidosis, but not ketoacidosis.
- Patients with hypoxemia, sepsis or dehydration should stop taking metformin.
- With impairment in renal function, the risk of lactic acidosis and accumulation increases.
-
Concentrations of Vitamin B12:
- Vitamin B-12 deficiency is a common side effect of long-term metformin usage.
- Long-term treatment with vitamin B-12 should be monitored regularly, especially for patients suffering from anemia or neuropathy.
-
Bariatric surgery
- Absorption altered:
- After surgery, take immediate-release tablets.
- The anatomical and transit changes may alter the absorption.
- Extended-release tablets can have a decreased effect after gastric bypass. This is due to the direct bypassing of the stomach and proximal bowel with gastric bypass, or a faster gastric emptying and transit with sleeve gastricectomy.
- As long as normal renal function remains intact, it is not necessary to reduce metformin doses after gastric bypass.
- Hypoglycemia
- Hypoglycemia may increase after gastric bypass, gastric band, or sleeve-gastrectomy.
- These procedures may partially or fully restore insulin secretion and sensitivity (gastric bypass is the most effective, followed closely by the sleeve then finally the band).
- In the days immediately following gastric bypass or sleeve-gastrectomy, first-phase insulin secretion as well as hepatic insulin sensitive were shown to be significantly increased.
- These procedures may have a longer-lasting effect on peripheral insulin sensitivity. This could happen in the 3 to 12 months following surgery.
- It is recommended to select antidiabetic drugs that are not hypoglycemic.
- Absorption altered:
-
Heart Failure:
-
- Metformin can be used for patients with stable or irreversible heart failure.
- Avoid use in patients who are unstable or have heart failure.
- Hypoperfusion may increase the risk of developing lactic acidosis.
- The American Heart Association has stated that metformin may be an agent that can exacerbate myocardial dysfunction (magnitude major). (AHA [Page 2016,]).
- Metformin may reduce mortality in patients with heart disease and decrease hospital readmissions.
-
-
Hepatic impairment
- Due to the possibility of lactic acidosis, the manufacturer suggests that patients with impaired liver function should be avoided.
- Metformin may have a survival benefit for certain patients who have diabetes with liver dysfunction.
-
Renal impairment
- Hypoglycemia can be more common in patients with impaired renal function.
- The kidney excretes a large amount of Metformin.
- Before starting therapy, assess the renal function. You can also use eGFR periodically to monitor your progress. The risk of metformin accumulation or lactic acidosis will increase with increasing renal impairment.
- Assess risk vs. benefit if eGFR is between 30 and 45 mL
- Metformin therapy should be continued. Reduce Metformin dosage by 50% (maximum Metformin 1,000 mg/day) while monitoring renal function every 3 months.
- Contraindicated for eGFR lower than 30ml
- Metformin disposition may be affected by concomitant medication that can affect renal function (i.e., tubular secretion).
- Metformin should be administered to patients suffering from dehydration or prerenal azotemia.
-
Stress-related disorders:
- If the patient is subject to stress (fever or trauma, infection, surgery), stop therapy and give insulin.
Repaglinide and metformin: Drug Interaction
|
Abemaciclib |
May increase the serum concentration of MetFORMIN. |
|
Abiraterone Acetate |
May increase the serum concentration of CYP2C8 Substrates (High risk with Inhibitors). |
|
Alpha-Lipoic Acid |
May enhance the hypoglycemic effect of Antidiabetic Agents. |
|
Androgens |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. |
|
Antidiabetic Agents |
May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. |
|
Bictegravir |
May increase the serum concentration of MetFORMIN. |
|
Bosentan |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Carbonic Anhydrase Inhibitors |
May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. |
|
Cephalexin |
May increase the serum concentration of MetFORMIN. |
|
CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
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. |
|
Dalfampridine |
MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. |
|
Deferasirox |
May increase the serum concentration of Repaglinide. |
|
Direct Acting Antiviral Agents (HCV) |
May enhance the hypoglycemic effect of Antidiabetic Agents. |
|
Dofetilide |
MetFORMIN may increase the serum concentration of Dofetilide. |
|
Eltrombopag |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. |
|
Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Erdafitinib |
May increase the serum concentration of OCT2 Substrates. |
|
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. |
|
Glycopyrrolate (Systemic) |
May increase the serum concentration of MetFORMIN. |
|
Guanethidine |
May enhance the hypoglycemic effect of Antidiabetic Agents. |
|
Herbs (Hypoglycemic Properties) |
May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. |
|
HMG-CoA Reductase Inhibitors (Statins) |
May increase the serum concentration of Repaglinide. |
|
Hyperglycemia-Associated Agents |
May diminish the therapeutic effect of Antidiabetic Agents. |
|
Hypoglycemia-Associated Agents |
May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. |
|
Hypoglycemia-Associated Agents |
Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. |
|
Isavuconazonium Sulfate |
May increase the serum concentration of MetFORMIN. |
|
Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
LamoTRIgine |
May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. |
|
Leflunomide |
May increase the serum concentration of Repaglinide. Specifically, the active metabolite of leflunomide may increase repaglinide concentrations. |
|
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. |
|
Maitake |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. |
|
Monoamine Oxidase Inhibitors |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. |
|
Ombitasvir, Paritaprevir, and Ritonavir |
May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. |
|
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir |
May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. |
|
Ondansetron |
May increase the serum concentration of MetFORMIN. |
|
Pegvisomant |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. |
|
Prothionamide |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. |
|
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. |
|
Ritodrine |
May diminish the therapeutic effect of Antidiabetic Agents. |
|
Salicylates |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. |
|
Sarilumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Selective Serotonin Reuptake Inhibitors |
May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. |
|
Siltuximab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Tecovirimat |
May increase the serum concentration of Repaglinide. |
|
Teriflunomide |
May increase the serum concentration of Repaglinide. |
|
Thiazide and Thiazide-Like Diuretics |
May diminish the therapeutic effect of Antidiabetic Agents. |
|
Tocilizumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Topiramate |
May enhance the adverse/toxic effect of MetFORMIN. |
|
Trimethoprim |
May decrease the metabolism of Repaglinide. |
|
Trimethoprim |
May increase the serum concentration of MetFORMIN. |
|
Trospium |
MetFORMIN may decrease the serum concentration of Trospium. |
|
Vandetanib |
May increase the serum concentration of MetFORMIN. |
|
Verapamil |
May diminish the therapeutic effect of MetFORMIN. |
|
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). |
|
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. |
|
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. |
|
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. |
|
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). |
|
Dabrafenib |
May decrease the serum concentration of CYP2C8 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). |
|
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. |
|
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. |
|
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. |
|
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. |
|
MiFEPRIStone |
May increase the serum concentration of CYP2C8 Substrates (High risk with Inhibitors). Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. |
|
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. |
|
Patiromer |
May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. |
|
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. |
|
RifAMPin |
May decrease the serum concentration of Repaglinide. Management: Consider alternatives to this combination. Dose timing may substantially affect this interaction; in clinical studies, the lowest magnitude of interaction was seen when repaglinide was given 1 h after rifampin (compared to 0, 12, or 24 h). |
|
St John's Wort |
May decrease the serum concentration 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. |
|
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. |
|
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. |
|
Tolvaptan |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. |
|
Alcohol (Ethyl) |
May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis. |
|
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. |
|
Gemfibrozil |
May increase the serum concentration of Repaglinide. The addition of itraconazole may augment the effect of gemfibrozil on repaglinide. |
Monitoring parameters:
Regular evaluation of
- Fasting blood glucose
- Postprandial blood glucose
- Hemoglobin A should be taken at least once every 6 months for patients with stable glycemic control. It should also be taken at once every 3 months for patients not meeting their treatment goals or who are undergoing therapy change.
- Monitoring of hemoglobin/hematocrit and red blood cell indexes (eg, hemoglobin/hematocrit) is recommended for both initial and ongoing monitoring.
- Before starting treatment, it is important to check your renal function (eGFR). This should be done at least once a year if you have eGFR between 45 and 60 mL/minute/1.73m2; or every 3 months if you have eGFR between 30 and 45 mL/minute/1.73m2.
- Long-term treatment with vitamin B-12 requires that you monitor your serum levels regularly
- Folate levels (if you suspect megaloblastic anemia).
How to administer PrandiMet (Repaglinide and metformin)?
- Oral: Administer up to 30 minutes before meals to avoid the risk of hypoglycemia/GI upset.
- In the case of a skipped meal, do not administer the dose.
Mechanism of action of PrandiMet (Repaglinide and metformin):
- It's a combination of metformin and Repaglinide.
- Metformin and Repaglinide work together to increase glycemic control through two different mechanisms.
- Repaglinide increases insulin release and is a non-sulfonylureahypoglycemic drug. It blocks ATP-dependent potassium channels, causing the membrane to depolarize. This results in calcium entering through calcium channels more efficiently. The intracellular calcium also stimulates insulin release from pancreatic beta cells.
- Metformin reduces hepatic glucose and intestinal absorption. It also increases peripheral glucose uptake, utilization, and insulin sensitivity. Contact individual agents (Metformin or Repaglinide).
International Brand Names of Repaglinide and metformin:
- PrandiMet
- Fulaihe
- Magicnorm
- Panmeglin
- Repanorm M
- Replitza
Repaglinide and metformin Brand Names in Pakistan:
No Brands Available in Pakistan.
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