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  • CLASSES

    Thiazolidinedione/Glitazone Antidiabetics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral thiazolidinedione (TZD) antidiabetic agent targeting insulin resistance
    Used as monotherapy for type 2 DM or in combination with metformin, a sulfonylurea, or insulin
    Monitor closely; TZDs can cause or exacerbate heart failure

    COMMON BRAND NAMES

    Actos

    HOW SUPPLIED

    Actos/Pioglitazone/Pioglitazone Hydrochloride Oral Tab: 15mg, 30mg, 45mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus.
    NOTE: Pioglitazone is not effective for type 1 diabetes mellitus.
    As monotherapy as an adjunct to diet and exercise to improve glycemic control.
    Oral dosage
    Adults

    Initially, 15 mg or 30 mg PO once daily. For an inadequate response, increase dose in 15 mg increments, up to 45 mg PO once daily; consider combination therapy in patients who have an inadequate response to monotherapy. After initiation or dose increases, monitor carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If a deterioration in cardiac status develops, manage according to current standards of care. Consider pioglitazone discontinuation or dose reduction.

    Adults receiving concomitant strong inhibitors of CYP2C8 (e.g., gemfibrozil, see Drug Interactions)

    Maximum recommended dose is 15 mg PO once daily.

    Adults without symptomatic heart disease but one or more risk factors for congestive heart failure or those with NYHA Class I or II heart failure

    Initially, no more than 15 mg PO once daily. As per the manufacturer's current label, pioglitazone is currently not recommended in patients with ANY level of symptomatic heart failure. If used, dose titration should be slow, allowing more time than normal to achieve a target HgbA1c. Carefully monitor the patient for weight gain, edema, or signs and symptoms of congestive heart failure; if symptoms occur, manage medically, and consider whether to discontinue the drug or reduce the dosage. Contraindicated in patients with NYHA III or IV heart failure.

    In combination with insulin.
    Oral dosage
    Adults

    Initially, 15 mg or 30 mg PO once daily; the current insulin dose can be continued. Reduce insulin dose by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Individualize further adjustments based on patient response. NOTE: Monitor closely. In general, initiate at the lowest dose and increase gradually after several months of therapy. The risk of edema, weight gain, or congestive heart failure is increased when higher doses of pioglitazone are used in combination with insulin in patients at risk of heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.

    In combination with metformin.
    Oral dosage
    Adults

    Initially, 15 mg or 30 mg PO once daily; the current metformin dose can be continued. It is unlikely that metformin dosage adjustments will be required.

    In combination with sulfonylureas.
    Oral dosage
    Adults

    Initially, 15 mg or 30 mg PO once daily; the current sulfonylurea dose can be continued. Decrease sulfonylurea dose if the patient reports hypoglycemia.

    MAXIMUM DOSAGE

    Adults

    45 mg/day PO.

    Elderly

    45 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use caution. Specific guidelines for dosage adjustments in hepatic impairment are not available. Clinical trials with pioglitazone have generally excluded patients with serum ALT > 2.5 times the upper limit of normal (ULN).
    Mild impairment (ALT <=  2.5 times the ULN): Start and continue pioglitazone cautiously; periodically check LFTs.
    Moderate impairment (clinical or laboratory evidence of active liver disease, ALT > 2.5 times the ULN before pioglitazone initiation or repeatedly > 3 times the ULN during drug receipt): Do not start or continue pioglitazone.
    Severe impairment (e.g., jaundice): Discontinue pioglitazone.

    Renal Impairment

    No dosage adjustment is required when pioglitazone is used as monotherapy. Since metformin is contraindicated in patients with renal impairment, concomitant administration of pioglitazone and metformin is also contraindicated in patients with renal impairment.
     
    Intermittent hemodialysis
    Pioglitazone is highly protein bound and is unlikely to be significantly removed by hemodialysis.

    ADMINISTRATION

    Oral Administration

    Pioglitazone may be taken with or without food.

    STORAGE

    Actos:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pioglitazone is contraindicated in patients with a known hypersensitivity to this product or any of its components.

    Diabetic ketoacidosis

    Pioglitazone is only active in the presence of insulin. It should not be used to treat either diabetic ketoacidosis or type 1 diabetes.

    Hypoglycemia

    Combination therapy of pioglitazone with insulin or other oral hypoglycemic agents may increase the risk for hypoglycemia. A reduction in the dose of the concomitant agent may be necessary.

    Acute heart failure, cardiac disease, edema, heart failure, peripheral edema, pulmonary edema

    Pioglitazone should be used with caution in patients with cardiac disease. Thiazolidinediones (TZDs), including pioglitazone, when used alone or in combination with other antidiabetic agents, can cause or exacerbate congestive heart failure. Patients should be carefully observed for signs and symptoms of heart failure including excessive, rapid weight gain, dyspnea, and/or edema (peripheral edema, pulmonary edema) after drug initiation and changes in dose. If these signs and symptoms develop, the heart failure should be managed according to current standards of care, and clinicians must consider reducing the dose or discontinuing pioglitazone. Therapy should be discontinued if deterioration in cardiac status occurs. The incidence of heart failure associated with pioglitazone use is higher in those patients receiving concomitant insulin therapy, older adult patients (65 years of age and older), those receiving higher doses of pioglitazone, and those with risk factors for congestive heart failure. In addition, in postmarketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known cardiac disease. When compared with glyburide during a postmarketing safety study, pioglitazone was associated with a higher incidence of overnight hospitalization for congestive heart failure (9.9% for pioglitazone vs. 4.7% for glyburide). Dose-related edema and weight gain have been reported in patients treated with pioglitazone therapy; caution is advised in patients with preexisting edema. An association between pioglitazone and myocardial infarction has not been demonstrated. In a study of patients with type 2 diabetes, the addition of pioglitazone to existing diabetes therapy did not result in increased all-cause mortality or total macrovascular events such as non-fatal myocardial infarction, stroke, acute coronary syndrome, cardiac intervention, major leg amputation, or leg revascularization (HR 0.90, 95% CI 0.80 to 1.02, p = 0.1). Dose-related edema and weight-gain have been reported in patients treated with pioglitazone therapy.

    Hepatic disease

    Cautious use of pioglitazone is needed for patients with hepatic disease. In all patients, obtain a liver function test (LFT) panel and assess the patient before pioglitazone initiation. Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause LFT abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Clinical trials with pioglitazone have generally excluded patients with serum ALT more than 2.5 times the upper limit of normal (ULN). Initiate therapy with caution in patients with abnormal LFTs. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. If the patient is found to have abnormal LFTs (i.e., ALT more than 3 times the ULN), interrupt treatment with pioglitazone and investigate the probable cause. Pioglitazone should not be restarted in these patients without another explanation for the LFT abnormalities. Do not restart pioglitazone in patients who have serum ALT more than 3 times the ULN with serum total bilirubin more than 2 times the ULN and do not have alternative etiologies. Pioglitazone may be used with caution in patients with lesser elevations of serum ALT or bilirubin and who have an alternate probable cause. There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date.

    Bladder cancer, secondary malignancy

    Pioglitazone should not be used in patients with active bladder cancer. In patients with a prior history of bladder cancer, the benefits of blood sugar control should be weighed against the unknown risks for cancer recurrence. In December 2016, the FDA concluded that use of pioglitazone may be linked to an increased risk of bladder cancer; this was based on an extensive evidence review after previous warnings of possible bladder cancer with pioglitazone. Patients currently taking pioglitazone are encouraged to report any symptoms of bladder cancer to their health care provider. Symptoms of bladder cancer include blood or red-colored urine (hematuria), new or worsening urge to urinate, and pain when urinating. Both patients and health care providers should report pioglitazone related adverse events to the FDA's MedWatch Safety Information and Adverse Events Reporting Program. In September 2010 and June 2011, the FDA warned about the possible risk of secondary malignancy, specifically bladder cancer, with pioglitazone based on interim results from a 10-year U.S. epidemiologic study and a French epidemiological study. Based on the results of the French study, France has suspended the use of pioglitazone and Germany has recommended not to start pioglitazone in new patients. The FDA has reviewed additional published studies evaluating the risk of bladder cancer in patients treated with pioglitazone, including the final 10-year results of the U.S. epidemiologic study. The results did not show an increased risk for bladder cancer in patients who used pioglitazone at some point (ever users) compared to patients who never used pioglitazone (never users), with a fully adjusted HR of 1.06 (95% CI 0.89 to 1.26). The investigators identified 1,075 newly diagnosed cases of bladder cancer in never users (n = 158,918) and 186 cases in ever users (n = 34,181). The study also suggested a modest trend towards higher risk with increasing duration of use, but this trend was not statistically significant; it could have been due to chance. Compared to the interim 5-year results, these final 10-year results found weaker associations that were not statistically significant. However, the directions of the associations remained unchanged. During the 3 year PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events), 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than 1 year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases receiving pioglitazone and 2 (0.08%) cases receiving placebo. In a 10-year observational follow-up of the PROactive Study, researchers investigated the occurrence of cardiovascular outcomes and malignancies after the PROactive clinical trial period ended. Among patients who entered the follow-up study, the median total follow-up (clinical trial and observational periods) was 12.8 years. Results revealed the imbalance in the number of bladder cancer cases observed in patients using pioglitazone during the clinical trial period (RR 2.83; 95% CI 1.02 to 7.85) did not persist during the combined 12.8-year period (HR 1; 95% CI 0.59 to 1.72). In contrast, in a retrospective cohort study that assessed the association between pioglitazone use and bladder cancer, statistically significant trends in the risk of bladder cancer were observed with increasing cumulative duration of use and cumulative dose of pioglitazone. The investigators used the United Kingdom Clinical Practice Research Datalink (CPRD) to identify a cohort of 145,806 patients newly treated with antidiabetic drugs (n = 10,951 initiators of pioglitazone) with a mean follow-up of 4.7 years, during which 622 patients received a diagnosis of bladder cancer. Of these, 54 developed bladder cancer after pioglitazone exposure. The fully adjusted HR for bladder cancer with pioglitazone use compared with no thiazolidinedione use was 1.63 (95% CI 1.22 to 2.19).

    Bone fractures, osteoporosis

    Use pioglitazone with caution in female patients with osteoporosis or risk factors for osteopenia. In a randomized trial (PROactive) in patients with type 2 diabetes, an increased incidence of bone fractures was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% for pioglitazone versus 2.5% for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with pioglitazone (1.7%) vs. placebo (2.1%). The risk of fracture should be considered in the care of patients treated with pioglitazone, especially female patients, and attention given to assessing and maintaining bone health according to current standards of care.

    Geriatric

    Use pioglitazone with caution in the geriatric patient, especially those patients with pre-existing cardiac or kidney disease, due to a risk for heart failure. Treatment is not recommended in geriatric patients with symptomatic or acute heart failure, and initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. Observe geriatric patients receiving pioglitazone for signs and symptoms of heart failure, and if heart failure or other deterioration in cardiac status develops, discontinue the drug and monitor for diabetic control. The incidence of heart failure associated with pioglitazone use is higher in those patients receiving concomitant insulin therapy, older adult patients (65 years of age and older), those receiving higher doses of pioglitazone, and those with risk factors for congestive heart failure. In a nested case-control analysis of more than 150,000 geriatric adults with diabetes and receiving at least 1 oral hypoglycemic drug, the use of a thiazolidinedione (TZD) as monotherapy or in combination with other antidiabetic agents was associated with an increased rate of heart failure, myocardial infarction, and death; when analyzed separately, the authors found the risks for all 3 endpoints to be significantly increased for rosiglitazone and NOT pioglitazone, although there may have not been enough power to detect a difference in patients receiving pioglitazone. The median duration of follow-up was 3.8 years. Patients treated with TZD monotherapy were more likely to have a history of renal or cardiovascular disease at baseline. Similarly, in an observational study of 28,361 geriatric patients (65 years and older) with diabetes who initiated treatment with rosiglitazone or pioglitazone, the use of rosiglitazone was associated with a 15% greater mortality (95% CI 5% to 26%) and a 13% greater risk of congestive heart failure (95% CI 1% to 26%) compared with pioglitazone; there were no differences, however, in the rates of MI or stroke between the two drugs.] According to the Beers Criteria, pioglitazone is considered a potentially inappropriate medication (PIM) for use in geriatric patients with heart failure and should be avoided in this patient population due to the potential for fluid retention and exacerbation of the condition. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function. In addition, pioglitazone has been associated with edema and weight gain; therefore, use should be avoided in LTCF residents with NYHA Stage III or Stage IV heart failure.

    Contraception requirements, menstrual irregularity, polycystic ovary syndrome

    Premenopausal anovulatory females with insulin resistance, such as those with polycystic ovary syndrome (PCOS) may resume ovulation as a result of pioglitazone therapy. These patients may be at risk of becoming pregnant if adequate contraception is not used. Adequate contraception requirements in premenopausal women of childbearing potential have been suggested and should be recommended. If unexpected menstrual irregularity occurs, the benefits of continued therapy with pioglitazone should be reviewed.

    Pregnancy

    There are no adequate and well-controlled studies of pioglitazone use during human pregnancy; a drug-associated risk for major birth defects or miscarriage cannot be determined. Animal data suggest no teratogenic effects; however, embryotoxicities (increased post implantation losses, delayed development, reduced fetal weights, and delayed parturition) have been observed in rats receiving 10-times or above the maximum recommended human dose (MRHD) and rabbits receiving 40-times the MRHD of pioglitazone. Because animal reproductive studies are not always predictive of human response, this drug should only be used in pregnancy if clearly needed. The American College of Obstetrician and Gynecologists (ACOG) recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    Breast-feeding

    It is unknown whether pioglitazone is excreted in human milk. Pioglitazone is found in the milk of lactating rats; however, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for pioglitazone and any potential adverse effects on the nursing infant from pioglitazone or from the underlying maternal condition. If blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered; insulin is considered by experts to be compatible with breast-feeding. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.

    Children

    Safety and effectiveness of pioglitazone in adolescents and children have not been established. Pioglitazone is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.

    ADVERSE REACTIONS

    Severe

    heart failure / Delayed / 1.1-5.7
    bone fractures / Delayed / 5.1-5.1
    hepatic failure / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    macular edema / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    Moderate

    edema / Delayed / 1.6-26.7
    peripheral edema / Delayed / 1.6-26.7
    hypoglycemia / Early / 0-8.5
    hypertension / Early / 4.1-5.5
    chest pain (unspecified) / Early / 5.1-5.1
    anemia / Delayed / 0.3-1.6
    elevated hepatic enzymes / Delayed / 0.3-0.3
    fluid retention / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    osteopenia / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known

    Mild

    infection / Delayed / 4.9-14.9
    weight gain / Delayed / 2.7-13.9
    headache / Early / 3.1-9.1
    back pain / Delayed / 2.1-6.4
    sinusitis / Delayed / 4.6-6.3
    flatulence / Early / 2.7-6.3
    diarrhea / Early / 5.5-5.8
    myalgia / Early / 5.4-5.4
    dizziness / Early / 2.6-5.3
    pharyngitis / Delayed / 5.1-5.1
    menstrual irregularity / Delayed / 0-0.4
    anorexia / Delayed / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with pioglitazone, as coadministration may result in decreased dolutegravir plasma concentrations. Pioglitazone is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Abiraterone: (Moderate) Use abiraterone, a strong CYP2C8 inhibitor, and pioglitazone, a CYP2C8 substrate, together cautiously, as levels of pioglitazone may be increased. Monitor closely for signs of pioglitazone toxicity such as weight gain, edema, hypoglycemia, and signs of liver dysfunction. If a stong CYP2C8 inhibitor, such as abiraterone, is started or stopped during pioglitazone therapy, changes in diabetes treatment may be warranted based on clinical response.
    Acebutolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    Acetaminophen; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Acrivastine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased. (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Amlodipine; Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents. With certain agents, such as pioglitazone and rosiglitazone, inhibition of the CYP3A4 enzyme by clarithromycin may be involved.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents. With certain agents, such as pioglitazone and rosiglitazone, inhibition of the CYP3A4 enzyme by clarithromycin may be involved.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Amphetamines may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia, it appears that amphetamines can be used concurrently.
    Amprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Androgens: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Angiotensin II receptor antagonists: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if pioglitazone and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in pioglitazone-related adverse effects for several days after administration of a multi-day aprepitant regimen. Pioglitazone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of pioglitazone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, pioglitazone is a weak CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Aripiprazole: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted. Atypical antipsychotics have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. In addition, because aripiprazole is metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as pioglitazone may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in oral aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inducer.
    Articaine; Epinephrine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Asenapine: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when asenapine is instituted. Atypical antipsychotics have been associated with hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma in some instances. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Atazanavir; Cobicistat: (Major) Coadministration of cobicistat with pioglitazone is not recommended as there is a potential for elevated pioglitazone concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Atenolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Atenolol; Chlorthalidone: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Atorvastatin: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Atorvastatin; Ezetimibe: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) It is possible that a decrease in exposure of pioglitazone will occur when coadministered with drugs that induce CYP2C8 including phenobarbital. Patients receiving phenobarbital in combination with pioglitazone should be monitored for changes in glycemic control; dosage adjustments may be necessary.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with pioglitazone is necessary, due to the risk of decreased efficacy of axitinib. Axitinib is a CYP3A4 substrate and pioglitazone is a weak CYP3A4 inducer. Pioglitazone decreased the AUC and Cmax of midazolam, another CYP3A4 substrate, by 26%. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin interferes with glucose metabolism and can result in hyperglycemia; monitor patients on antidiabetic agents for loss of blood glucose control if niacin therapy is added.
    Azelastine; Fluticasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Azilsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Azilsartan; Chlorthalidone: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Baclofen: (Minor) Because baclofen can increase blood glucose, doses of antidiabetic agents may need adjustment in patients receiving these drugs concomitantly.
    Beclomethasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) It is possible that a decrease in exposure of pioglitazone will occur when coadministered with drugs that induce CYP2C8 including phenobarbital. Patients receiving phenobarbital in combination with pioglitazone should be monitored for changes in glycemic control; dosage adjustments may be necessary.
    Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Bendroflumethiazide; Nadolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Benzphetamine: (Moderate) Benzphetamine may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia, it appears that benzphetamine can be used concurrently.
    Beta-blockers: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Betamethasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Betaxolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Bexarotene: (Moderate) Systemic bexarotene may enhance the action of thiazolidinediones resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with these agents; monitor for hypoglycemia and the need for diabetic therapy adjustments.
    Bisoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering pioglitazone with boceprevir due to an increased potential for pioglitazone-related adverse events and the potential for boceprevir treatment failure. If pioglitazone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of pioglitazone and boceprevir. Pioglitazone is a substrate and inducer of the hepatic isoenzyme CYP3A4; boceprevir is a substrate and an inhibitor of this isoenzyme. When used in combination, the plasma concentrations of pioglitazone may increase and the plasma concentrations of boceprevir may decrease.
    Bortezomib: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Bosentan: (Major) Bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan can increase the hepatic clearance of pioglitazone, a CYP3A4 substrate.
    Brexpiprazole: (Moderate) Patients taking medications for diabetes should be closely monitored for worsening glycemic control when brexpiprazole therapy is instituted. Atypical antipsychotics have been associated with metabolic changes including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. In addition, brexpiprazole is a CYP3A4 substrate and pioglitazone and troglitazone (off-market) are CYP3A4 inducers. Theoretically, there might be a decrease in brexpiprazole concentrations. A dosage adjustment of brexpiprazole may be necessary if these thiazolidinediones are used.concomitantly. Monitor for signs and symptoms of decreased antipsychotic efficacy.
    Brimonidine; Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Brompheniramine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Budesonide: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Budesonide; Formoterol: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Bumetanide: (Minor) Bumetanide has been associated with hyperglycemia, possibly due to potassium depletion, and, glycosuria has been reported. Because of this, a potential pharmacodynamic interaction exists between bumetanide and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and pioglitazone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; pioglitazone induces CYP3A4.
    Candesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Captopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Carbinoxamine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Cariprazine: (Moderate) If cariprazine is used along with pioglitazone, montitor the patient for signs or symptoms of reduced antipsychotic efficacy and adjust therapy as clinically indicated. Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as pioglitazone, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Carteolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Carvedilol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Cetirizine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the thiazolidinediones, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorthalidone; Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Chromium: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Ciclesonide: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including the thiazolidinediones (e.g., rosiglitazone, pioglitazone), are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Clarithromycin: (Major) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents. With certain agents, such as pioglitazone and rosiglitazone, inhibition of the CYP3A4 enzyme by clarithromycin may be involved.
    Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Clopidogrel: (Major) Do not exceed 15 mg/day of pioglitazone if coadministered with clopidogrel. Coadministration may result in increased concentrations of pioglitazone. Pioglitazone is a CYP2C8 substrate and clopidogrel is a strong inhibitor of CYP2C8. When coadministered with gemfibrozil, another strong CYP2C8 inhibitor, the exposure to pioglitazone was increased by 226%.
    Clozapine: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when clozapine is instituted. Atypical antipsychotics have been associated with causing metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Cobicistat: (Major) Coadministration of cobicistat with pioglitazone is not recommended as there is a potential for elevated pioglitazone concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with pioglitazone is not recommended as there is a potential for elevated pioglitazone concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. (Major) Coadministration of elvitegravir with pioglitazone is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with pioglitazone is not recommended as there is a potential for elevated pioglitazone concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. (Major) Coadministration of elvitegravir with pioglitazone is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and pioglitazone is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and pioglitazone is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    Codeine; Phenylephrine; Promethazine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Minor) The phenothiazines such as promethazine may increase blood sugar. Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Codeine; Promethazine: (Minor) The phenothiazines such as promethazine may increase blood sugar. Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Conjugated Estrogens: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Corticosteroids: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Corticotropin, ACTH: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Cortisone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Cyclosporine: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Dabrafenib: (Major) The concomitant use of dabrafenib and pioglitazone may lead to decreased pioglitazone exposure and loss of efficacy. Use of an alternative agent is recommended. If concomitant use is unavoidable, monitor patients for loss of pioglitazone efficacy. A change in diabetes treatment may be needed based upon clinical response if dabrafenib is started or stopped during treatment with pioglitazone; do not exceed the maximum recommended dose of 45 mg/day. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Pioglitazone is a moderately sensitive CYP2C8 substrate. Administration of Rifampin 600 mg/day for 5 days with a single 30 mg dose of pioglitazone decreased the AUC of pioglitazone by 54% in a drug interaction study (n = 10).
    Danazol: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Dapsone: (Minor) The metabolism of dapsone may be accelerated when administered concurrently with pioglitazone, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with pioglitazone is not recommended as there is a potential for elevated pioglitazone concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of pioglitazone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated pioglitazone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, pioglitazone is metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Deflazacort: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Desloratadine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dexamethasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dextromethorphan; Promethazine: (Minor) The phenothiazines such as promethazine may increase blood sugar. Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Diazoxide: (Minor) Diazoxide inhibits the release of insulin from pancreatic islet cells. Because diazoxide increases blood glucose, a pharmacodynamic interaction exists between this drug and all other antidiabetic agents.
    Dienogest; Estradiol valerate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Diethylpropion: (Moderate) Diethylpropion exhibits intrinsic hypoglycemic activity and can lower postprandial blood glucose concentrations. Diethylpropion should be used cautiously in diabetic patients who are stabilized on antidiabetic agents.
    Diethylstilbestrol, DES: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Digoxin: (Moderate) Concentrations of digoxin may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of digoxin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with digoxin 0.2 mg twice daily (loading dose) then 0.25 mg daily (maintenance dose, 7 days) resulted in a 15% and 17% increase in digoxin AUC and Cmax, respectively. Carefully monitor serum digoxin concentrations; observe patients carefully for signs of digoxin toxicity.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving disopyramide concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Dobutamine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dolutegravir: (Major) Avoid concurrent use of dolutegravir with pioglitazone, as coadministration may result in decreased dolutegravir plasma concentrations. Pioglitazone is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Dopamine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dorzolamide; Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Doxorubicin: (Major) Pioglitazone is a mild CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of pioglitazone and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with pioglitazone is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; pioglitazone is a weak inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A. Pioglitazone induces and is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, such as pioglitazone, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy; the plasma concentrations of pioglitazone may also be increased.
    Drospirenone; Estradiol: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Drospirenone; Ethinyl Estradiol: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir; grazoprevir with pioglitazone. Pioglitazone is a mild CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together may decrease the plasma concentrations of both elbasvir and grazoprevir, and could result in decreased virologic response. Conversely, concentrations of pioglitazone (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Elvitegravir: (Major) Coadministration of elvitegravir with pioglitazone is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Pioglitazone is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
    Empagliflozin; Linagliptin: (Major) Inducers of CYP3A4 (e.g., pioglitazone) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering pioglitazone with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering pioglitazone with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Enalapril, Enalaprilat: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Felodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ephedrine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Epinephrine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Eprosartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with pioglitazone if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pioglitazone is a weak CYP3A4 inducer. The AUC and Cmax of another CYP3A4 substrate, midazolam, were each decreased by 26% when administered with pioglitazone. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with pioglitazone may also decrease erlotinib exposure.
    Erythromycin; Sulfisoxazole: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Esmolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Esterified Estrogens: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Esterified Estrogens; Methyltestosterone: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Estradiol: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Estradiol; Levonorgestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Estradiol; Norethindrone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Estradiol; Norgestimate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Estramustine: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Estrogens: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Estropipate: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethacrynic Acid: (Moderate) Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Ethanol: (Moderate) A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with thiazolidinediones in clinical studies. However, in general, excessive amounts of alcoholic beverages can increase the risk of low blood sugar in patients with diabetes, The calories in these beverages also need consideration, as increased blood sugar may occur due to the caloric intake.
    Ethinyl Estradiol: (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Desogestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Etonogestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Levonorgestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norelgestromin: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norethindrone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norgestimate: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethinyl Estradiol; Norgestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ethotoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Etonogestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide if used concomitantly with pioglitazone. Pioglitazone is a weak inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Fenofibrate: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments.
    Fenofibric Acid: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments.
    Fexofenadine: (Minor) Concentrations of fexofenadine may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of fexofenadine was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with fexofenadine 60 mg twice daily for 7 days resulted in a 30% and 37% increase in fexofenadine AUC and Cmax, respectively. Patients should be monitored for increased side effects from fexofenadine.
    Fexofenadine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted. (Minor) Concentrations of fexofenadine may be increased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of fexofenadine was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with fexofenadine 60 mg twice daily for 7 days resulted in a 30% and 37% increase in fexofenadine AUC and Cmax, respectively. Patients should be monitored for increased side effects from fexofenadine.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as pioglitazone, is not recommended.
    Fluconazole: (Moderate) Fluconazole is an inhibitor of CYP3A4 and CYP2C9. Because pioglitazone is a substrate of CYP3A4, concomitant use with fluconazole may increase plasma concentrations of pioglitazone. Patients should be monitored for changes in glycemic control if pioglitazone is coadministered with fluconazole.
    Fludrocortisone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Flunisolide: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluoxetine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when olanzapine is instituted. Atypical antipsychotics have been associated with causing metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Fluoxymesterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Fluticasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluticasone; Salmeterol: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluticasone; Vilanterol: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with pioglitazone. Pioglitazone is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with pioglitazone, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be increased. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol; Mometasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Fosinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosphenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Furosemide: (Minor) Furosemide may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between furosemide and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Garlic, Allium sativum: (Moderate) Selected constituents in Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring.
    Gefitinib: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with pioglitazone. Gefitinib is metabolized significantly by CYP3A4 and pioglitazone is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing pioglitazone, such as alogliptin; pioglitazone, glimepiride; pioglitazone; metformin; pioglitazone. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Gemfibrozil: (Major) Do not exceed 15 mg per day PO of pioglitazone if coadministered with gemfibrozil; monitor for changes in glycemic control. The exposure to pioglitazone is increased approximately 3-fold when combined with gemfibrozil. Gemfibrozil is a strong CYP2C8 inhibitor and pioglitazone is a CYP2C8 substrate. Fibric acid derivatives may also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Gemifloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Rare cases of severe hypoglycemia have been reported with concomitant use of quinolones and glyburide. Therefore, careful monitoring of blood glucose is recommended when gemifloxacin and antidiabetic agents are coadministered.
    Glucagon: (Minor) Glucagon increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with glucagon is instituted.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Guaifenesin; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Hydantoins: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Triamterene can interfere with the hypoglycemic effects of antidiabetic agents. This can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Hydrocortisone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including the thiazolidinediones, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent.
    Hydroxyprogesterone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Ibuprofen; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with pioglitazone, a CYP3A substrate, as pioglitazone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when iloperidone is instituted. Atypical antipsychotics have been associated with metabolic changes including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma in some instances. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, such as thiazolidinediones. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Insulins: (Major) The risk of heart failure and/or edema is increased when thiazolidinediones (including pioglitazone) are combined with insulins; monitor combined therapy closely for signs or symptoms of congestive heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently.
    Irbesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Irinotecan: (Major) Pioglitazone is a mild inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not aaffect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Isavuconazonium: (Major) Coadministration of isavuconazonium with pioglitazone is not recommended as there is a potential for elevated pioglitazone concentrations and decreased isavuconazonium concentrations. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Pioglitazone is a CYP3A4 substrate/inducer. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme.
    Isocarboxazid: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Isoniazid, INH: (Minor) Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic drugs should be closely monitored for loss of diabetic control when this drug is initiated.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Concomitant administration of rifampin with pioglitazone resulted in a decrease in the AUC of pioglitazone. Patients receiving rifampin with pioglitazone should be monitored for changes in glycemic control; dosage adjustments may be necessary. (Minor) Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic drugs should be closely monitored for loss of diabetic control when this drug is initiated.
    Isoniazid, INH; Rifampin: (Minor) Concomitant administration of rifampin with pioglitazone resulted in a decrease in the AUC of pioglitazone. Patients receiving rifampin with pioglitazone should be monitored for changes in glycemic control; dosage adjustments may be necessary. (Minor) Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic drugs should be closely monitored for loss of diabetic control when this drug is initiated.
    Isoproterenol: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Itraconazole: (Moderate) Itraconazole should be used cautiously with oral antidiabetic agents. The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
    Ivabradine: (Major) Avoid coadministration of ivabradine and pioglitazone. Ivabradine is primarily metabolized by CYP3A4; pioglitazone is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and pioglitazone concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is an inhibitor of CYP3A, and pioglitazone is partially metabolized by CYP3A. Co-administration may increase pioglitazone exposure leading to increased or prolonged therapeutic effects and adverse events. In addition, ivacaftor is a CYP3A substrate and pioglitazone is a mild CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Ketoconazole: (Moderate) Ketoconazole appears to significantly inhibit the metabolism of pioglitazone. It is recommended that patients receiving both pioglitazone and ketoconazole be evaluated more frequently with respect to glycemic control.
    Labetalol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Lanreotide: (Moderate) Monitor blood glucose levels if administration of lanreotide is necessary with antidiabetic agents; adjust the dosage of the antidiabetic agent as clinically appropriate. Lanreotide inhibits the secretion of insulin and glucagon.
    Leuprolide; Norethindrone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Levobetaxolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Levobunolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Levocarnitine: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Levofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including the thiazolidinediones, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Levonorgestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and pioglitazone may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; pioglitazone induces CYP3A4.
    Linagliptin: (Major) Inducers of CYP3A4 (e.g., pioglitazone) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Linagliptin; Metformin: (Major) Inducers of CYP3A4 (e.g., pioglitazone) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Linezolid: (Moderate) Hypoglycemia, including symptomatic episodes, has been noted in post-marketing reports with linezolid in patients with diabetes mellitus receiving therapy with antidiabetic agents, such as insulin and oral hypoglycemic agents. Diabetic patients should be monitored for potential hypoglycemic reactions while on linezolid. If hypoglycemia occurs, discontinue or decrease the dose of the antidiabetic agent or discontinue the linezolid therapy. Linezolid is a reversible, nonselective MAO inhibitor and other MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents.
    Lisdexamfetamine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Lisinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic agents. Monitor blood glucose concentrations closely if lithium is coadministered with antidiabetic agents. Dosage adjustments of antidiabetic agents may be necessary.
    Lomefloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are co-administered.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with pioglitazone. Loperamide is metabolized by the hepatic enzyme CYP3A4; pioglitazone is a mild inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with pioglitazone. Loperamide is metabolized by the hepatic enzyme CYP3A4; pioglitazone is a mild inducer of this enzyme.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Loratadine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Lorcaserin: (Moderate) In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with antidiabetic agents, such as insulin and/or insulin secretagogues (e.g., sulfonylureas). In clinical trials, lorcaserin use was associated with reports of hypoglycemia. Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during lorcaserin treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, lorcaserin has not been studied in combination with insulin.
    Losartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may decrease the therapeutic effects of pioglitazone by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a pioglitazone dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Pioglitazone is a substrate of CYP3A4 and CYP2C8. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce and/or inhibit CYP2C8. (Moderate) Use caution when administering ivacaftor and pioglitazone concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is an inhibitor of CYP3A, and pioglitazone is partially metabolized by CYP3A. Co-administration may increase pioglitazone exposure leading to increased or prolonged therapeutic effects and adverse events. In addition, ivacaftor is a CYP3A substrate and pioglitazone is a mild CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may decrease the therapeutic effects of pioglitazone by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a pioglitazone dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Pioglitazone is a substrate of CYP3A4 and CYP2C8. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce and/or inhibit CYP2C8.
    Lurasidone: (Moderate) Patients taking pioglitazone should be closely monitored for worsening glycemic control when treatment with lurasidone is instituted. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. In addition, lurasidone is a CYP3A4 substrate and pioglitazone is a CYP3A4 inducer, and theoretically these agents for diabetes might decrease the concentrations of lurasidone; an interaction has not been established. Monitor the patient clinically. A dosage adjustment of lurasidone may be necessary if pioglitazone is used concomitantly.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with pioglitazone is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and pioglitazone is a weak CYP3A4 inducer. Monitor for a decrease in efficacy with concomitant use.
    Mecasermin rinfabate: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Medroxyprogesterone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Megestrol: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Meperidine; Promethazine: (Minor) The phenothiazines such as promethazine may increase blood sugar. Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Mestranol; Norethindrone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (Moderate) Coadministration of pioglitazone with oral contraceptives can increase the elimination of estrogens. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Methamphetamine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Methazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methylprednisolone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metoclopramide: (Moderate) Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Metyrapone: (Moderate) In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
    Midazolam: (Minor) Administration of pioglitazone for 15 days followed by a single dose midazolam syrup, 7.5 mg PO, resulted in a 26% reduction in the midazolam AUC. Higher doses of midazolam may be necessary when coadministered with pioglitazone.
    Midodrine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Mitotane: (Moderate) Use caution if mitotane and pioglitazone are used concomitantly, and monitor for decreased efficacy of pioglitazone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and pioglitazone is a minor CYP3A4 substrate; coadministration may result in decreased plasma concentrations of pioglitazone.
    Moexipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Mometasone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Monoamine oxidase inhibitors: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Montelukast: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as montelukast.
    Moxifloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Monitor blood glucose when quinolones and antidiabetic agents are coadministered.
    Nadolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Nandrolone Decanoate: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Naproxen; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Nebivolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Nebivolol; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Nicotine: (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Nifedipine: (Minor) Concentrations of nifedipine may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of nifedipine ER was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with nifedipine ER 30 mg once daily for 4 days resulted in a 13% and 17% reduction in nifedipine ER AUC and Cmax, respectively. In addition, coadministration for 7 days resulted in a 5% and 4% increase in pioglitazone AUC and Cmax, respectively. Patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure; nifedipine dosages may need to be adjusted while the patient is receiving pioglitazone. Close monitoring of blood glucose is also recommended; dosage adjustments in pioglitazone may be needed.
    Nintedanib: (Major) Pioglitazone is a mild CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as pioglitazone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Norepinephrine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Norethindrone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Norfloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Monitor blood glucose when quinolones and antidiabetic agents are coadministered.
    Norgestrel: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Octreotide: (Moderate) Administration of octreotide to patients receiving oral antidiabetic agents or insulin can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added.
    Ofloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Olanzapine: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when olanzapine is instituted. Atypical antipsychotics have been associated with causing metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of pioglitazone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated pioglitazone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, pioglitazone is metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Oritavancin: (Moderate) Pioglitazone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of pioglitazone may be reduced if these drugs are administered concurrently.
    Orlistat: (Minor) Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in diabetic patients. Lower blood glucose may necessitate a dosage reduction of antidiabetic agents.
    Oxandrolone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Oxymetholone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Paliperidone: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when paliperidone is instituted. Paliperidone has been associated with metabolic changes including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma in some instances. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Pasireotide: (Major) Pasireotide may cause hyperglycemia. Closely monitor patients receiving antidiabetic therapy for changes in glycemic control; adjustments in the dosage of antidiabetic agents may be necessary during pasireotide receipt and after its discontinuation.
    Pazopanib: (Moderate) Pazopanib is a substrate for and a weak inhibitor of CYP3A4 and CYP2C8. Coadministration of pazopanib and pioglitazone, a CYP3A4 and CYP2C8 substrate, may cause an increase in systemic concentrations of pioglitazone. In addition, pioglitazone is a weak inhibitor of CYP3A4 and may cause an increase in systemic concentrations of pazopanib. Use caution when administering these drugs concomitantly.
    Pegvisomant: (Moderate) Patients who have both acromegaly and diabetes mellitus and are being treated with oral antidiabetic agents may require dose reductions of these medications after the initiation of pegvisomant. Growth hormone decreases insulin sensitivity by opposing the effects of insulin on carbohydrate metabolism; therefore, pegvisomant, which antagonizes growth hormone, is expected to have the opposite effect. Although none of the acromegalic patients with diabetes mellitus who were treated with pegvisomant during the clinical studies developed clinically relevant hypoglycemia, such patients should monitor their blood glucose regularly, with doses of anti-diabetic medications reduced as necessary.
    Penbutolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Pentamidine: (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.
    Pentoxifylline: (Moderate) Pentoxiphylline has been used concurrently with antidiabetic agents without observed problems, but it may enhance the hypoglycemic action of antidiabetic agents. Patients should be monitored for changes in glycemic control while receiving pentoxifylline in combination with antidiabetic agents.
    Perindopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perindopril; Amlodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as pioglitazone, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Phendimetrazine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenelzine: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Phenobarbital: (Minor) It is possible that a decrease in exposure of pioglitazone will occur when coadministered with drugs that induce CYP2C8 including phenobarbital. Patients receiving phenobarbital in combination with pioglitazone should be monitored for changes in glycemic control; dosage adjustments may be necessary.
    Phenothiazines: (Minor) The phenothiazines may increase blood sugar. Patients who are receiving antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Phentermine: (Moderate) Use caution in combining with phentermine with antidiabetic agents, as requirements for antidiabetic agents may be altered. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Additionally, diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently.
    Phentermine; Topiramate: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy. (Moderate) Use caution in combining with phentermine with antidiabetic agents, as requirements for antidiabetic agents may be altered. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Additionally, diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently.
    Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenylephrine; Promethazine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Minor) The phenothiazines such as promethazine may increase blood sugar. Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Phenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Pindolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Posaconazole: (Major) Posaconazole and pioglitazone should be coadministered with caution due to an increased potential for pioglitazone-related adverse events including ypoglycemia. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of pioglitazone. These drugs used in combination may result in elevated pioglitazone plasma concentrations, causing an increased risk for pioglitazone-related adverse events. Monitor patients carefully with respect to glycemic control if these drugs are administered together.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with pioglitazone, a weak CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Prednisolone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Prednisone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Pregabalin: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Prilocaine; Epinephrine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Progesterone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Progestins: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Promethazine: (Minor) The phenothiazines such as promethazine may increase blood sugar. Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when a phenothiazine is instituted.
    Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    Propranolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Pyrimethamine; Sulfadoxine: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Quetiapine: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when quetiapine is instituted. Atypical antipsychotics have been associated with causing hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Quinapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ramipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ranitidine: (Minor) Concentrations of pioglitazone may be decreased with concomitant use of ranitidine. The effect of capistration on the systemic exposure of pioglitazone was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with ranitidine 150 mg twice daily for 4 days resulted in a 13% and 16% reduction in pioglitazone AUC and Cmax, respectively. Close monitoring of blood glucose is recommended; dosage adjustments in pioglitazone may be needed.
    Rasagiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor rasagiline, are added to any regimen containing antidiabetic agents.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ribociclib: (Moderate) Coadminister ribociclib and pioglitazone with caution, as the systemic exposure of pioglitazone may be increased resulting in pioglitazone-related adverse reactions; adjust the dose of pioglitazone if necessary. Exposure to ribociclib may also decrease, resulting in reduced efficacy. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor in vitro; pioglitazone is a CYP3A4 substrate and inducer.
    Ribociclib; Letrozole: (Moderate) Coadminister ribociclib and pioglitazone with caution, as the systemic exposure of pioglitazone may be increased resulting in pioglitazone-related adverse reactions; adjust the dose of pioglitazone if necessary. Exposure to ribociclib may also decrease, resulting in reduced efficacy. Ribociclib is extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor in vitro; pioglitazone is a CYP3A4 substrate and inducer.
    Rifampin: (Minor) Concomitant administration of rifampin with pioglitazone resulted in a decrease in the AUC of pioglitazone. Patients receiving rifampin with pioglitazone should be monitored for changes in glycemic control; dosage adjustments may be necessary.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering pioglitazone with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Risperidone: (Moderate) Because risperidone has been associated with hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic states, diabetic coma, and overall worsening of glycemic control, patients taking antidiabetic agents such as thiazolidinediones should be closely monitored for worsening glycemic control when risperidone is instituted. Possible mechanisms for risperidone-related effects on glycemic control include insulin resistance or direct beta-cell inhibition.
    Ritodrine: (Moderate) Intravenous administration of ritodrine has been shown to elevate plasma insulin and glucose concentrations. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with ritodrine is instituted.
    Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and pioglitazone may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Pioglitazone is a mild inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like pioglitazone, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Sacubitril; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Salicylates: (Moderate) Salicylates can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar. In large doses, salicylates can cause hyperglycemia and glycosuria.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Selegiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Simeprevir: (Moderate) Use caution with concurrent use of simeprevir and pioglitazone. Pioglitazone is a weak CYP3A4 inducer in vitro, and the FDA labeling states that moderate or strong inducers may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of pioglitazone, which is a CYP3A4 substrate. Monitor patients for adverse effects of pioglitazone, such as hypoglycemia.
    Sofosbuvir; Velpatasvir: (Major) Use caution when administering velpatasvir with pioglitazone. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; pioglitazone is a weak inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Use caution when administering velpatasvir with pioglitazone. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; pioglitazone is a weak inducer of CYP3A4.
    Somatropin, rh-GH: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Sonidegib: (Moderate) Use caution with the concomitant use of sonidegib and pioglitazone; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and pioglitazone is a weak CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Sotalol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Sparfloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Sulfadiazine: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as trimethoprim. Monitor for changes in glycemic control if trimethoprim is coadministered with pioglitazone. (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Sulfasalazine: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Sulfisoxazole: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Sulfonamides: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Tacrolimus: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Tamoxifen: (Major) Pioglitazone is a mild CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Pioglitazone may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Tegaserod: (Moderate) Because tegaserod can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic drugs, such as pioglitazone.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering pioglitazone with telaprevir due to an increased potential for pioglitazone-related adverse events and the potential for telaprevir treatment failure. If pioglitazone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of pioglitazone and telaprevir. Pioglitazone is a substrate and inducer of the hepatic isoenzyme CYP3A4; telaprevir is a substrate and an inhibitor of this isoenzyme. When used in combination, the plasma concentrations of pioglitazone may increase and the plasma concentrations of telaprevir may decrease.
    Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and pioglitazone is necessary, as the systemic exposure of pioglitazone may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of pioglitazone; consider increasing the dose of pioglitazone if necessary. Pioglitazone is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with pioglitazone. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; pioglitazone induces this enzyme. Monitor patients for breakthrough fungal infections.
    Teriflunomide: (Moderate) Increased monitoring is recommended if teriflunomide is administered concurrently with CYP2C8 substrates, such as pioglitazone. In vivo studies demonstrated that teriflunomide is an inhibitor of CYP2C8. Coadministration may lead to increased exposure to CYP2C8 substrates; however, the clinical impact of this has not yet been determined. Monitor for increased adverse effects.
    Testolactone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Testosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Thiazide diuretics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Thyroid hormones: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
    Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Tobacco: (Minor) Tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Pioglitazone is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Topiramate: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Torsemide: (Minor) Hyperglycemia has been detected during torsemide therapy, but the incidence is low. Patients on antidiabetic medications should monitor their blood glucose regularly if torsemide is prescribed.
    Trandolapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Trandolapril; Verapamil: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Tranylcypromine: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Triamcinolone: (Moderate) Drugs which may cause hyperglycemia, including corticosteroids, may cause temporary loss of glycemic control. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Triamterene: (Minor) Triamterene can interfere with the hypoglycemic effects of antidiabetic agents. This can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Trimethoprim: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with other drugs that inhibit CYP2C8 such as trimethoprim. Monitor for changes in glycemic control if trimethoprim is coadministered with pioglitazone.
    Ulipristal: (Moderate) Ulipristal is a substrate of CYP3A4 and pioglitazone is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with pioglitazone is necessary, due to a possibly unpredictable effect on vandetanib efficacy and toxicity. Pioglitazone is a weak inducer of CYP3A4. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively.
    Vemurafenib: (Major) Concomitant use of vemurafenib and pioglitazone may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and pioglitazone; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and pioglitazone is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including pioglitazone. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including pioglitazone. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and pioglitazone. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with pioglitazone, a mild CYP3A inducer.
    Voriconazole: (Moderate) Because pioglitazone is metabolized by CYP3A4, exaggerated therapeutic effect or hypoglycemia is possible if pioglitazone is coadministered with voriconazole.
    Zafirlukast: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
    Ziprasidone: (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when ziprasidone is instituted. Atypical antipsychotics have been associated with metabolic changes including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. In addition, ziprasidone is a CYP3A4 substrate and pioglitazone and troglitazone (off-market) are CYP3A4 inducers. Theoretically, there might be a decrease in ziprasidone concentrations. A dosage adjustment ofziprasidone may be necessary if these thiazolidinediones are used concomitantly.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of pioglitazone use during human pregnancy; a drug-associated risk for major birth defects or miscarriage cannot be determined. Animal data suggest no teratogenic effects; however, embryotoxicities (increased post implantation losses, delayed development, reduced fetal weights, and delayed parturition) have been observed in rats receiving 10-times or above the maximum recommended human dose (MRHD) and rabbits receiving 40-times the MRHD of pioglitazone. Because animal reproductive studies are not always predictive of human response, this drug should only be used in pregnancy if clearly needed. The American College of Obstetrician and Gynecologists (ACOG) recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    It is unknown whether pioglitazone is excreted in human milk. Pioglitazone is found in the milk of lactating rats; however, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for pioglitazone and any potential adverse effects on the nursing infant from pioglitazone or from the underlying maternal condition. If blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered; insulin is considered by experts to be compatible with breast-feeding. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.

    MECHANISM OF ACTION

    Mechanism of Action: Pioglitazone is an oral thiazolidinedione used in the treatment of type 2 diabetes mellitus. Its primary action is enhancement of insulin sensitivity in adipose tissue, skeletal muscle, and the liver. Clinically, pioglitazone decreases plasma glucose concentrations, insulin concentrations, and glycosylated hemoglobin. Additional favorable metabolic effects include decreased hepatic glucose output, lower free fatty acid concentrations, and improved lipid profiles. In addition, preliminary evidence suggests that the thiazolidinediones may preserve beta cell function, a key component in the development of type 2 diabetes mellitus in patients with insulin resistance. Unlike oral sulfonylureas, pioglitazone does not stimulate insulin secretion. All oral agents used in the management of type 2 diabetes mellitus, including pioglitazone, are ineffective in patients with insulin deficiency (e.g., type 1 diabetes mellitus).The mechanisms of pioglitazone are complex and not fully understood. Pioglitazone is a highly selective and potent agonist for the peroxisome proliferator activated receptor (PPAR-gamma) that regulates the transcription of a number of insulin responsive genes. PPAR receptors can be found in key targets for insulin action including adipose tissue, skeletal muscle, and the liver. Pioglitazone is more potent than troglitazone with a 10 to 15 fold higher binding affinity for the PPAR-gamma receptor. Rosiglitazone is even more potent than pioglitazone with a 100 to 200 fold higher binding affinity for the PPAR-gamma receptor when compared to troglitazone. The clinical significance of this is unknown. Activation of the PPAR-gamma receptor enhances insulin sensitivity through several mechanisms. First, expression of the glucose transporter GLUT4 is increased in adipose tissue resulting in improved glucose utilization in skeletal muscle and the liver. Second, insulin sensitivity is enhanced by the lowering of plasma free fatty acid concentrations and shifting the storage of free fatty acids from non-adipose cells to adipocytes. Finally, the release of adipocytokines such as tumor necrosis factor alfa, resistin, and adiponectin is regulated to promote insulin sensitivity. Furthermore, thiazolidinedione-mediated receptor activation promotes adipogenesis and the differentiation of adipocytes causing a favorable redistribution of fat from visceral to subcutaneous stores. Subcutaneous adipocytes tend to be less lipolytic and more insulin sensitive. These effects contribute to the overall improved metabolic effects associated with thiazolidinedione use including insulin sensitivity peripherally.Pioglitazone decreases serum triglyceride concentrations and increases serum HDL cholesterol; increases and decreases in serum LDL cholesterol have been described. In two randomized clinical trials, the overall lipid profile of patients receiving pioglitazone improved. In the first study, which was 24 weeks in duration, patients receiving 45 mg of pioglitazone/day experienced a decrease in triglycerides of 12%, an increase in HDL cholesterol of 14.9%, an increase in LDL cholesterol of 15.7%, and an increase in total cholesterol of 5.7% (P<0.05 compared to baseline for all parameters). A second randomized clinical trial of 12 months in duration demonstrated significant improvements in all lipid parameters including a 22.4% reduction in triglycerides, a 15% increase in HDL cholesterol, a 12% decrease in LDL cholesterol, and a 11% decrease in total cholesterol (P<0.05 compared to baseline for all parameters). Furthermore, in one study, the LDL/HDL cholesterol ratio improved with pioglitazone therapy resulting in a lipid profile that was less atherogenic. In addition, the LDL cholesterol changed from small dense particles to larger and more buoyant ones. While the thiazolidinediones have been shown to have positive effects on myocardial function, blood pressure, endothelial function, fibrinolysis, microalbuminuria, and inflammation , meta-analyses of available clinical trials indicate that there may be an increased risk of myocardial infarction with another drug in this class, rosiglitazone. These effects have not been found in a clinical trial or a meta-analysis of patients taking pioglitazone. Investigations by the FDA are ongoing and will help to determine the role of thiazolidinediones in the treatment of diabetes mellitus.

    PHARMACOKINETICS

    Pioglitazone is administered orally. Steady-state serum concentrations are achieved within 7 days. Protein binding is extensive (> 99%), primarily to serum albumin. Binding also occurs to other serum proteins, but with lower affinity. Pioglitazone is extensively metabolized by hydroxylation and oxidation. The major hepatic cytochrome P450 enzymes involved are CYP2C8 and CYP3A4 with contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1 enzyme. In animal models of type 2 diabetes, metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active. Metabolites M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady state, serum concentrations of metabolites M-III and M-IV are equal to or greater than serum concentrations of pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30—50% of the total peak serum concentrations and 20—25% of the total AUC at steady state. Approximately 15—30% of the total dose is recovered in the urine. Renal elimination is negligible, and the drug is excreted primarily as metabolites and their conjugates. Most of an oral dose is presumed to be excreted into the bile either unchanged or as metabolites and eliminated in the feces. The mean serum half-lives of pioglitazone and its metabolites is 3—7 hours and 16—24 hours, respectively.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8
    Pioglitazone is a CYP3A4 substrate. It has been demonstrated to have weak CYP3A4 inducer activity in vitro and in vivo. Theoretical interactions may be clinically significant when administered with some CYP3A4 substrates. In addition, pioglitazone is a substrate of CYP2C8. Clinically significant interactions may occur when administered with drugs that inhibit or induce CYP2C8. If coadministered with a strong CYP2C8 inhibitor, the maximum recommended dose of pioglitazone is 15 mg daily.

    Oral Route

    Following oral administration, serum concentrations of pioglitazone are first measurable within 30 minutes. Peak serum concentrations occur within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Steady-state serum concentrations are achieved within 7 days.