Interactions of Thiazolidinediones

1
Drug Interactions of antidiabetics (part 6)

• Dr.P.Naina Mohamed
• Pharmacologist

2
ORAL Antidiabetic Drugs

• Insulin sensitizers
• Thiazolidinediones (TZDs)
• Rosiglitazone (Avandia)
• Pioglitazone (Actos)
• The thiazolidinediones (TZDs) or 'glitazones'
  improve metabolic control in patients with type 2
  diabetes through the improvement of insulin
  sensitivity.
• TZDs reduce insulin resistance in adipose tissue,
  muscle and the liver.

3
Thiazolidinediones AND Abiraterone

• Thiazolidinediones
• Abiraterone
• Abiraterone inhibits CYP2C8- and CYP2C9
• Blockade of metabolism of TZDs
• Increased plasma concentrations of TZDs
• If TZDs and abiraterone acetate are administered
  concurrently, patients should be monitored
  closely.
• Changes to diabetes therapy may be needed,
  especially when abiraterone acetate is started or
  stopped during treatment with TZDs.

4
Thiazolidinediones AND Pixantrone

• Thiazolidinediones
• Pixantrone
• Pixantrone inhibits CYP2C8
• Inhibition of metabolism of TZDs
• Enhanced plasma concentrations of TZDs
• If concomitant use is required, careful
  monitoring for side effects associated with
  increased concentrations of the TZDs is
  recommended.

5
Thiazolidinediones AND Azole Antifungals

• Thiazolidinediones
• Azole Antifungals (Fluconazole, Ketoconazole,
  Itraconazole, Miconazole)
• Inhibition of CYP enzymes (CYP2C9, CYP3A4,
  CYP2C8)
• Blockade of metabolism of Thiazolidinediones
• Accumulation of TZDs
• Increased glucose lowering effects
• Caution is advised if ketoconazole is used with
  pioglitazone.
• Monitor blood glucose concentrations if
  ketoconazole is added to or withdrawn from a
  treatment regimen that includes pioglitazone.
• Dose adjustments to pioglitazone may be
  necessary.

6
Thiazolidinediones AND Fibrates

• Thiazolidinediones
• Fibrates (Gemfibrozil, Fenofibrate)
• Fibrates inhibit CYP2C8
• Inhbition of metabolism of TZDs
• Elevated Plasma levels of TZDs
• Increased risk of hypoglycemia
• If used in combination with gemfibrozil, the
  maximum recommended dose of pioglitazone is 15
  mg/day.
• Blood glucose levels should be carefully
  monitored during coadministration.

7
Thiazolidinediones and Teriflunomide

• Thiazolidinediones
• Teriflunomide
• Teriflunomide inhibit CYP2C8
• Inhbition of metabolism of TZDs
• Elevated Plasma levels of TZDs
• Increased risk of hypoglycemia
• If concomitant use is required, monitoring is
  recommended.
• Pioglitazone dose adjustment may be necessary.

8
Thiazolidinediones and Dabrafenib

• Thiazolidinediones
• Dabrafenib
• Dabrafenib induces CYP3A4 and possibly CYP2C8,
  CYP2C9, CYP2C19, and CYP2B6
• Increased metabolism of TZDs
• If possible, substitute the use of TZDs (multiple
  enzyme substrates) during dabrafenib therapy.
• If concomitant use of dabrafenib and a TZD is
  required, monitor patients for loss of efficacy.

9
Thiazolidinediones and Rifampin

• Thiazolidinediones
• Rifampin
• Rifampin induces CYP2C8
• Induction of metabolism of TZDs
• Decreased Plasma levels of TZDs
• Increased risk of hyperglycemia
• Caution is advised if these 2 agents are
  coadministered.
• TZDs dosage should be adjusted based on clinical
  response.

10
Pioglitazone and CCBs

• Pioglitazone
• CCBs (Nifedipine , Amlodipine, Nimidipine)
• Pioglitazole induce CYP3A4-mediated nifedipine
  metabolism
• Decreased nifedipine exposure
• Coadministration of Pioglitazone and CCBs
  (Nifedipine , Amlodipine, Nimidipine) may
  significantly reduce the effectiveness of CCBs.
• Avoid concomitant use of CCBs and any known
  CYP3A4 inducer.
• Alternate antihypertensive treatment should be
  considered.

11
Pioglitazone and Cobicistat

• Pioglitazone
• Cobicistat
• Pioglitazole induce CYP3A4-mediated Cobicistat
  metabolism
• Decreased plasma concentrations of Cobicistat
• Loss of therapeutic efficacy of Cobicistat
• Development of viral resistance
• Caution is advised when using cobicistat together
  with a CYP3A inducer.
• If concomitant use is required, consider
  monitoring HIV virologic response.

12
Pioglitazone and Piperaquine

• Pioglitazone
• Piperaquine
• Pioglitazole induce CYP3A4-mediated Piperaquine
• metabolism
• Decreased plasma concentrations of Piperaquine
• Loss of therapeutic efficacy of Piperaquine
• The concomitant use of piperaquine (a CYP3A4
  substrate) with a CYP3A4 inducer may decrease
  piperaquine exposure and is not recommended.

13
Pioglitazone and Ifosfamide

• Pioglitazone
• Ifosfamide
• Pioglitazole induce CYP3A4-mediated Ifosfamide
• Metabolism
• Increased formation of active alkylating
  metabolites of Ifosfamide
• Increased risk of neurotoxic and nephrotoxic side
  effects of ifosfamide
• Patients taking ifosfamide and CYP3A4 inducers,
  such as pioglitazone, should be carefully
  monitored for toxicity.
• Ifosfamide dose adjustment may be required.

14
Pioglitazone and Tolvaptan

• Pioglitazone
• Tolvaptan
• Pioglitazone induce CYP3A-mediated tolvaptan
  metabolism
• Decreased tolvaptan plasma concentrations
• Concomitant use of pioglitazone and tolvaptan
  should be avoided due to a risk of reduced plasma
  concentrations of tolvaptan.
• If concomitant use is required, the dose of
  tolvaptan may need to be increased to achieve the
  same clinical effect.

15
Pioglitazone and Midazolam

• Pioglitazone
• Midazolam
• Pioglitazone induce CYP3A4-mediated metabolism of
  midazolam
• Decreased plasma concentrations of midazolam
• The concomitant administration of midazolam and
  pioglitazone should be approached with caution.
• Dosage adjustments of midazolam may be necessary
  when pioglitazone is added to or withdrawn from
  the therapy regimen.

16
Pioglitazone and Tipranavir/Ritonavir

• Pioglitazone
• Tipranavir/Ritonavir
• Inhibition of CYP3A enzymes by Tipranavir/Ritonavi
  r
• Altered pioglitazone plasma concentrations
• Coadministration of tipranavir/ritonavir and
  pioglitazone may result in altered (increased or
  decreased) pioglitazone levels.
• Monitor glucose levels when pioglitazone is
  administered concurrently with tipranavir/ritonavi
  r.

17
Pioglitazone and Macrolide antibiotics

• Pioglitazone
• Macrolide antibiotics (Clarithromycin)
• Clarithromycin inhibits CYP3A4
• Reduced metabolism of Pioglitazone
• Increased plasma concentrations of pioglitazone
• May cause hypoglycemia
• Caution is advised if clarithromycin and
  pioglitazone are coadministered.
• If concomitant use is necessary, advise the
  patient to carefully monitor blood glucose
  concentrations.

18
Pioglitazone and Sulphonamides

• Pioglitazone
• Sulphonamides (Trimethoprim, Sulphamethoxazole)
• Trimethoprim inhibits CYP2C8
• Reduced metabolism of pioglitazone
• Increased pioglitazone exposure
• Potentiation of hypoglycemic effects
• Use caution with the coadministration of
  pioglitazone and trimethoprim.
• If concomitant use is required, monitor blood
  glucose as clinically indicated.

19
Pioglitazone and Amiodarone

• Pioglitazone
• Amiodarone
• Amiodarone induces CYP3A4
• Increased metabolism of Pioglitazone
• Decreased plasma concentrations of pioglitazone
• Loss of efficacy
• Additional monitoring and amiodarone dose
  adjustment may be warranted.

20
Pioglitazone and Topiramate

• Pioglitazone
• Topiramate
• Decreased pioglitazone exposure
• Loss of Therapeutic efficacy
• If topiramate and pioglitazone are administered
  concurrently, routinely monitor patients for
  adequate control of their diabetes.

21
Pioglitazone and Oral Contraceptives

• Pioglitazone
• Oral Contraceptives
• Loss of contraceptive efficacy
• During administration of pioglitazone, the use of
  contraceptives containing ethinyl estradiol or
  norethindrone may not be effective.
• Additional caution regarding contraceptive use
  and alternative methods of contraception should
  be considered.

22
Pioglitazone and Atorvastatin

• Pioglitazone
• Atorvastatin
• Decreased pioglitazone serum concentrations
• Loss of therapeutic efficacy
• Caution is advised if atorvastatin is used with
  pioglitazone.
• Monitor blood glucose concentrations if
  atorvastatin is added to or withdrawn from a
  treatment regimen that includes pioglitazone.
• Dose adjustments to pioglitazone may be
  necessary.

23
Pioglitazone and Danazol

• Pioglitazone
• Danazol
• Danazol can cause insulin resistance
• Increased blood glucose levels
• Use caution with the concomitant use of danazol
  and antidiabetic medications, such as
  pioglitazone.
• Increased blood sugar monitoring and dose
  adjustments of antidiabetic medications may be
  warranted during coadministration and after
  discontinuation of danazol.

24
Pioglitazone and Trandolapril

• Pioglitazone
• Trandolapril
• Increased blood glucose lowering effect
• Elevated risk of hypoglycemia
• More frequent blood glucose monitoring and/or
  observation for signs or symptoms of hypoglycemia
  may be necessary.

25
Conclusion

• The diabetics should consult their physician and
  pharmacist.
• The diabetics should bring a list of all of the
  drugs they are taking (or simply bring the drugs
  themselves), including prescription drugs,
  over-the-counter drugs, and any supplements,
  herbal or otherwise, during their visit to the
  doctor or pharmacist.
• They are encouraged to ask their doctor or
  pharmacist to look over their list for any
  potentially dangerous combinations.
• It is recommended that people fill all their
  prescriptions at one pharmacy, if possible. In
  addition, they should maintain a list of all of
  their medicines and update it when one is added
  or removed.
• They should review their list with their doctor
  or pharmacist regularly, particularly when they
  begin to take a new medicine.

26
References

• Stockleys Drug Interactions, 9e
• Karen Baxter
• British National Formulary
• June 2013
• Basic Clinical Pharmacology, 12e Bertram
  G. Katzung, Susan B. Masters, Anthony J. Trevor
• Goodman Gilman's The Pharmacological Basis of
  Therapeutics, 12e Laurence L. Brunton, Bruce
  A. Chabner, Björn C. Knollmann

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References

• http//www.micromedexsolutions.com
• http//www.ncbi.nlm.nih.gov/pmc/articles/PMC301938
  7/
• http//spectrum.diabetesjournals.org/content/19/4/
  202.full.pdfhtml
• http//www.fda.gov/cder/consumerinfo/druginteracti
  ons.htm
• http//medicine.iupui.edu/clinpharm/ddis/
• http//www.australianprescriber.com/magazine/24/4/
  83/5