Ponstan 250mg Capsules

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4.5       Interaction with other medicinal products and other forms of interaction

Concurrent administration with other protein bound drugs may require adjustment in their dosage.

Anticoagulants:  NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4, Special warnings and precautions for use). Concurrent administration of mefenamic acid with oral anticoagulant drugs requires careful prothrombin time monitoring.

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Lithium: A reduction in renal lithium clearance and an elevation of plasma lithium levels. Patients should be observed carefully for signs of lithium toxicity.

The following interactions have been reported with NSAIDs but have not necessarily been associated with Ponstan:

Other analgesics:  Concomitant use of two or more NSAIDs (including aspirin) should be avoided (see section 4.3, Contraindications).

Antidepressants:  Selective serotonin re-uptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4, Special warnings and precautions for use).

Antihypertensives and diuretics: A reduction in antihypertensive and diuretic effect has been observed.  Diuretics can increase the risk of nephrotoxicity of NSAIDs.

ACE Inhibitors and angiotensin-II receptor antagonists: A reduction in antihypertensive effect and an increased risk of renal impairment especially in elderly patients. Patients should be adequately hydrated and the renal function assessed in the beginning and during concomitant therapy.

Aminoglycosides: Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Anti-platelet agents: Increased risk of gastrointestinal bleeding (see section 4.4,

Special warnings and precautions for use).

Cardiac glycosides:  NSAIDs may exacerbate cardiac failure and increase in plasma cardiac glycoside levels may occur when renal function is affected.

Ciclosporin:  The risk of nephrotoxicity of ciclosporin may be increased with NSAIDs.

Corticosteroids:  Increased risk of gastrointestinal ulceration or bleeding (see section 4.4, Special warnings and precautions for use).

Oral hypoglycaemic agents:  Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Mifepristone:  NSAIDs should not be taken for 8-12 days after mifepristone administration, NSAIDs can reduce the effects of mifepristone.

Methotrexate:  Elimination can be reduced resulting in increased plasma levels.

Probenecid:  Reduction in metabolism and elimination of NSAIDs and metabolites.

Quinolone antibiotics:  Animal data indicated that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics.  Patients taking NSAIDs and quinolone may have an increased risk of developing convulsions.

Tacrolimus:  Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemaophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

4.5       Interaction with other medicinal products and other forms of interaction

Concurrent administration with other protein bound drugs may require adjustment in their dosage.

Anticoagulants:  NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4, Special warnings and precautions for use). Concurrent administration of mefenamic acid with oral anticoagulant drugs requires careful prothrombin time monitoring.

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Lithium: A reduction in renal lithium clearance and an elevation of plasma lithium levels. Patients should be observed carefully for signs of lithium toxicity.

The following interactions have been reported with NSAIDs but have not necessarily been associated with Ponstan:

Other analgesics:  Concomitant use of two or more NSAIDs (including aspirin) should be avoided (see section 4.3, Contraindications).

Antidepressants:  Selective serotonin re-uptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4, Special warnings and precautions for use).

Antihypertensives and diuretics: A reduction in antihypertensive and diuretic effect has been observed.  Diuretics can increase the risk of nephrotoxicity of NSAIDs.

ACE Inhibitors and angiotensin-II receptor antagonists: A reduction in antihypertensive effect and an increased risk of renal impairment especially in elderly patients. Patients should be adequately hydrated and the renal function assessed in the beginning and during concomitant therapy.

Aminoglycosides: Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Anti-platelet agents: Increased risk of gastrointestinal bleeding (see section 4.4,

Special warnings and precautions for use).

Cardiac glycosides:  NSAIDs may exacerbate cardiac failure and increase in plasma cardiac glycoside levels may occur when renal function is affected.

Ciclosporin:  The risk of nephrotoxicity of ciclosporin may be increased with NSAIDs.

Corticosteroids:  Increased risk of gastrointestinal ulceration or bleeding (see section 4.4, Special warnings and precautions for use).

Oral hypoglycaemic agents:  Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Mifepristone:  NSAIDs should not be taken for 8-12 days after mifepristone administration, NSAIDs can reduce the effects of mifepristone.

Methotrexate:  Elimination can be reduced resulting in increased plasma levels.

Probenecid:  Reduction in metabolism and elimination of NSAIDs and metabolites.

Quinolone antibiotics:  Animal data indicated that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics.  Patients taking NSAIDs and quinolone may have an increased risk of developing convulsions.

Tacrolimus:  Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemaophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

In patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance (see section 5.2).

Section 5.2 Pharmacokinetics properties - amendment to

Absorption and distribution

Mefenamic acid is absorbed from the gastrointestinal tract.  Peak levels of 10 mg/l occur two hours after the administration of a 1g oral dose to adults.

Metabolism

Mefenamic acid is predominantly metabolised by cytochrome P450 enzyme CYP2C9 in the liver, first to a 3 hydroxymethyl derivative (metabolite I) and then a 3 carboxyl derivative (metabolite II).  Both metabolites undergo secondary conjugation to form glucuronides.

Therefore in patients who are known or suspected to be poor CYP2C9 metabolisers based

on previous history/experience with other CYP2C9 substrates, mefenamic acid should be

administered with caution as they may have abnormally high plasma levels due to

reduced metabolic clearance.

Elimination

Fifty two percent of a dose is recovered from the urine, 6% as mefenamic acid, 25% as metabolite I and 21% as metabolite II.  Assay stools over a 3 day period accounted for 10-20% of the dose chiefly as unconjugated metabolite II.

The plasma levels of unconjugated mefenamic acid decline with half life of approximately two hours.

In patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance (see section 5.2).

Section 5.2 Pharmacokinetics properties - amendment to

Absorption and distribution

Mefenamic acid is absorbed from the gastrointestinal tract.  Peak levels of 10 mg/l occur two hours after the administration of a 1g oral dose to adults.

Metabolism

Mefenamic acid is predominantly metabolised by cytochrome P450 enzyme CYP2C9 in the liver, first to a 3 hydroxymethyl derivative (metabolite I) and then a 3 carboxyl derivative (metabolite II).  Both metabolites undergo secondary conjugation to form glucuronides.

Therefore in patients who are known or suspected to be poor CYP2C9 metabolisers based

on previous history/experience with other CYP2C9 substrates, mefenamic acid should be

administered with caution as they may have abnormally high plasma levels due to

reduced metabolic clearance.

Elimination

Fifty two percent of a dose is recovered from the urine, 6% as mefenamic acid, 25% as metabolite I and 21% as metabolite II.  Assay stools over a 3 day period accounted for 10-20% of the dose chiefly as unconjugated metabolite II.

The plasma levels of unconjugated mefenamic acid decline with half life of approximately two hours.