Trinomia 20 mg hard capsules

Section 4.4 - Information on Nervous system disorders and eye disorders added

Section 8 - Myasthenia gravis added

Section 10 - Date of revision updated

Section 2 - updated to include warnings on myasthenia

Section 4 - update to include Myasthenia gravis 

Section 6 - Date of revision updated

Section 4.4 - minor update by including the word excipients as a header before excipient warnings 

Section 4.8 - HPRA AE reporting details updated

Section 5.1 - Info regarding Peadiatric population moved to end of section 5.1

Section 6.1 - E numbers added

Section 10 - Revision date updated 

Section 4 - HPRA reporting details updated

Section 6 - headings updated and E numbers added

Section 6 - date of revision updated 

New interaction added for metamizole:

2.  What you need to know before you take Trinomia

Other medicines and Trinomia

Please tell your doctor if you are taking any of the following medicines that can make acetylsalicylic acid work less well:

• Metamizole: Metamizole (substance to decrease pain and fever) may reduce the effect of acetylsalicylic acid on platelet aggregation (blood cells sticking together and forming a blood clot), when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

New interaction added for metamizole:

4.5       Interaction with other medicinal products and other forms of interaction

Acetylsalicylic acid: pharmacodynamic & pharmacokinetic interactions:

- Effect of co-administered medicinal products on Acetylsalicylic acid

Metamizole: Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

Section 4 Side-effects is updated

The following sections are updated:

4.2       Posology and method of administration

New information added:

Co-administration with other medicines

In patients taking hepatitis C antiviral agents elbasvir/grazoprevir concomitantly with atorvastatin, the dose of atorvastatin should not exceed 20 mg/day (see sections 4.4 and 4.5).

4.3       Contraindications

New contra-indications:

- Patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir

- Concomitant use with sacubitril/valsartan therapy. Trinomia must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5).

4.4       Special warnings and precautions for use

Warning on ACE inhibitors and hyperkalaemia added (replacing previous warning on hyperkalaemia):

• Serum potassium: ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassiumsparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5). Other situations that may increase the risk of hyperkalaemia are: age >70 years, uncontrolled diabetes mellitus, dehydration, acute cardiac decompensation or metabolic acidosis.

Increased risk of rhabdomyolysis warning – updated:

Tipranavir/ritonavir and antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elvasvir/grazoprevir) added.

Angioedema - additional warnings added:

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of Trimomia. Treatment with Trinomia must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

4.5       Interaction with other medicinal products and other forms of interaction

Atorvastatin: pharmacodynamic & pharmacokinetic interactions

- Effect of co-administered medicinal products on atorvastatin

Updated information:

Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see section 5.2).

CYP3A4 inhibitors:

Some antivirals used in the treatment of HCV (e.g. elbasvir/grazoprevir)

Amended wording: In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 1).

Transport inhibitors

Amended wording: If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).

Table 1: Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin amended to add Glecaprevir / Pibrentasvir and Elbasvir / Grazoprevir.

Ramipril: pharmacodynamic & pharmacokinetic interactions

Interaction added:

- Medicines increasing the risk of angioedema: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4).

Precautions for use

Wording amended and/or added:

- Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes: Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with ramipril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when ramipril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of ramipril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

- Heparin: Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

- Medicines increasing the risk of angioedema: Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).

- Ciclosoporin: Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

4.8       Undesirable effects

Muscle rupture added (rare)

Lupus-like syndrome added (very rare)

5.2       Pharmacokinetic properties

Atorvastatin

Elimination – additional information added:

Atorvastatin is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin.

The SmPCs wording is updated to correct formatting errors and to align to the 40 mg strengths.

The main changes are as follows:

·         Section 4.4 Special warnings and precautions for use

o    Warning for specific side-effects

§  Liver effects: Information expanded on liver function testing with atorvastatin, liver injury or increased transaminase levels and to use with caution in alcohol or history of liver disease.

§  New information added on stroke prevention by aggressive reduction in cholesterol levels

§  “Before the treatment” section added regarding atorvastatin and including pre-disposing factors for rhabdomyolsis.  Monitor CK levels before and during statin treatment in the situations listed.

§  Concomitant treatments – information on the risk of rhabdomyolsis with use of atorvastatin and potent CYP3A4 inhibitors, transport proteins or HIV protease inhibitors expanded giving examples and further guidance.  Risk of myopathy information amended to say consider alternative treatments if possible.  Consider a lower starting or maximum dose for atorvastatin and appropriate clinical monitoring with potent CYP3A4 inhibitors and medicinal products that increase the plasma concentration of atorvastatin respectively. 

·         Section 4.5 Interactions

o    CYP3A4 inhibitors
New information to recommend a lower maximum dose of atorvastatin be considered with potent CYP3A4 inhibitors

o    Update to Table 1 on effect of co-administered products on pharmacokinetic effects of atorvastatin – clinical recommendations updated for lopinavir/ritonavir, clarithromycin, saquinavir/ritonavir, darunavir/ritonavir, itraconazole, fosamprenavir/ritonavir, fosamprenavir, erythromycin, gemfribrozil and fenofibrate.

·         Section 4.6 Fertility, pregnancy and lactation

o    Information on women of child bearing potential included as a separate heading.

o    Information on lactation updated and to contra-indicate use during breastfeeding.

o    Information on fertility updated to say in animal studies atorvastatin had no effect on male or female fertility.

·         Section 5.1 Pharmacodynamic properties

o    Section on Prevention of cardiovascular disease added including information from a randomized, double-blind, placebo-controlled study on the effect of atorvastatin on fatal and non-fatal coronary heart disease.

The changes are as follows:

·      Section 4.4 Special warnings and precautions for use

Warnings for specific side-effects

- Skeletal muscle effects

Trinomia must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Trinomia and fusidic acid should only be considered on a case by case basis and under close medical supervision.

- Interstitial lung disease:

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

·      Section 4.5 Interactions

Atorvastatin: pharmacodynamic & pharmacokinetic interactions

- Effect of co-administered medicinal products on atorvastatin