No interactions between the two components of this fixed dose combinations have been observed in clinical studies.
Interactions linked to the combination: No drug interaction studies have been performed with TWYNSTA and other medicinal products.
Other antihypertensive agents: The blood pressure lowering effect of TWYNSTA can be increased by concomitant use of other antihypertensive medicinal products.
Agents with blood pressure lowering potential: Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including TWYNSTA, e.g. baclofen, amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics, or antidepressants.
Corticosteroids (systemic route): Reduction of the antihypertensive effect.
Interactions linked to telmisartan: Telmisartan may increase the hypotensive effect of other antihypertensive agents.
Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.
In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors.
Cases have also been reported with angiotensin II receptor antagonists including telmisartan. Therefore, serum lithium level monitoring is advisable during concomitant use.
Treatment with NSAIDs (i.e. ASA at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the Renin-Angiotensin-System like telmisartan may have synergistic effects. Patients receiving NSAIDs and telmisartan should be adequately hydrated and be monitored for renal function at the beginning of combined treatment.
A reduced effect of antihypertensive drugs like telmisartan by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications and Precautions).
Aliskiren: Do not co-administer aliskiren with TWYNSTA in patients with diabetes. Avoid use of aliskiren with TWYNSTA in patient with renal impairment (GFR < 60 ml/min).
Interactions linked to amlodipine: Grapefruit and grapefruit juice: Administration of TWYNSTA with grapefruit or grapefruit juice is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Simvastatin: Co-administration of multiple doses of 10mg of amlodipine with simvastatin 80 mg resulted in an increase in exposure to simvastatin up to 77% compared to simvastatin alone. Therefore, limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.
Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
Additional information: In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.