Telmipin

Telmisartan + Amlodipine (as besilate) 40 mg/5 mg tablet appears as white to off-white and light brown to beige oblong shaped two layer tablets, biconvex, plain on both sides.
Each tablet contains: Telmisartan, USP 40 mg, Amlodipine (as besilate) 5 mg.

Pharmacotherapeutic group: Angiotensin II antagonists, plain (telmisartan), combinations with dihydropyridine derivatives (amlodipine).
Pharmacology: Mode of action: Telmisartan + Amlodipine besilate combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridinic calcium channel blocker, amlodipine.
The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Telmisartan + Amlodipine besilate once daily produces effective and consistent reductions in blood pressure across the 24-hour therapeutic dose range.
Telmisartan: Telmisartan is an orally effective and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor.
Telmisartan selectively binds the AT1 receptor. The binding is long lasting. Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan.
Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.
In man, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
Amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, leading to reductions in peripheral vascular resistance and in blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
Pharmacodynamics: Telmisartan: After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy. The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 mg and 80 mg of telmisartan in placebo controlled clinical studies.
There is an apparent trend to a dose relationship to a time to recovery of baseline SBP. In this respect data concerning DBP are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agents representative of other classes of antihypertensive drugs (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, lisinopril, ramipril and valsartan). Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension. Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy. Telmisartan treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
Amlodipine: In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.
Pharmacokinetics: Pharmacokinetics of the Fixed Dose Combination: The rate and extent of absorption of Telmisartan + Amlodipine besilate are equivalent to the bioavailability of telmisartan and amlodipine when administered as individual tablets.
Pharmacokinetic of the single components: Absorption: Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%.
When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food.
The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.
After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (Vss) is approximately 500 L.
The volume of distribution of amlodipine is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Amlodipine is extensively (approximately 90%) metabolised by the liver to inactive metabolites.
Elimination: Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (C_max) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan. After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the faeces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose. Total plasma clearance (CL_tot) is high (approximately 900 mL/min compared with hepatic blood flow (about 1500 mL/min). Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten percent (10%) of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Paediatric population (age below 18 years): No pharmacokinetic data for Telmisartan + Amlodipine besilate are available in the paediatric population.
Gender effects: Gender differences in plasma concentrations of telmisartan were observed, C_max and AUC being approximately 3 and 2-fold higher, respectively, in females compared to males without relevant influence on efficacy.
Elderly Patients: The pharmacokinetics of telmisartan do not differ between younger and elderly patients. Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life.
Renal impairment: Lower plasma concentrations of telmisartan were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability of telmisartan up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of approximately 40-60% in AUC.
Toxicology: Since the non-clinical toxicity profiles of telmisartan and amlodipine besilate are not overlapping, no exacerbation of toxicity was expected for the combination.
This has been shown in a subchronic (13-week) toxicology study in rats, in which dose levels of 3.2/0.8, 10/2.5 and 40/10 mg/kg of telmisartan and amlodipine besilate were tested. In this study no additive or greater than additive adverse effects of amlodipine and telmisartan in combination as well as no change of the toxicity with regard to target organs were observed.
With respect to Telmisartan + Amlodipine besilate separate reproduction toxicity studies assessing the potential effects of telmisartan and amlodipine on male and female fertility when both compounds are given in combination, have not been conducted.
Telmisartan: In non-clinical safety studies doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit) and changes in renal haemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically mediated side effects, known from non-clinical studies with both angiotensin converting enzyme inhibitors and angiotensin II antagonists, were prevented by oral saline supplementation.
In both species increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of ACE-inhibitors and other angiotensin II antagonists, do not appear to have clinical significance.
No clear evidence of a teratogenic effect was observed; at toxic doses levels, however, non-clinical studies indicated some hazardous potential of telmisartan to fetal development (increased number of late resorptions in rabbits) and to the postnatal development of the offspring: lower body weight, delayed eye opening, and higher mortality.
No effects of telmisartan on male and female fertility were observed.
There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.
Amlodipine: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In reproductive toxicity studies in rats, delayed parturition, difficult labour and impaired fetal and pup survival were seen at high doses. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).
No effects of amlodipine on male and female fertility were observed.

Treatment of essential hypertension.
Replacement Therapy: Patients receiving telmisartan and amlodipine besilate from separate tablets may instead receive Telmisartan + Amlodipine containing the same component doses.
Add on Therapy: Telmisartan + Amlodipine besilate is indicated in patients whose blood pressure is not adequately controlled on telmisartan or amlodipine monotherapy.
Initial therapy: Telmisartan + Amlodipine besilate may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of Telmisartan + Amlodipine besilate as initial therapy for hypertension should be based on an assessment of potential benefits and risks.

Adults: Telmisartan + Amlodipine besilate should be taken once daily.
Replacement therapy: Patients receiving telmisartan and amlodipine besilate from separate tablets can instead receive Telmisartan + Amlodipine besilate containing the same component doses in one tablet once daily, e.g. to enhance convenience or compliance.
Add on therapy: Telmisartan + Amlodipine besilate may be administered in patients whose blood pressure is not adequately controlled with amlodipine or telmisartan alone.
Patients treated with 10 mg amlodipine who experience any dose limiting adverse reactions such as oedema, may be switched to Telmisartan + Amlodipine besilate 40 mg/5 mg once daily, reducing the dose of amlodipine without reducing the overall expected antihypertensive response.
Initial therapy: A patient may be initiated on Telmisartan + Amlodipine besilate if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose of Telmisartan + Amlodipine besilate is 40 mg/5 mg once daily. Patients requiring larger blood pressure reductions may be started on Telmisartan + Amlodipine besilate 80 mg/5 mg once daily.
If additional blood pressure lowering is needed after at least 2 weeks of therapy, the dose may be titrated up to a maximum of 80 mg/10 mg once daily.
Telmisartan + Amlodipine besilate can be administered with other antihypertensive drugs.
Special population: Renal impairment: No posology adjustment is required for patients with renal impairment, including those on haemodialysis. Amlodipine and telmisartan are not dialyzable.
Hepatic impairment: In patients with mild to moderate hepatic impairment Telmisartan + Amlodipine besilate should be administered with caution. For telmisartan the posology should not exceed 40 mg once daily.
Elderly patients: No dose adjustment is necessary for elderly patients. Normal amlodipine dosage regimens are recommended in the elderly, but increase of dosage should take place with care.
Pediatric population: Telmisartan + Amlodipine besilate is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.
Method of Administration: Tablet for oral administration: Telmisartan + Amlodipine besilate may be taken with or without food.

Symptoms: There is no experience of overdose with Telmisartan + Amlodipine besilate. Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects. The most prominent manifestations of telmisartan overdosage were hypotension, tachycardia; bradycardia might also occur. Overdose with amlodipine may result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome may occur.
Therapy: Supportive treatment should be instituted. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and amlodipine besilate are not removed by haemodialysis.

Hypersensitivity to the active substances, or to any of the excipients.
Hypersensitivity to dihydropyridine derivatives.
Second and third trimesters of pregnancy.
Lactation.
Biliary obstructive disorders.
Severe hepatic impairment.
Cardiogenic shock.
The concomitant use of Telmisartan + Amlodipine besilate with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).
In case of rare hereditary conditions that may be incompatible with an excipient of the product (refer to Precautions) the use of the product is contraindicated.

Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Intravascular hypovolaemia: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Telmisartan + Amlodipine besilate.
Dual blockade of the renin-angiotensin-aldosterone system: As a consequence of inhibiting the renin-angiotensin-aldosterone system changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Telmisartan + Amlodipine besilate can be administered with other antihypertensive drugs, however dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE Inhibitor or the direct renin-inhibitor aliskiren to an angiotensin II receptor antagonists) is not recommended and should therefore be limited to individually defined cases with close monitoring or renal function.
Other conditions with stimulation of the renin-angiotensin-aldosterone system: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.
Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Unstable angina pectoris, acute myocardial infarction: There are no data to support the use of Telmisartan + Amlodipine besilate in unstable angina pectoris and during or within one month of a myocardial infarction.
Patients with cardiac failure: In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Hyperkalaemia: During treatment with medicinal products that affect the renin-angiotensin-aldosterone system hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended.
Based on experience with the use of medicinal products that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with telmisartan.
Diabetes mellitus: In diabetic patients with an additional cardiovascular risk, i.e. patients with diabetes mellitus and coexistent coronary artery disease (CAD), the risk of fatal myocardial infarction and unexpected cardiovascular death may be increased when treated with blood pressure lowering agents such as ARBs or ACE-inhibitors. In patients with diabetes mellitus CAD may be asymptomatic and therefore undiagnosed. Patients with diabetes mellitus should undergo appropriate diagnostic evaluation, e.g. exercise stress testing, to detect and to treat CAD accordingly before initiating treatment with Telmisartan + Amlodipine besilate.
Other: Telmisartan + Amlodipine besilate was effective when treating black patients (usually a low-renin population). As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Driving and using machines: No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as syncope, somnolence, dizziness, or vertigo during treatment. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience these adverse experiences, they should avoid potentially hazardous tasks such as driving or operating machinery.
Hepatic impairment: Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Furthermore, as with all calcium antagonists, amlodipine half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Telmisartan + Amlodipine besilate should therefore be used with caution in these patients.
Renal impairment and kidney transplant: When Telmisartan + Amlodipine besilate is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Telmisartan + Amlodipine besilate in patients with a recent kidney transplant. Telmisartan and amlodipine besilate are not dialyzable.
Use in Pregnancy: Angiotensin II receptor antagonists should not be initiated during pregnancy.
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and if appropriate, alternative therapy should be started.

Telmisartan: The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy and should not be initiated during pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy. Non-clinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity. Angiotensin II receptor antagonists exposure during the second and third trimester is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension.
Amlodipine: Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.
Lactation: It is not known whether telmisartan is excreted in human milk. Non-clinical studies have shown excretion of telmisartan in breast milk. Amlodipine has been identified in breastfed infants of treated women. The effect of amlodipine on infants is unknown. Because of the potential adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of this therapy for the mother.
Fertility: No data from controlled clinical studies with the Fixed Dose Combination or with the individual components are available. Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not been conducted. In non-clinical studies, no effects of telmisartan on male and female fertility were observed. Similarly, no effects on male and female fertility were reported for amlodipine.

Fixed Dose Combination: The safety and tolerability of Telmisartan + Amlodipine besilate has been evaluated in five controlled clinical studies with over 3500 patients, over 2500 of whom received telmisartan in combination with amlodipine.
Adverse reactions reported in clinical trials with telmisartan + amlodipine are shown as follows according to system organ class.
Infections and infestations: Cystitis.
Psychiatric disorders: Depression, anxiety, insomnia.
Nervous system disorders: Dizziness, somnolence, migraine, headache, paraesthesia, syncope, peripheral neuropathy, hypoaesthesia, dysgeusia, tremor.
Ear and labyrinth disorders: Vertigo.
Cardiac disorders: Bradycardia, palpitations.
Vascular disorders: Hypotension, orthostatic hypotension, flushing.
Respiratory, thoracic and mediastinal disorders: Cough.
Gastrointestinal disorders: Abdominal pain, diarrhoea, nausea, vomiting, gingival hypertrophy, dyspepsia, dry mouth.
Skin and subcutaneous tissue disorders: Pruritus, eczema, erythema, rash.
Musculoskeletal and connective tissue disorders: Arthralgia, muscle spasms (cramps in legs), myalgia, back pain, pain in extremity (leg pain).
Renal and urinary disorders: Nocturia.
Reproductive system and breast disorders: Erectile dysfunction.
General disorders: Peripheral oedema, asthenia (weakness), chest pain, fatigue, oedema, malaise.
Investigations: Hepatic enzymes increased, blood uric acid increased.
Additional information on the combination: Peripheral oedema, a recognised dose dependent side effect of amlodipine, was generally observed at a lower incidence in patients who received the telmisartan + amlodipine combination than in those who received amlodipine alone.
Additional information on individual components: Side effects previously reported with one of the individual components (amlodipine or telmisartan) may be potential side effects with Telmisartan + Amlodipine besilate as well, even if not observed in clinical trials or during the post-marketing period.
Telmisartan: Infections and infestations: Urinary tract infections, upper respiratory tract infections, sepsis including fatal outcome.
Blood and lymphatic system disorders: Anaemia, eosinophilia, thrombocytopenia.
Immune system disorders: Anaphylactic reaction, hypersensitivity.
Metabolism and nutrition disorders: Hyperkalaemia, hypoglycaemia (in diabetic patients).
Eye disorders: Visual disturbance.
Cardiac disorders: Tachycardia.
Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Gastrointestinal disorders: Flatulence, stomach discomfort.
Hepatobiliary disorders: Hepatic function abnormal/liver disorder*.
*Most cases of hepatic function abnormal/liver disorder from post-marketing experience with telmisartan occurred in patients in Japan, who are most likely to experience these adverse reactions.
Skin and subcutaneous tissue disorders: Angioedema (with fatal outcome), hyperhidrosis, urticaria, drug eruption, toxic skin eruption.
Musculoskeletal and connective tissue disorders: Tendon pain (tendinitis like symptoms).
Renal and urinary disorders: Renal impairment including acute renal failure (see also Precautions).
General disorders: Influenza-like illness.
Investigations: Blood creatinine increased, haemoglobin decreased, blood creatine phosphokinase (CPK) increased.
Amlodipine: Blood and lymphatic system disorders: Leucopenia, thrombocytopenia.
Immune system disorders: Hypersensitivity.
Metabolism and nutrition disorders: Hyperglycaemia.
Psychiatric disorders: Mood change, confusional state.
Nervous system disorders: Extrapyramidal disorder.
Eye disorders: Visual impairment.
Ear and labyrinth disorders: Tinnitus.
Cardiac disorders: Myocardial infarction, arrhythmia, ventricular tachycardia, atrial fibrillation.
Vascular disorders: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, rhinitis.
Gastrointestinal disorders: Change of bowel habit, pancreatitis, gastritis.
Hepatobiliary disorders: Hepatitis, jaundice, hepatic enzyme elevations (mostly consistent with cholestasis).
Skin and subcutaneous tissue disorders: Hyperhidrosis, angioedema, urticaria, alopecia, purpura, skin discolouration, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity reaction.
Renal and urinary disorders: Micturition disorder, pollakiuria.
Reproductive system and breast disorders: Gynaecomastia.
General disorders: Pain, weight increased, weight decreased.

No interactions between the two components of this fixed dose combinations have been observed in clinical studies.
Interactions common to the combination: No drugs interaction studies have been performed with Telmisartan + Amlodipine besilate and other medicinal products.
Concomitant use to be taken into account: Other antihypertensive agents: The blood pressure lowering effect of Telmisartan + Amlodipine besilate 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 Telmisartan + Amlodipine besilate, 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 AUC_0-24 and C_max 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.
Interaction linked to amlodipine: Concomitant use requiring caution: Grapefruit and grapefruit juice: Administration of Telmisartan + Amlodipine besilate with grapefruit is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.
CYP3A4 inhibitors: A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is increased).
The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded.
CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone], rifampicin, Hypericum perforatum): Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and after its withdrawal.
Concomitant use to be taken into account: Simvastatin: Co-administration of multiple doses 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.
Immunosuppressants: Amlodipine may increase the systemic exposure of ciclosporin or tacrolimus when co-administered. Frequent monitoring of trough blood levels of ciclosporin and tacrolimus and dose adjustment when appropriate is recommended.
Others: In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long acting nitrates, sublingual nitroglycerin, non-steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Additional information: Concomitant administration of 240 mL of grapefruit juice with a single oral dose of 10 mg amlodipine in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of amlodipine.
Co-administration of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine. Co-administration of amlodipine with atorvastatin, digoxin or warfarin had no significant effect on the pharmacokinetics or pharmacodynamics of these agents.

Store at temperatures not exceeding 30°C. Protect from moisture.

Angiotensin II Antagonists / Calcium Antagonists

C09DB04 - telmisartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.

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