Telpres

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TELPRES

Composition:

Active substance: telmisartan;

1 tablet contains telmisartan 20 mg, or 40 mg, or 80 mg;

Excipients: sodium hydroxide, povidone, meglumine, mannitol (E 421), crospovidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

20 mg tablets: white to almost white round tablets with a score line and engraved «LC» on one side of the tablet;

40 mg tablets: white, capsule-shaped, biconvex tablets with engraved «LC» on one side;

80 mg tablets: white, capsule-shaped, biconvex tablets with engraved «LC» on one side.

Pharmacotherapeutic group.

Simple angiotensin II antagonist preparations. ATC code C09CA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Telmisartan is an orally active, specific antagonist of angiotensin II receptors (type AT1). Telmisartan very highly displaces angiotensin II from its binding sites on AT1 subtype receptors, which mediate the actions of angiotensin II. Telmisartan has no partial agonistic effect on the AT1 receptor. Telmisartan selectively binds to AT1 receptors. The binding is long-lasting. Telmisartan shows no affinity for other receptors, including AT2 and other less-characterized AT receptors. The functional role of these receptors is unknown, as is the effect of their possible "overstimulation" by angiotensin II, whose levels increase under the influence of telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not inhibit plasma renin activity and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (ACE) (kininase II), the enzyme that also degrades bradykinin. Therefore, an increase in bradykinin-related adverse reactions is not expected.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the increase in blood pressure induced by angiotensin II. The blocking effect persists for 24 hours and remains evident up to 48 hours.

Pharmacokinetics.

Absorption. Absorption of telmisartan is rapid, but the amount absorbed varies. The mean absolute bioavailability of telmisartan is approximately 50%. When telmisartan is taken with food, the reduction in the area under the concentration-time curve (AUC0–∞) for telmisartan ranges from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). Three hours after administration, plasma concentrations are similar regardless of whether the patient takes telmisartan fasting or with food.

Linearity/non-linearity. The slight reduction in AUC is not expected to result in a decrease in therapeutic efficacy. There is no linear relationship between dose and plasma concentration. Cmax and AUC increase disproportionately with dose when it exceeds 40 mg.

Distribution. Telmisartan is highly bound to plasma proteins (>99.5%), primarily to albumin and alpha-1 acid glycoprotein. The mean apparent volume of distribution at steady state (Vdss) is approximately 500 L.

Metabolism. Telmisartan is metabolized primarily by conjugation of the parent substance with glucuronic acid. The pharmacological activity of the conjugate has not been established.

Elimination. Telmisartan exhibits a biexponential pharmacokinetic profile with a terminal elimination half-life of >20 hours. Cmax and AUC increase disproportionately with dose. There are no data indicating clinically relevant accumulation of telmisartan with recommended doses. Plasma concentrations were higher in women than in men, without a corresponding impact on efficacy.

After oral administration, telmisartan is almost entirely excreted in feces, mainly in unchanged form. Cumulative renal excretion accounts for <1% of the dose. Total plasma clearance (Cltot) is high (approximately 1000 mL/min), compared to hepatic blood flow (approximately 1500 mL/min).

Special patient populations

Children. The pharmacokinetics of two doses of telmisartan were evaluated as a secondary objective in hypertensive patients (n = 57) aged 6 to <18 years after administration of telmisartan at 1 mg/kg or 2 mg/kg for 4 weeks of treatment. Pharmacokinetic objectives included determination of steady-state telmisartan levels in children and adolescents and investigation of age-related differences. Although the study was too small to reliably assess pharmacokinetics in children under 12 years of age, overall results are consistent with data obtained in adults and confirm the non-linearity of telmisartan, particularly for Cmax.

Gender. Differences in plasma concentrations were observed; Cmax and AUC were approximately 3 and 2 times higher, respectively, in women than in men.

Elderly patients. The pharmacokinetics of telmisartan are comparable in patients under 65 years of age and in elderly patients.

Patients with renal impairment. In patients with mild, moderate, and severe renal impairment, plasma concentrations were doubled. However, in patients with renal failure undergoing dialysis, plasma concentrations were low. Telmisartan has high plasma protein binding in patients with renal failure and cannot be removed by dialysis. The elimination half-life is not altered in patients with renal impairment.

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability to approximately 100%. The elimination half-life is not altered in patients with hepatic impairment.

Clinical characteristics.

Indications.

Hypertension.

Treatment of essential hypertension in adults.

Cardiovascular disease prophylaxis in patients with:

• established atherothrombotic cardiovascular disease (ischemic heart disease, stroke, or peripheral arterial disease in medical history);
• type 2 diabetes mellitus with diagnosed target organ damage.

Contraindications.

• Hypersensitivity to the active substance or to any excipient of the medicinal product (see section "Composition");
• pregnancy or planned pregnancy (see sections "Special precautions", "Use during pregnancy or breastfeeding");
• biliary obstruction;
• severe hepatic impairment;
• pediatric use (under 18 years of age).

Concomitant use of telmisartan and aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

Interaction with other medicinal products and other forms of interaction.

Digoxin

Concomitant use of telmisartan and digoxin resulted in average increases in digoxin plasma peak concentration (by 49%) and trough concentration (by 20%). Digoxin levels should be monitored at the beginning of telmisartan therapy, during dose adjustments, and upon discontinuation to maintain them within the therapeutic range.

Like other drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), telmisartan may cause hyperkalemia (see section "Special precautions"). The risk may increase when used concomitantly with other agents that may also cause hyperkalemia (potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim).

Cases of hyperkalemia depend on associated risk factors. The risk increases with the use of the above-mentioned therapeutic combinations. The risk is particularly high when combined with potassium-sparing diuretics or potassium-containing salt substitutes. Combination with ACE inhibitors or NSAIDs is considered less risky provided strict precautionary measures are followed during use.

Concomitant use is not recommended.

Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists such as telmisartan reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium concentration. If concomitant use is indicated due to documented hypokalemia, these agents should be used with caution and serum potassium levels should be monitored frequently.

Lithium. Cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors and angiotensin II receptor antagonists, including telmisartan. If use of this combination is considered necessary, serum lithium levels should be closely monitored during concomitant therapy.

Concomitant use requires caution.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (i.e., acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with impaired renal function (particularly in dehydrated patients or elderly patients with reduced renal function), concomitant use of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured; additionally, renal function should be monitored after initiation of combination therapy and periodically thereafter.

During use of the medicinal product, it has been reported that concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0–24 and Cmax of ramipril and ramiprilat. The clinical significance of this observation is unknown.

Diuretics (thiazide or loop diuretics). Prior treatment with high doses of diuretics such as furosemide (a loop diuretic) or hydrochlorothiazide (a thiazide diuretic) may lead to volume depletion and risk of developing arterial hypotension when initiating telmisartan therapy.

Should be considered during concomitant use.

Other antihypertensive agents. The ability of telmisartan to lower blood pressure may be enhanced by concomitant use of other antihypertensive agents.

Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Special precautions", "Contraindications", and "Pharmacodynamics").

Based on the pharmacological properties of baclofen and amifostine, these medicinal products may enhance the hypotensive effect of all antihypertensive agents, including telmisartan. Furthermore, orthostatic hypotension may be exacerbated by alcohol, barbiturates, narcotics, and antidepressants.

Corticosteroids (systemic use). Reduced antihypertensive effect.

Special precautions for use.

Pregnancy. Angiotensin II receptor antagonists must not be initiated during pregnancy. If treatment with angiotensin II receptor antagonists is considered no longer essential in a female patient who is planning pregnancy, she should be switched to an alternative antihypertensive therapy with an established safety profile during pregnancy. Angiotensin II receptor antagonists must be discontinued as soon as pregnancy is diagnosed and, if necessary, alternative treatment should be started (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Hepatic impairment. Telmisartan is contraindicated in patients with cholestasis, obstructive biliary disorders, or severe hepatic impairment (see section "Contraindications"), as telmisartan is primarily excreted via bile. Reduced hepatic clearance of telmisartan may be expected in such patients.

Telmisartan should be used with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension. There is an increased risk of severe hypotension and renal impairment in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney when treated with drugs affecting the RAAS.

Renal impairment and kidney transplantation. In patients with impaired renal function receiving telmisartan, periodic monitoring of serum potassium and creatinine levels is recommended. There is no experience with the use of telmisartan in patients with recent kidney transplantation.

Reduced intravascular volume. Symptomatic hypotension, especially after the first dose, may occur in patients with depleted sodium and/or intravascular volume due to vigorous diuretic therapy, dietary salt restriction, diarrhoea, or vomiting. Therefore, correction of these conditions should be performed prior to initiating Telprex.

Before starting treatment with Telprex, sodium levels and/or intravascular fluid volume should be normalized.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalaemia, and reduced renal function (including acute renal failure).

Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision and with continuous careful monitoring of renal function, electrolytes, and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Other conditions requiring RAAS stimulation.

In patients in whom vascular tone and renal function depend primarily on RAAS activity (e.g., patients with severe congestive heart failure or significant renal disease, including renal artery stenosis), treatment with Telprex and other medicinal products affecting the RAAS may lead to acute hypotension, hyperazotaemia, oliguria, and rarely, acute renal failure (see section "Adverse reactions").

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via RAAS blockade. Therefore, the use of Telprex is not recommended in these patients.

Stenosis of aortic and mitral valves, obstructive hypertrophic cardiomyopathy. As with other vasodilators, Telprex should be administered with particular caution in patients diagnosed with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Diabetic patients treated with insulin or antidiabetic medicinal products.

Hypoglycaemia may occur during treatment with telmisartan in such patients. Appropriate monitoring of blood glucose levels should be considered in these patients. Dose adjustment of insulin or antidiabetic medicinal products may be required.

In diabetic patients with cardiovascular risk (diabetic patients with concomitant coronary artery disease), the risk of fatal myocardial infarction and sudden cardiovascular death may be higher when treated with antihypertensive agents such as angiotensin II receptor antagonists and ACE inhibitors. Coronary artery disease in diabetic patients may be asymptomatic and therefore undiagnosed. Diabetic patients should be carefully evaluated, for example by stress testing, to detect and treat concomitant coronary artery disease before initiating treatment with the medicinal product.

Hyperkalaemia. Hyperkalaemia may occur during treatment with medicinal products affecting the RAAS.

In elderly patients, patients with renal impairment, diabetes, those receiving other medicinal products that may increase potassium levels, and/or those with concomitant diseases, hyperkalaemia may lead to fatal outcomes.

The benefit-risk ratio should be carefully considered before initiating concomitant therapy with drugs affecting the renin-angiotensin system.

Key risk factors for hyperkalaemia that require attention:

• diabetes mellitus, renal impairment, age over 70 years;
• combination therapy with one or more other medicinal products affecting the renin-angiotensin-aldosterone system and/or potassium-containing dietary supplements. Medicinal products or therapeutic groups that may provoke hyperkalaemia include potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• concomitant conditions, particularly dehydration, acute heart failure, metabolic acidosis, worsening renal function, sudden deterioration of kidney function (e.g., due to infections), and cellular lysis (e.g., acute limb ischaemia, acute skeletal muscle necrosis, extensive trauma).

Patients at risk require close monitoring of serum potassium concentration (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences. As with all other angiotensin II receptor antagonists, telmisartan is less effective in reducing blood pressure in black patients compared to patients of other races. This may be explained by the higher prevalence of low-renin states in black patients with arterial hypertension.

Others. As with any other antihypertensive agents, a significant reduction in blood pressure in patients with ischaemic heart disease or ischaemic cerebrovascular disease may lead to myocardial infarction or stroke.

Mannitol. The medicinal product contains mannitol (E 421). This medicinal product may have a mild laxative effect.

Sodium. Each tablet contains less than 1 mmol sodium (23 mg), which is considered essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

The medicinal product is contraindicated in pregnant women or women who are planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy (see sections «Contraindications» and «Special precautions»).

There are no adequate data on the use of Telpres in pregnant women.

Epidemiological evidence of teratogenic risk associated with the use of angiotensin-converting enzyme (ACE) inhibitors during the first trimester of pregnancy has not been conclusive, but a small increased risk cannot be ruled out. Although there are no controlled epidemiological data on the teratogenic risk of angiotensin II receptor antagonists, similar risks may exist for this class of medicinal products. When pregnancy is planned, the drug should be replaced in advance with another antihypertensive agent with an established safety profile during pregnancy. Upon confirmation of pregnancy, treatment with angiotensin II receptor antagonists must be discontinued immediately, and alternative therapy should be initiated if necessary.

It is known that the use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy causes fetal toxicity in humans (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If angiotensin II receptor antagonists are administered from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended. Newborns whose mothers received angiotensin II receptor antagonists must be closely monitored for signs of hypotension (see sections "Contraindications" and "Special precautions").

Breast-feeding

Due to the lack of information on the use of telmisartan during breast-feeding, Telpres is not recommended for administration to women who are breast-feeding. Alternative treatment with a better-established safety profile is preferred, especially when breast-feeding a newborn or preterm infant.

Fertility

Studies have not revealed any effects of telmisartan on fertility in men or women.

Ability to influence reaction rate while driving or operating machinery

During antihypertensive therapy, including treatment with telmisartan, caution should be exercised when driving or operating machinery due to the possible occurrence of dizziness or hypersomnia.

Dosage and Administration

Arterial hypertension treatment

The usual effective dose of telmisartan is 40 mg once daily. Some patients may respond adequately to a daily dose of 20 mg. If the desired blood pressure is not achieved, the dose of telmisartan may be increased to 80 mg once daily. Alternatively, telmisartan may be prescribed in combination with thiazide diuretics, such as hydrochlorothiazide, which have demonstrated additional blood pressure reduction when used concomitantly with telmisartan. When considering dose escalation, it should be noted that the maximum antihypertensive effect is generally achieved within 4–8 weeks after initiation of treatment.

Cardiovascular disease prevention

The recommended dose is 80 mg once daily. The efficacy of telmisartan at doses lower than 80 mg in preventing cardiovascular disease is unknown.

When initiating telmisartan for the prevention of cardiovascular disease, monitoring of blood pressure is recommended, and dose adjustment of antihypertensive medications may be necessary.

Elderly patients

No dose adjustment is required for elderly patients.

Special patient groups

Renal impairment. Experience with telmisartan in patients with renal insufficiency or those undergoing hemodialysis is limited. Such patients should be started on the lowest initial dose of telmisartan, 20 mg (see section "Special warnings and precautions for use"). No dose adjustment is required for patients with mild to moderate renal impairment.

Concomitant use of telmisartan and aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) is contraindicated (see section "Contraindications").

Hepatic impairment. Telmisartan is contraindicated in patients with severe hepatic impairment.

For patients with mild to moderate hepatic impairment, the daily dose should not exceed 40 mg once daily (see section "Special warnings and precautions for use").

Administration

Telprex should be taken once daily orally with sufficient fluid, independent of food intake.

Storage and handling precautions

Telprex should be stored in its original sealed blister packaging, as the tablets are highly hygroscopic. Tablets should be removed from the blister immediately before administration.

Pediatric population

The safety and efficacy of Telprex in children (under 18 years of age) have not been established.

Current available data are provided in the "Pharmacokinetics" section, but no dosage recommendations can be made.

Overdose

Information regarding telmisartan overdose is limited.

Symptoms

The most prominent manifestations of telmisartan overdose were hypotension and tachycardia. Bradycardia, dizziness, increased serum creatinine concentration, and acute renal failure have also been reported.

Treatment

Telmisartan is not removed from the body by hemodialysis. Patients should be closely monitored and receive symptomatic and supportive treatment. The choice of treatment depends on the time since overdose and the severity of symptoms. Measures such as induction of emesis and/or gastric lavage should be considered. Activated charcoal may be beneficial in managing overdose. Serum electrolytes and creatinine levels should be monitored frequently. In case of hypotension, the patient should be placed in a supine position and promptly administered saline replacement and fluid volume repletion.

Adverse reactions.

Serious adverse reactions, including anaphylactic reaction and angioneurotic edema, are possible in isolated cases (from ≥ 1/10,000 to < 1/1,000); acute renal failure has also been observed.

The overall incidence of adverse reactions in patients with arterial hypertension during clinical studies on telmisartan was generally comparable to that with placebo (41.4% vs. 43.9%). The incidence of adverse reactions was not dose-dependent and had no association with gender, age, or race of patients. Safety data for the drug Telprex in the prevention of cardiovascular diseases were comparable to those in the treatment of arterial hypertension.

The adverse reactions listed below are based on results from controlled clinical trials involving hypertensive patients and post-marketing reports. This list also includes serious adverse reactions and those leading to discontinuation of the drug during three long-term clinical trials involving 21,642 patients who received telmisartan for the prevention of cardiovascular diseases over a period of up to six years.

Adverse reactions are listed with frequency categories defined as follows: very common (≥ 1/10); common (from 1/100 to < 1/10); uncommon (from 1/1,000 to < 1/100); rare (from 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Within each category, adverse effects are listed in order of decreasing severity.

Infections and infestations: uncommon – urinary tract infections, including cystitis, upper respiratory tract infections, including pharyngitis and sinusitis; rare – sepsis, including fatal cases¹.

Blood and lymphatic system disorders: uncommon – anemia; rare – eosinophilia, thrombocytopenia.

Immune system disorders: rare – anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders: uncommon – hyperkalemia; rare – hypoglycemia (in patients with diabetes mellitus).

Psychiatric disorders: uncommon – insomnia, depression; rare – anxiety.

Nervous system disorders: uncommon – syncope; rare – somnolence.

Eye disorders: rare – visual disturbances.

Ear and labyrinth disorders: uncommon – vertigo.

Cardiac disorders: uncommon – bradycardia, arterial hypotension², orthostatic hypotension; rare – tachycardia.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, cough; very rare – interstitial lung disease⁴.

Gastrointestinal disorders: uncommon – abdominal pain, diarrhea, dyspepsia, flatulence, vomiting; rare – dry mouth, gastric discomfort, dysgeusia.

Hepatobiliary disorders: rare – liver function abnormalities/liver disorders³.

Skin and subcutaneous tissue disorders: uncommon – pruritus, increased sweating, rash; rare – angioneurotic edema (including fatal cases), eczema, erythema, urticaria, drug dermatitis, toxic dermatitis.

Musculoskeletal and connective tissue disorders: uncommon – back pain (e.g., sciatica), muscle cramps, myalgia; rare – arthralgia, limb pain, tendon pain (symptoms similar to tendinitis).

Renal and urinary disorders: uncommon – renal function impairment, including acute renal failure.

General disorders and administration site conditions: uncommon – chest pain, asthenia (weakness); rare – influenza-like symptoms.

Investigations: uncommon – increased blood creatinine; rare – decreased hemoglobin levels, increased blood uric acid, increased liver enzymes, increased blood creatine phosphokinase.

^{1, 2, 3, 4} See section "Adverse reactions. Description of selected adverse reactions".

Description of selected adverse reactions

Sepsis. In the PRoFESS study, a higher incidence of sepsis was observed among patients receiving telmisartan compared to those receiving placebo. This may be due to chance or may reflect an unknown underlying process.

Arterial hypotension. This adverse reaction was observed commonly in patients with controlled blood pressure who received telmisartan for the reduction of cardiovascular risk in addition to standard therapy.

Liver function abnormalities/Liver disorders. According to post-marketing data, most cases of liver function abnormalities/liver disorders were observed in patients of Japanese nationality. Patients of Japanese nationality appear to be more susceptible to these adverse reactions.

Interstitial lung disease. Cases of interstitial lung disease have been reported temporally associated with telmisartan use during post-marketing surveillance. However, a causal relationship has not been established.

Reporting of adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 14 tablets in a blister; 2 or 7 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

LABORATORIOS LICONSA, S.A.

Manufacturer's address and place of business.

Avda. Miralcampo, 7, Pol. Ind. Miralcampo, Azuqueca de Henares, Guadalajara, 19200, Spain.