Bupirol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUPIROL (BUPIROL)

Composition:

Active substance: ibuprofen;

1 ml of solution contains 4 mg of ibuprofen;

Excipients: sodium chloride, trometamol, hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that has demonstrated efficacy in standard animal models of inflammation, likely due to inhibition of prostaglandin synthesis. Ibuprofen exerts antipyretic effects and reduces inflammatory pain and swelling. Experimental data indicate that ibuprofen may competitively inhibit the effect of low doses of acetylsalicylic acid on platelet aggregation when administered concomitantly. Some pharmacodynamic studies have shown that when a single 400 mg dose of ibuprofen was taken within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg), the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation was reduced.

Clinical studies have shown that intravenous infusion of ibuprofen at doses of 100 mg, 200 mg, and 400 mg administered as a single dose reduces glomerular filtration rate in a dose-dependent manner by 15 to 30%.

Pharmacokinetics.

Absorption.

Bupirolo is administered intravenously; therefore, the absorption process does not occur, and the bioavailability of ibuprofen is complete.

Distribution.

The calculated volume of distribution ranges from 0.11 to 2.21 L/kg. Ibuprofen is highly bound to plasma proteins, primarily to albumin.

Metabolism.

Ibuprofen is metabolized in the liver into two inactive metabolites, which together with unchanged ibuprofen are excreted by the kidneys.

Elimination.

Renal elimination occurs rapidly and completely. The elimination half-life is approximately 2 hours.

Linearity/non-linearity.

Ibuprofen exhibits linearity of the area under the plasma concentration-time curve (AUC) following single-dose administration of ibuprofen (within the range of 200–800 mg). Pharmacokinetic/pharmacodynamic relationship.

There is a relationship between plasma levels of ibuprofen, its pharmacodynamic properties, and overall safety profile. The pharmacokinetics of ibuprofen are stereoselective following either intravenous or oral administration. The mechanism of action and pharmacology of intravenous ibuprofen do not differ from that of oral ibuprofen.

Clinical characteristics.

Indications.

Symptomatic, short-term treatment of acute moderate pain and short-term symptomatic treatment of fever, when intravenous administration is clinically justified and other routes of administration are not possible.

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the medicinal product.
• Hypersensitivity reactions (e.g., bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
• Active peptic ulcer/gastrointestinal bleeding or history of recurrent episodes (two or more distinct episodes of peptic ulcer or bleeding).
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Severe hepatic impairment, severe renal impairment, severe heart failure (NYHA class IV).
• Active cerebrovascular or other bleeding conditions.
• Hemorrhagic diathesis or coagulation disorders (thrombocytopenia).
• Unexplained disturbances of blood formation.
• Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).
• Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Other NSAIDs, including COX-2 inhibitors and salicylates. Due to synergistic effects, concomitant use of two or more NSAIDs may increase the risk of gastrointestinal ulceration and bleeding. Therefore, simultaneous administration of ibuprofen and other NSAIDs should be avoided. Concurrent use of the medicinal product with other NSAIDs should also be avoided, as it may increase the risk of gastrointestinal ulceration and hemorrhage.

Acetylsalicylic acid. Concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential for increased adverse effects. Experimental data indicate that ibuprofen may competitively inhibit the antiplatelet effect of low-dose acetylsalicylic acid when administered concomitantly. Although uncertainties exist regarding extrapolation of these data to clinical settings, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. A clinically significant interaction is not considered likely with occasional use of ibuprofen.

Digoxin. Concomitant administration of ibuprofen with digoxin-containing preparations may increase serum digoxin levels. Serum digoxin monitoring is usually not required with appropriate use (maximum duration of 3 days).

Corticosteroids. Corticosteroids may also increase the risk of adverse reactions, particularly those related to the gastrointestinal tract (GIT) (ulceration or gastrointestinal bleeding).

Antiplatelet agents (e.g., clopidogrel and ticlopidine). Increased risk of gastrointestinal bleeding.

Anticoagulants. NSAIDs may potentiate the effects of anticoagulants such as warfarin and heparin. In case of concomitant use, coagulation parameters should be monitored. Phenytoin. Concomitant use of ibuprofen with phenytoin-containing preparations may increase serum phenytoin levels. Serum phenytoin monitoring is usually not required with appropriate use (maximum duration of 3 days). Selective serotonin reuptake inhibitors (SSRIs). May increase the risk of gastrointestinal bleeding.

Lithium. Concomitant use of ibuprofen with lithium-containing preparations may increase serum lithium levels. Serum lithium monitoring is usually not required with appropriate use (maximum duration of 3 days).

Probenecid and sulfinpyrazone. Medicinal products containing probenecid or sulfinpyrazone may slow the elimination of ibuprofen.

Diuretics, ACE inhibitors, beta-blockers, and angiotensin II antagonists. Diuretics and ACE inhibitors may enhance the nephrotoxicity of NSAIDs. NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In patients with renal impairment (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant therapy with ACE inhibitors, beta-blockers, angiotensin II antagonists, and cyclooxygenase inhibitors may be associated with renal dysfunction, including acute renal failure, which are usually reversible. Therefore, concomitant therapy should be administered with caution, especially in elderly patients. Patients should be adequately hydrated, and monitoring of renal function should be considered after initiation of concomitant therapy and performed periodically. Concomitant use of ACE inhibitors and ibuprofen may lead to hyperkalemia.

Potassium-sparing diuretics. Concomitant use of ibuprofen and potassium-sparing diuretics may be associated with increased potassium levels; therefore, plasma potassium levels should be monitored.

Methotrexate. NSAIDs inhibit tubular secretion of methotrexate and thus may cause metabolic interactions leading to reduced methotrexate clearance. Administration of ibuprofen within 24 hours before or after methotrexate may increase plasma methotrexate levels, thereby enhancing its toxic effects. Therefore, concomitant use of NSAIDs and high-dose methotrexate should be avoided. Additionally, potential interaction risks during low-dose methotrexate therapy should be considered, especially in patients with impaired renal function. Renal function should be monitored during combination therapy. Cyclosporine. The risk of renal impairment is increased with concomitant use of certain NSAIDs. This effect cannot be excluded when combining cyclosporine with ibuprofen.

Zidovudine. Increased risk of hematological toxicity when NSAIDs are taken concomitantly with zidovudine. Data indicate an increased risk of hemarthrosis and hematomas in HIV(+) hemophiliacs who concurrently use zidovudine and ibuprofen. Blood analysis is recommended 1–2 weeks after initiation of combined therapy.

Sulfonylureas. Clinical studies have demonstrated interactions between NSAIDs and sulfonylureas. Although specific data on interactions between ibuprofen and sulfonylureas are lacking, plasma glucose levels should be monitored as a precautionary measure during concomitant use.

Quinolone antibiotics. Animal data suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones may have an increased risk of developing seizures.

Mifepristone. NSAIDs should not be administered within 8–12 days after mifepristone administration, as the effect of mifepristone may be reduced.

Baclofen. Ibuprofen may enhance baclofen toxicity by possible accumulation due to ibuprofen-induced renal impairment.

Pentoxifylline. In patients taking ibuprofen in combination with pentoxifylline, an increased risk of bleeding may occur; therefore, bleeding time should be monitored. Tacrolimus. Concomitant use with ibuprofen may increase the risk of nephrotoxicity. Aminoglycosides. NSAIDs may enhance the nephrotoxicity of aminoglycosides, particularly when aminoglycosides are administered in high doses over a prolonged period. Alcohol. The use of ibuprofen should be avoided in individuals with chronic alcohol consumption due to an increased risk of gastrointestinal adverse effects, including bleeding. Herbal extracts. Ginkgo biloba may enhance the risk of bleeding when used concomitantly with this medicinal product.

Special precautions for use.

Adverse reactions after administration of ibuprofen and nonsteroidal anti-inflammatory drugs (NSAIDs) in general can be minimized by using the lowest effective dose required to treat symptoms over the shortest possible treatment duration.

Elderly patients are more likely to experience adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. Respiratory: bronchospasm may occur in patients suffering from bronchial asthma, allergic conditions, or with a history of such diseases.

Anaphylactoid reactions: careful monitoring of the patient is recommended during intravenous infusion, especially at the beginning of the infusion, to detect any anaphylactic reaction caused by the active substance or excipients. Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rare. If the first signs of hypersensitivity occur after taking ibuprofen, treatment should be discontinued and symptomatic therapy initiated.

Other NSAIDs: concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, increases the risk of adverse reactions and should therefore be avoided.

Systemic lupus erythematosus and mixed connective tissue diseases: ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue diseases due to an increased risk of aseptic meningitis.

Renal and hepatic function impairment: ibuprofen should be used cautiously in patients with a history of renal or hepatic disease, especially when concomitantly treated with diuretics, as prostaglandin inhibition may cause fluid retention and renal dysfunction. In such patients, the dose of ibuprofen should be kept as low as possible, and renal function should be monitored regularly. In cases of dehydration, appropriate fluid intake should be ensured, as dehydration may trigger the development of renal failure. Long-term regular use of analgesics, particularly combinations of different analgesics, may lead to chronic kidney damage with a risk of renal failure (analgesic nephropathy). Patients at highest risk include elderly patients, those with impaired renal or hepatic function, and those treated with diuretics or angiotensin-converting enzyme (ACE) inhibitors. Cases of hyperkalemia have been reported in patients with renal insufficiency and dehydration after high-dose tromethamine administration. As with other NSAIDs, ibuprofen may cause slight transient increases in some liver function parameters, as well as significant elevations in transaminase levels. If such parameters increase markedly, treatment should be discontinued.

Cardiovascular and cerebrovascular effects:

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction.

Patients with a history of arterial hypertension and/or moderate to severe congestive heart failure should begin long-term treatment with caution (medical consultation required), as fluid retention, arterial hypertension, and edema have been reported during ibuprofen therapy, as with other NSAIDs. Data indicate that the use of ibuprofen, particularly at high doses (2400 mg daily) or over prolonged periods, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Generally, low-dose ibuprofen (e.g., ≤1200 mg daily) is not expected to increase the risk of myocardial infarction. Long-term treatment may be prescribed by a physician only after careful evaluation for patients with uncontrolled arterial hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Long-term NSAID treatment should be prescribed only after careful consideration for patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Female fertility impairment: limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment. Long-term use of ibuprofen (doses of 2400 mg daily and treatment duration exceeding 10 days) may impair female fertility and is therefore not recommended for women attempting to conceive. This medication should be discontinued in women experiencing difficulty conceiving or undergoing infertility investigations.

Gastrointestinal tract: NSAIDs should be used cautiously in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, sometimes fatal, have been reported at any stage of NSAID therapy, regardless of prior warning symptoms or history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment with the lowest possible doses. Caution should be exercised when treating patients receiving concomitant medications that may increase the risk of gastropathy or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), or antiplatelet agents (e.g., acetylsalicylic acid). For patients undergoing long-term treatment, as well as those requiring concomitant low-dose acetylsalicylic acid (aspirin) or other drugs increasing gastrointestinal risk, the physician should consider prescribing combination therapy with misoprostol or proton pump inhibitors. Patients with a history of gastrointestinal disorders, particularly elderly patients, should be informed about any unusual gastrointestinal symptoms (especially bleeding), particularly gastrointestinal bleeding at the start of treatment. If gastrointestinal bleeding or ulcers occur in patients receiving ibuprofen, treatment should be discontinued immediately.

Serious skin adverse reactions (SSARs):

Serious skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month of treatment.

If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately and alternative treatment considered (if necessary). In rare cases, varicella may cause severe skin infections and soft tissue complications. The role of NSAIDs in exacerbating these infections cannot currently be ruled out. Therefore, ibuprofen should be avoided in cases of varicella.

Hematological effects: ibuprofen may transiently inhibit platelet function (platelet aggregation), prolonging bleeding time and increasing the risk of bleeding. Therefore, patients with coagulation disorders should be monitored. Ibuprofen should be used with particular caution in patients receiving acetylsalicylic acid for platelet aggregation inhibition.

Ophthalmological effects: reports have been received of blurred vision, scotomas, and color vision changes with oral ibuprofen use.

Other special precautions and warnings: NSAIDs may mask signs of infection.

Prolonged use of analgesic medications may cause headache that cannot be treated by increasing the drug dose.

Masking symptoms of underlying infections: ibuprofen may mask symptoms of infection, potentially leading to delayed initiation of appropriate treatment and thus worsening the outcome of infectious disease. This has been observed in bacterial pneumonias and bacterial complications of varicella. When ibuprofen is administered to reduce fever and relieve pain during infection, patient monitoring is recommended. In outpatient settings, patients should seek immediate medical attention if symptoms persist or their condition worsens.

In patients receiving long-term ibuprofen therapy, renal and hepatic function, as well as hematological blood parameters, should be monitored.

Transient hypoglycemia has been reported with tromethamine use. Plasma glucose levels should be monitored during treatment. Prolonged use of analgesic drugs may cause headache that cannot be treated by increasing the drug dose.

Careful monitoring of the patient at the beginning of infusion is necessary to promptly detect anaphylactoid or hypersensitivity reactions. If such symptoms occur, the infusion should be stopped immediately and appropriate symptomatic treatment initiated. In rare cases, varicella may cause serious skin and soft tissue infections. The role of NSAIDs in exacerbating these infections cannot currently be excluded. Therefore, ibuprofen use should be avoided in varicella.

Effects on laboratory tests:

• Bleeding time (may be prolonged for up to 1 day after discontinuation).
• Blood glucose concentration (may decrease).
• Creatinine clearance (may decrease).
• Hematocrit or hemoglobin (may decrease).
• Blood urea nitrogen, creatinine, and potassium concentrations (may increase).
• Liver function: increased transaminase levels.

Ibuprofen should be used only after careful benefit-risk assessment in patients with congenital porphyrin metabolism disorders (e.g., acute intermittent porphyria).

Precautions required in patients with certain conditions that may worsen:

• Patients with allergic reactions to other substances, as they have an increased risk of hypersensitivity reactions to this medication.
• Patients with hay fever, nasal polyps, or chronic obstructive respiratory disorders, as they have an increased risk of allergic reactions, which may manifest as asthma attacks (so-called analgesic asthma), angioedema, or urticaria.

Important information about excipients.

This medicinal product contains 13 mmol (303 mg) of sodium per 100 ml of solution. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Study data indicate an increased risk of miscarriage and congenital malformations following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is considered to increase with higher doses and longer duration of therapy. From the 20th week of gestation, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible upon discontinuation. Additionally, cases of arterial duct constriction have been reported after second-trimester treatment, most of which resolved after stopping therapy. Therefore, NSAIDs should not be used during the first two trimesters of pregnancy or during labor unless the expected benefit to the patient outweighs the potential risk to the fetus.

If ibuprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and treatment duration as short as possible. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, use of any prostaglandin synthesis inhibitors may cause fetal effects such as cardiopulmonary toxicity (premature constriction/closure of the fetal arterial duct with pulmonary hypertension) and renal dysfunction (see above), which may progress to renal failure manifesting as oligohydramnios. Ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications") due to the potential for inhibition of uterine contractility, which may prolong labor and increase bleeding tendency in both mother and child, even with low-dose administration.

Breastfeeding period.

Small amounts of ibuprofen have been detected in breast milk. No harmful effects on infants are currently known; therefore, interruption of breastfeeding is usually not required for short-term, low-dose treatment. However, breastfeeding should be interrupted when doses exceeding 1200 mg daily are used or during prolonged treatment periods due to the potential to inhibit prostaglandin synthesis in newborns.

Fertility.

Medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Ability to affect reaction speed when driving or operating machinery.

When used at recommended doses, this medicinal product does not affect reaction speed during driving or operating machinery. However, patients experiencing dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving and operating machinery.

Method of Administration and Dosage.

To minimize adverse effects, Bupirolo should be administered at the lowest effective dose for the shortest duration necessary.

Adequate hydration of the patient should be maintained in order to minimize the risk of possible renal adverse reactions.

Adults. The recommended dose is 400 mg of ibuprofen every 6–8 hours as needed, not exceeding the maximum recommended daily dose of 1200 mg. The medicinal product is intended for short-term treatment (maximum treatment duration is 3 days). Patients should be advised to switch to oral therapy as soon as possible. Elderly patients. Dose adjustment is not required. However, caution should be exercised when treating elderly patients, as they are generally more susceptible to adverse reactions (see sections "Special Warnings" and "Adverse Reactions") and more frequently have renal, hepatic, or cardiovascular impairment, as well as concomitant medication use. Monitoring of these patients is recommended. Treatment should be regularly reviewed and discontinued if no positive response is observed or if intolerance occurs. Renal impairment. In patients with mild to moderate renal impairment, the initial dose should be reduced and maintained at the lowest possible level for the shortest necessary duration. Bupirolo is contraindicated in patients with severe renal impairment.

Hepatic impairment. In patients with mild to moderate hepatic impairment, treatment should be initiated with reduced doses, which should be kept as low as possible for the shortest necessary treatment period. Bupirolo is contraindicated in patients with severe hepatic impairment.

Method of administration.

For intravenous use. The medicinal product should be administered as a 30-minute intravenous infusion.

Children.

The use of Bupirolo in children and adolescents has not been studied; therefore, it should not be used in this patient population. Safety and efficacy have not been established.

Overdose.

The elimination half-life in overdose is 1.5–3 hours.

Symptoms. In most patients, ingestion of large amounts of NSAIDs causes only nausea, vomiting, epigastric pain, and very rarely diarrhea. Tinnitus, headache, dizziness, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as drowsiness, nystagmus, visual disturbances, and occasionally agitation, disorientation, or coma. Seizures may also occur. In severe poisoning, hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory depression, and cyanosis may occur. In patients with bronchial asthma, exacerbation of asthma may be observed.

Treatment. There is no specific antidote; symptomatic treatment should be initiated. Therapeutic management of intoxication should be based on the severity, clinical manifestations, and serum levels, in accordance with standard intensive care practices.

Adverse reactions

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data). The most frequent adverse reactions are gastrointestinal, which are mostly dose-dependent. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes fatal, may occur, particularly in elderly patients. Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported. Gastritis has been observed less frequently. Very rarely, serious hypersensitivity reactions (including infusion site reactions, anaphylactic shock) and serious skin reactions such as bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme and alopecia have been reported.

Exacerbations of infectious inflammation (e.g., development of necrotizing fasciitis) have been described in association with NSAID use. This may be related to the mechanism of action of NSAIDs.

During varicella infection, photosensitivity and allergic vasculitis may occur; in exceptional cases, severe skin infections and soft tissue complications may develop. Edema, hypertension and heart failure have been reported in association with NSAID therapy.

Clinical studies suggest that the use of ibuprofen, particularly at high doses (2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of the reach of children.

Incompatibilities.

Compatibility studies have not been performed; this medicinal product must not be mixed with other medicinal products.

Packaging. 100 ml in a container within a protective pouch.

Prescription status. Prescription only.

Manufacturer.

ALTA PHARMACEUTICALS, S.A.

Manufacturer's location and address of its place of business.

Polígono Industrial de Bernedo, s/n, Bernedo, Álava, 01118, Spain.