Carvedilol Akrihin Tablets 12.5mg N30
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Description
Tablets Carvedilol-Akrikhin 12.5 mg each - a drug from the group of beta-blockers. It is often prescribed for heart failure, and is also used to treat hypertension. Carvedilol has been widely used since the late 1980s, but it still does not lose its popularity. The reason - it works better than other drugs for heart failure. Extends the life of the sick and does not develop addiction to other drugs (nitrates). However, carvedilol can cause weight gain. It is convenient to combine it with other medicines for pressure and heart disease.
Active ingredients
Carvedilol
Release form
Pills
Composition
Carvedilol 12.5 mg. Auxiliary substances: ludepress LCE (lactose monohydrate - 94.7-98.3%, povidone - 3-4%) - 95.3 mg, sodium carboxymethyl starch - 1.1 mg, magnesium stearate - 1.1 mg.
Pharmacological effect
Carvedilol is an α1-, β1, - and β2-adrenoreceptor blocker, has an organ-protective effect, is an antioxidant that eliminates free oxygen radicals, has anti-proliferative action against vascular smooth muscle cells. Carvedilol is a racemic mixture of R (+) and S (-) stereoisomers, each of which has the same alpha-adreno-blocking and antioxidant properties. The beta-adrenergic blocking effect of carvedilol is non-selective in nature and is due to the levorotatory S (-) stereoisomer. Carvedilol has no internal sympathomimetic activity and, like propranolol, has membrane stabilizing properties. By blocking β-adrenoreceptors, it reduces the activity of the renin-angiotensin-aldosterone system, reducing renin release, so fluid retention (characteristic of selective alpha-adrenergic blockers) rarely occurs. By selectively blocking α1-adrenoreceptors, carvedilol reduces OPSS. profile, maintaining the normal ratio of high and low density lipoproteins (HDL / LDL). In patients with arterial hypertension, carvedilol lowers blood pressure due to combined blockade of α1- and β-adreno receptors. Decrease in blood pressure is not accompanied by a simultaneous increase in OPSS, which is observed when taking non-selective beta-blockers. HR decreases slightly.Renal blood flow and renal function in patients with arterial hypertension remain. It was shown that carvedilol does not change the stroke volume of the blood and reduces the round fist, does not disturb the blood supply to the organs and peripheral blood flow, incl. in skeletal muscles, forearms, lower limbs, skin, brain, and carotid artery. Cooling of the limbs and fatigue during exercise are rare. The hypotensive effect of carvedilol in hypertension persists for a long time. In patients with coronary artery disease, carvedilol has anti-ischemic and antianginal effects (an increase in the total duration of exercise, the time until depression of the ST segment is 1 mm deep and the time is before an attack of angina) that persists with prolonged therapy. Carvedilol significantly reduces the oxygen demand of the myocardium and the activity of the sympathoadrenal system. Also reduces preload (pulmonary arrest pressure and pulmonary capillary pressure) and afterload (OPS). Carvedilol reduces mortality and reduces the frequency of hospitalizations, reduces symptoms and improves left ventricular function in patients with chronic heart failure of ischemic and non-ischemic genesis. The effects of carvedilol are dose-dependent.
Pharmacokinetics
AbsorptionAfter ingestion, carvedilol is rapidly absorbed. Carvedilol is a substrate of a carrier protein that acts as a pump in the intestinal lumen, the glycoprotein P. Cmax in the blood plasma is reached in approximately 1 hour. The absolute bioavailability of carvedilol is approximately 25%. Distribution Carvedilol has a high lipophilicity. About 98-99% of carvedilol binds to plasma proteins. Its Vd is approximately 2 l / kg. Carvedilol is biotransformed in the liver by oxidation and conjugation to form a number of metabolites. 60-75% of the absorbed drug is metabolized during the "first pass" through the liver. The existence of the enterohepatic circulation of the parent substance has been shown. MetabolismMethobolism of carvedilol by oxidation is stereoselective. The R stereoisomer is metabolized mainly by CYP2D6 and CYP1A2, and the S stereoisomer is mainly metabolized by CYP2D9 and to a lesser extent by CYP2D6. Other P450 isoenzymes involved in carvedilol metabolism include CYP3A4, CYP2E1, and CYP2C19.The plasma Cmax R stereoisomer is approximately 2 times higher than that of the S stereoisomer. The stereoisomer is metabolized mainly by hydroxylation. The slow metabolizers of CYP2D6 may increase the plasma concentration of carvedilol, primarily the R stereoisomer, which results in an increase in the alpha-adrenoceptor blocking activity of carvedilol. As a result of the demethylation and hydroxylation of the phenol ring, 3 metabolites are formed (their concentration is 10 times lower than the concentration of the original substance) with beta-adrenoblokiruyuschego activity (in the 4'-hydroxyphenol metabolite, it is about 13 times stronger than that of carvedilol itself). 3 active metabolites have less pronounced vasodilating properties than carvedilol. 2 of the hydroxycarbazole metabolites of carvedilol are extremely powerful antioxidants, and their activity in this regard is 30-80 times higher than that of carvedilol. Excretion of T1 / 2 carvedilol is about 6 hours, plasma clearance is about 500-700 ml / min. Excretion occurs mainly through the intestines, the main route of excretion is with bile. A small part of the dose is excreted by the kidneys in the form of various metabolites. Pharmacokinetics in special groups of patients Patients with impaired renal function During prolonged therapy with carvedilol, the intensity of the renal blood flow remains, the glomerular filtration rate does not change. In patients with arterial hypertension and impaired renal function, AUC, T1 / 2 and Cmax do not change . Renal excretion of unchanged drug in patients with renal insufficiency is reduced, but changes in pharmacokinetic parameters are not significant. Patients with impaired liver function In patients with cirrhosis, the systemic bioavailability of the drug is increased by 80% due to a decrease in metabolism during the first passage through the liver. Consequently, carvedilol is contraindicated in patients with clinically manifestly impaired liver function. Patients with heart failure In some studies in patients with heart failure, the R and S clearance of carvedilol stereoisomers was significantly lower compared with the previously observed clearance in healthy volunteers.These results suggest that the pharmacokinetics of R and S stereoisomers of carvedilol in heart failure changes significantly. Patients of old and old age. Age does not have a statistically significant effect on the pharmacokinetics of carvedilol in patients with arterial hypertension. The data on the pharmacokinetics of the drug in patients under 18 are limited. diabetes In patients with type 2 diabetes mellitus and arterial hypertension, carvedilol does not affect the concentration of fasting blood glucose and after food, the level of glycated hemoglobin (HbA1) or the dose of hypoglycemic agents for oral administration. In some clinical studies, it was shown that in patients with type 2 diabetes mellitus, carvedilol does not cause a decrease in glucose tolerance. In patients with arterial hypertension who had insulin resistance (Syndrome X), but without concomitant diabetes, carvedilol improves insulin sensitivity. Similar results were obtained in patients with hypertension and type 2 diabetes.
Indications
- arterial hypertension: essential hypertension (in monotherapy or in combination with other antihypertensive agents, for example, slow calcium channel blockers or diuretics), - ischemic heart disease (including in patients with unstable stenocardia and painless myocardial ischemia) - chronic heart failure : treatment of stable and symptomatic mild, moderate and severe chronic heart failure (II-IV functional classes according to the New York Heart Association / NYHA /) ischemic or non-ischemic one genesis in combination with ACE inhibitors and diuretics with or without cardiac glycosides (standard therapy), in the absence of contraindications.
Contraindications
- acute and chronic heart failure in the decompensation stage, requiring IV injection of inotropic drugs, - clinically significant liver dysfunction, - age up to 18 years (the efficacy and safety of the drug Acridilol® have not been established), - AV-blockade II and III degrees ( except for patients with an artificial pacemaker), - severe bradycardia (HR less than 50 beats / min), - SSS (including sinoatrial blockade), - severe arterial hypotension (systolic blood pressure less than 85 mm Hg), - cardiogenic shock, - Anamnestic indications for bronchospasm and bronchial asthma - lactose intolerance, lactase deficiency,glucose-galactose malabsorption, - hypersensitivity to carvedilol or any component of the drug. Caution: for COPD, depression, myasthenia, hypoglycemia, AV-blockade of I degree, thyrotoxicosis, with extensive surgical interventions and general anesthesia, Prinzmetal angina, anesthetic, stenocardia, diabetes mellitus, anchoxicopathy, anchoxicopathy, anchoxicosis, anemic of angina, Prinzmetal angina, ausculta, auspicious sufferers, anesthetic, stenocardia, Prinzmetal, anchoxicosis, anchoxicopathy, anchoxicosis, anesthesia, Prinzmetal angina, ausculta, aloe sacrosis, anesthesia, stenocardia, Prinzmetal, anchoxicopathy, anchoxicopathy, anchoxicosis, anesthesia, Prinzmetal's angina, auspicious sugars, anesthesia, hypertrophy, and hypertrophy; occlusive peripheral vascular diseases, with suspected pheochromocytoma, renal failure, psoriasis.
Precautionary measures
Dosing in special groups of patients Existing data on pharmacokinetics in patients with varying degrees of renal dysfunction (including renal failure) suggests that patients with moderate and severe renal insufficiency do not require dose adjustment of Acridilol®. Acridilol is contraindicated in patients with clinical manifestations of abnormal liver function. Data that would dictate the need for dose adjustment in elderly patients are not available.
Use during pregnancy and lactation
Beta-blockers reduce placental blood flow, which can lead to fetal death and premature birth. In addition, unwanted reactions may occur in the fetus and newborn (in particular, hypoglycemia and bradycardia, complications of the heart and lungs). Studies on animals did not reveal a teratogenic effect in carvedilol. There is no sufficient experience with Acridilol® in pregnant women. Carvedilol is contraindicated in pregnancy, unless the possible benefits of its use in the mother exceed the potential risk to the fetus. In animals, carvedilol and its metabolites pass into breast milk. There is no data on the penetration of carvedilol into human breast milk, therefore, if taking the drug is necessary during lactation, breastfeeding should be stopped.
Dosage and administration
Inside, regardless of the meal, drinking a sufficient amount of fluid. Essential hypertension. The recommended initial dose is 12.5 mg 1 time / day for the first 2 days of therapy, then 25 mg 1 time / day. If necessary, the dose can be further increased at intervals of at least 2 weeks, bringing to the maximum recommended dose of 50 mg 1 time / day (or divided into 2 doses). Coronary heart disease The recommended initial dose is 12.5 mg 2 times / day for the first 2 days, then 25 mg 2 times / day.If necessary, subsequently, the dose can be increased at intervals of at least 2 weeks, bringing to a higher daily dose of 100 mg divided into 2 doses. Chronic heart failure. The dose is selected individually, it is necessary to carefully monitor the doctor. In patients receiving cardiac glycosides, diuretics, and ACE inhibitors, their doses should be adjusted before starting treatment with Acridilol®. The recommended starting dose is 3.125 mg (1/2 tab. 6.25 mg) 2 times / day for 2 weeks. With good tolerance, the dose is increased at intervals of at least 2 weeks to 6.25 mg 2 times / day, then to 12.5 mg 2 times / day, then to 25 mg 2 times / day. The dose should be increased to a maximum dose that is well tolerated by the patient. The recommended maximum dose is 25 mg 2 times / day for all patients with severe chronic heart failure and for patients with mild and moderate degrees of chronic heart failure with a patient's body weight less than 85 kg. In patients with mild and moderate chronic heart failure and a body weight of more than 85 kg, the recommended maximum dose is 50 mg 2 times / day. Before each increase in dose, the doctor should examine the patient to identify a possible increase in symptoms of chronic heart failure or vasodilation. With a transient increase in symptoms of chronic heart failure or fluid retention in the body, the dose of diuretics should be increased, although sometimes it is necessary to reduce the dose of the drug Acridilol® or temporarily cancel it. Symptoms of vasodilation can be eliminated by reducing the dose of diuretics. If the symptoms persist, you can reduce the dose of the ACE inhibitor (if the patient is taking it), and then, if necessary, the dose of the drug Acridilol®. In such a situation, the dose of Acridilol® should not be increased until the symptoms of worsening chronic heart failure or arterial hypotension improve. If treatment with Acridilol® is interrupted for more than 1 week, then its prescription is resumed at a lower dose, and then increased in accordance with the above above recommendations. If treatment with Acridilol® is interrupted for more than 2 weeks, then its administration should be resumed at a dose of 3.125 mg (1/2 tab.at 6.25 mg) 2 times / day, then select the dose in accordance with the above recommendations.
Side effects
Adverse reactions occurring with a frequency of <10% are regarded as very common. Adverse reactions occurring at a frequency of <1% to <10% are considered as frequent. Adverse reactions occurring at a frequency of <0.1% to <1% are considered infrequent. Adverse reactions occurring with a frequency of <0.01% to <0.1% are regarded as rare. Adverse reactions occurring with a frequency of <0.01%, including individual messages, are regarded as very rare. The frequency of adverse reactions, with the exception of dizziness, visual disturbances and bradycardia, does not depend on the dose of the drug. Adverse reactions in patients with chronic heart failure. From the CNS: very often - dizziness, headache (usually lungs and occurring more often at the beginning of treatment), asthenia ( including fatigue), depression. From the cardiovascular system: often - bradycardia, postural hypotension, marked decrease in blood pressure, edema (including generalized, peripheral, depending on the position of the body , perineal edema, lower extremity edema, hypervolemia, fluid retention), infrequently - syncopal conditions (including presinkopalnye), AV-blockade and heart failure during the dose increase period. Of the gastrointestinal tract: often - nausea, diarrhea, vomiting. : rarely - thrombocytopenia, very rarely - leukopenia. On the side of metabolism: often - weight gain, hypercholesterolemia, in patients with existing diabetes mellitus - hyperglycemia or hypoglycemia, glycemic control disorders. Other: often - violated vision, rarely - renal failure and impaired renal function in patients with diffuse vasculitis and / or impaired renal function. Adverse reactions in patients with arterial hypertension and ischemic heart disease. The side effects of the cardiovascular system in the treatment of arterial hypertension and long-term treatment of IHD are similar to those in chronic heart failure, however, their frequency is somewhat less. From the side of the CNS: often - dizziness, headache and general weakness, usually lungs and arising, in particular, the beginning of treatment,infrequently - mood lability, sleep disturbances, paresthesia. From the cardiovascular system: often - bradycardia, postural hypotension, syncopal states (infrequently), especially at the beginning of therapy, infrequently - peripheral circulatory disorders (cooling of limbs, exacerbation of intermittent claudication and syndrome Rayno), AV-blockade, stenocardia (chest pain), development or worsening of symptoms of heart failure and peripheral edema. On the respiratory system: often - bronchospasm and shortness of breath patients, rarely - nasal congestion. From the side of the gastrointestinal tract: often - dyspeptic disorders (including nausea, abdominal pain, diarrhea), rarely - constipation, vomiting. From the skin: rarely - skin reactions (skin rash, dermatitis, urticaria and pruritus). Laboratory indicators: very rarely - increased activity of hepatic transaminases (ALT, ACT and GGT) thrombocytopenia and leukopenia. Others: often - pain in the extremities, reduction of tearing and eye irritation, rarely - decrease in potency, visual impairment rarely dry mouth and impaired Nia urination, very rarely - worsening of psoriasis, sneezing, flu-like symptoms. Selected cases of allergic reactions.
Overdose
Symptoms: marked reduction in blood pressure, bradycardia, heart failure, cardiogenic shock, cardiac arrest, respiratory disorders, bronchospasm, vomiting, confusion and generalized seizures are possible. Treatment: in addition to general measures, it is necessary to monitor and correct vital signs, if necessary intensive care unit. You can use the following measures: - put the patient on his back (with raised legs), - with severe bradycardia - atropine 0.5-2 mg IV, - to maintain cardiovascular activity - glucagon 1-10 mg IV / jet, then 2–5 mg per hour in the form of a long-term infusion — sympathomimetics (dobutamine, isoprenaline, orciprenaline, or epinephrine (adrenaline) in various doses, depending on body weight and response to treatment. If the arterial hypotension dominates in the clinical picture of overdose, norepinephrine (norepinephrine), it is called start in conditions of continuous monitoring of blood circulation parameters.In case of treatment-resistant bradycardia, the use of an artificial pacemaker is indicated. In case of bronchospasm, beta-adrenomimetics are administered in the form of an aerosol (in case of inefficiency - iv) or aminophylline IV. With convulsions, IV is slowly injected with diazepam or clonazepam. Since severe overdose with symptoms of shock can prolong the half-life of carvedilol and remove the drug from the depot, it is necessary to continue the maintenance therapy for a long time. The duration of maintenance / detoxification therapy depends on the severity of the overdose, it should be continued until the patient’s clinical condition stabilizes.
Interaction with other drugs
Since carvedilol is both a substrate and an inhibitor of glycoprotein P, when it is taken concurrently with drugs transported by glycoprotein P, the bioavailability of the latter can increase. In addition, the bioavailability of carvedilol can be altered by the action of glycoprotein P inducers or inhibitors. CYP2D6 and CYP2C9 inhibitors and inducers can stereoselectively alter the systemic and / or presystemic metabolism of carvedilol, leading to an increase or decrease in the R and S concentrations of carvedilol stereoisomers in plasma. Some examples of such interactions observed in patients or in healthy volunteers are listed below, but this list is not complete. Digoxin When co-administered with carvedilol and digoxin, the concentration of digoxin increases by about 15%. At the beginning of carvedilol therapy, when selecting its dose or discontinuation of the drug, regular monitoring of the concentration of digoxin in the blood plasma is recommended. Cyclosporin In two studies, carvedilol was prescribed to patients undergoing kidney and heart transplants and given cyclosporine orally, an increase in cyclosporine concentration was noted. It turned out that due to the inhibition of glycoprotein P activity in the intestine, carvedilol increases the absorption of cyclosporin when it is taken orally. To maintain the concentration of cyclosporine in the therapeutic range, it was necessary to reduce the dose of cyclosporine by an average of 10-20%. In connection with pronounced individual fluctuations in the concentration of cyclosporine, careful monitoring of its concentration is recommended after initiating carvedilol therapy and, if necessary, a corresponding adjustment in the daily dose of cyclosporine.In the case of intravenous administration of cyclosporine, no interaction with carvedilol is expected. Rifampicin In a study involving healthy volunteers, rifampicin reduced plasma concentrations of carvedilol, most likely by inducing glycoprotein P, leading to a decrease in carvedilol absorption in the intestine and a decrease in its antihypertensive effect. with heart failure, amiodarone reduced the clearance of the carvedilol stereoisomer S by suppressing CYP2C9. The mean R concentration of the carvedilol stereoisomer did not change. Consequently, due to an increase in S concentration of carvedilol stereoisomer, there is a risk of an increase in beta-adrenergic blocking effect. Fluoxetin In a randomized, cross-design study in patients with heart failure, concurrent fluoxetine (a CYP2D6 inhibitor) resulted in stereoselective suppression of carvedilol metabolism — an increase in the average CY factor 2 R (+) at 77%. However, differences in side effects, blood pressure or heart rate between the two groups were not observed. Pharmacodynamic interaction Insulin or hypoglycemic agents for oral administration Preparations with beta-adrenoceptor blocking properties may enhance the hypoglycemic effect of insulin or hypoglycemic agents for oral administration. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. Patients receiving insulin or hypoglycemic agents for oral administration, it is recommended regular monitoring of blood glucose. Preparations that reduce the content of catecholaminesPatients who take both means with beta-adrenoceptor blocking properties and means that reduce the content of catecholamines (for example, reserpine and MAO inhibitors) must be under careful observation of the risk of arterial hypotension and / or severe bradycardia. Digoxin Combined therapy of drugs with beta-adrenoblokiru properties of digoxin can lead to an additional slowdown of atrioventricular conductivity. Verapamil, diltiazem, amiodarone, or other antiarrhythmic agents. Simultaneous administration with carvedilol may increase the risk of AV conduction disturbance. ClonidineA simultaneous administration of clonidine with drugs with beta-adrenoceptor blocking properties may potentiate the antihypertensive and bradycardic effect.If you plan to stop the combination drug therapy with beta-adrenergic blocking properties and clonidine, you should first cancel the beta-blocker, and after a few days you can cancel clonidine, gradually reducing its dose. conduction disorders (rarely with impaired hemodynamic parameters). As in the case of other drugs with beta-adrenergic blocking properties, carvedilol should be prescribed together with BMCC type of verapamil or diltiazem under ECG and AD control. (for example, alpha1-blockers) or drugs that cause arterial hypotension as a side effect. General anesthesia drugs. lead careful observation of the main vital signs of the body during general anesthesia in connection with the possibility of a synergistic negative inotropic action of carvedilol and general anesthesia agents. adrenoreceptors) Since non-cardio selective beta adrenergic blockers inhibit the bronchodilator effect of bronchodilators, which are stimulators of β-adrenocept It is necessary to carefully monitor patients receiving these drugs.
special instructions
Chronic heart failure In patients with chronic heart failure during the period of selecting the dose of the drug Akridilol®, symptoms of chronic heart failure or fluid retention may increase. If such symptoms occur, it is necessary to increase the dose of diuretics and not to increase the dose of Acridilol® until the hemodynamic parameters stabilize. Sometimes it is necessary to reduce the dose of Acridilol® or, in rare cases, temporarily cancel the drug. Such episodes do not prevent further proper selection of the dose of the drug Akridilol®. Acridilol® is used with caution incombinations with cardiac glycosides (possibly excessive slowing of AV conduction). Renal function in chronic heart failureWhen prescribing the drug Acridilol® to patients with chronic heart failure and low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse changes of blood vessels and / or renal insufficiency, there was a reversible deterioration in renal function. The dose of the drug is selected depending on the functional state of the kidneys. In patients with COPD (including bronchospastic syndrome) who do not receive oral or inhaled anti-asthma drugs, Acridilol is prescribed only if the possible benefits of its use exceed the potential risk. If there is an initial predisposition to the bronchospastic syndrome, while taking the drug Akridilol® as a result of an increase in the resistance of the respiratory tract, dyspnea may develop. At the beginning of the reception and with an increase in the dose of the drug Akridilol®, these patients should be carefully observed, reducing the dose when the initial signs of bronchospasm appear. Diabetes mellitus With caution, the drug is prescribed for diabetic patients, since it can mask or alleviate the symptoms of hypoglycemia (especially tachycardia). In patients with chronic heart failure and diabetes mellitus, the use of Acridilol® may be accompanied by impaired glycemic control. Peripheral vascular diseases Precaution is necessary when prescribing Acridilol® to patients with peripheral vascular diseases (including Raynaud's syndrome), since beta-adrenergic blockers may increase arterial symptoms deficiency. Thyrotoxicosis Like other beta-blockers, Acridylol® can reduce the severity of thyrotoxic symptoms goat. General anesthesia and extensive surgical interventions Precaution is required in patients undergoing surgery under general anesthesia because of the possibility of summing up the negative effects of Acridilol® and general anesthesia drugs. BradycardiaAcridilol® can cause bradycardia when the heart rate decreases to less than 55 beats / The dose should be reduced. Increased sensitivity. Care must be taken when prescribing Acridilol® to patients with anamnestic indications of severe reactions. hypersensitivity or undergoing a course of desensitization,Because beta-blockers can increase sensitivity to allergens and severity of anaphylactic reactions. Psoriasis Patients with anamnestic indications of the occurrence or worsening of psoriasis when using beta-blockers, Acridilol® can be prescribed only after a thorough analysis of the possible benefits and risks. Simultaneous blockers of slow calcium calcium BMCC) For patients who simultaneously take BMCC like verapamil or diltiazem, as well as other antiarrhythmic drugs, you must regularly itorirovat ECG and AD.FeohromotsitomaBolnym pheochromocytoma prior to the use of any beta-blocker, you must assign an alpha-blocker. Although Akridilol® has both beta and alpha adreno-blocking properties, there is no experience with its use in such patients, so it should be prescribed with caution in patients with suspected pheochromocytoma. Prinzmetal's angina pectoris Non-selective beta-adrenergic blockers can cause pain in patients with angina pectoris Printsmetal. There is no experience of prescribing Acridilol® to these patients. Although its alpha-adrenergic blocking properties can prevent similar symptoms, carvedilol should be prescribed in such cases with caution. Contact lensesPatients using contact lenses should be aware of the possibility of reducing the amount of tear fluid. Acridilol® is treated for a long time. It should not be stopped abruptly, it is necessary to gradually reduce the dose of the drug at weekly intervals. This is especially important in patients with IBS. If surgery is necessary using general anesthesia, an anesthesiologist should be warned about prior therapy with Acridilol®. Alcohol consumption is excluded during the treatment period. Influence on the ability to drive motor vehicles and control mechanisms when driving and doing other potentially hazardous activities that require increased concentration attention and speed of psychomotor reactions.