Twynsta pills 10 mg + 80 mg 28 pcs
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Active ingredients
Amlodipine + Telmisartan
Release form
Pills
Composition
1 tab. amlodipine besylate 13.87 mg, which corresponds to the content of amlodipine 10 mg telmisartan 80 mg. Excipients: sodium hydroxide - 6.
Pharmacological effect
Pharmacotherapeutic group: blocker of "slow" calcium channels + angiotensin II receptor antagonist. Combined antihypertensive drug containing two active ingredients with a complementary effect, allowing to control blood pressure in patients with arterial (essential) hypertension: angiotensin II receptor antagonist (telmisartan) and slow calcium channel blocker, dihydropyridine derivative (amlodipine). The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater extent than each component separately. The drug Twynsta, taken 1 time / day, leads to an effective and sustained decrease in blood pressure within 24 hours. Telmisartan: Telmisartan is a specific angiotensin II receptor antagonist (type AT1) that is effective when taken orally. It has a high affinity for the AT1 receptor subtype angiotensin II, through which the action of angiotensin II is realized. Displaces angiotensin II from its association with the receptor, not having the action of an agonist on this receptor. Telmisartan binds only to the angiotensin II receptor AT1 subtype. The binding is long lasting. Does not have affinity for other receptors, incl. to the AT2 receptor. Reduces the concentration of aldosterone in the blood, does not inhibit renin in the blood plasma and does not block the ion channels. Telmisartan does not inhibit ACE (kininase II) - an enzyme that also destroys bradykinin, so an increase in side effects caused by bradykinin is not expected. In patients with telmisartan in a dose of 80 mg completely blocks the hypertensive effect of angiotensin II. The onset of the antihypertensive effect is noted within 3 hours after the first dose of telmisartan. The effect of the drug lasts for 24 hours and remains significant until 48 hours. A pronounced antihypertensive effect usually develops after 4-8 weeks of regular use. In patients with arterial hypertension, telmisartan reduces systolic and diastolic blood pressure without affecting heart rate.In the case of abrupt cancellation of telmisartan, blood pressure gradually returns to its original level without the development of withdrawal syndrome. Amlodipine: Amlodipine, a dihydropyridine derivative, belongs to the class of slow calcium channel blockers. Inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle cells, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure. In patients with arterial hypertension, the use of amlodipine 1 time / day provides a clinically significant reduction in blood pressure for 24 hours. Orthostatic hypotension is not characteristic when using amlodipine due to the slow onset of the drug. In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses resulted in a decrease in renal vascular resistance, an increase in glomerular filtration rate, and effective plasma blood flow in the kidney, without changing filtration or proteinuria. Amlodipine does not cause any metabolic adverse effects or changes in plasma lipid levels, and is therefore suitable for use in patients with bronchial asthma, diabetes mellitus and gout. The use of amlodipine in patients with heart failure is not accompanied by a negative inotropic effect (exercise tolerance does not decrease, the left ventricular ejection fraction does not decrease).
Pharmacokinetics
The speed and extent of absorption of the drug Tvinsta equivalent to the bioavailability of telmisartan and amlodipine when used separately. Telmisartan: Absorption: Ingestion is rapidly absorbed from the gastrointestinal tract. Bioavailability - 50%. When taken simultaneously with food, the decrease in AUC ranges from 6% (when used at a dose of 40 mg) to 19% (when applied at a dose of 160 mg). 3 h after ingestion, the concentration in the blood plasma levels off, regardless of the meal. Cmax in plasma and, to a lesser extent, AUC increase disproportionately to the dose. Distribution: Plasma protein binding is 99.5%, mainly with albumin and alpha1-glycoprotein. The average value of the visible Vd at an equilibrium concentration of 500 l.Data on clinically significant accumulation of telmisartan is not available. Metabolism Metabolized by telmisartan by conjugation with glucuronic acid. Metabolites are pharmacologically inactive. Excretion: T1 / 2 is more than 20 hours. Excreted in unchanged form with faeces, excretion in the urine - less than 2%. Total plasma clearance is high (900 ml / min) compared with hepatic blood flow (about 1500 ml / min). Pharmacokinetics in special clinical situations: There is a difference in plasma concentrations of telmisartan in men and women. Cmax and AUC were approximately 3 and 2 times, respectively, higher in women compared to men without significant effect on efficacy. The pharmacokinetics of telmisartan in elderly patients does not differ from the pharmacokinetics in young patients. Telmisartan binds to plasma proteins and is not removed during hemodialysis in patients with renal insufficiency. Also marked lower concentrations of telmisartan in the blood plasma, T1 / 2 does not change. Pharmacokinetic studies conducted in patients with impaired liver function have shown that the absolute bioavailability of telmisartan increases to almost 100%. T1 / 2 in patients with impaired liver function does not change. Amlodipine: Absorption: After taking amlodipine by mouth in therapeutic doses, Cmax in the blood plasma is reached in 6-12 hours. The absolute bioavailability value ranges from 64% to 80%. Eating does not affect the bioavailability of amlodipine. Distribution: Amlodipine Vd is approximately 21 L / kg. In vitro studies have shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine binds to plasma proteins. Stable plasma concentrations are achieved after continuous use of the drug for 7-8 days. Metabolism: Amlodipine is largely (approximately 90%) metabolized in the liver to form inactive metabolites. Withdrawal: The removal of amlodipine from the blood plasma occurs in two phases. T1 / 2 is approximately 30-50 hours. Amlodipine is excreted in the urine both unchanged (10%) and as metabolites (60%). Pharmacokinetics in special clinical situations: Elderly patients tend to reduce the clearance of amlodipine, which leads to an increase in AUC and T1 / 2.The pharmacokinetics of amlodipine in patients with impaired renal function does not change significantly. In patients with hepatic insufficiency, amlodipine clearance decreased, leading to an increase in the AUC value of approximately 40-60%.
Indications
For the treatment of arterial hypertension: - in patients whose blood pressure is not sufficiently controlled by telmisartan or amlodipine used as monotherapy - in patients who have been shown combination therapy - in patients receiving telmisartan and amlodipine as separate dosage forms as a substitute for this therapy.
Contraindications
- obstructive diseases of the biliary tract - severe arterial hypotension - obstruction of the left ventricular output tract (including a high degree of aortic stenosis) - hemodynamically unstable heart failure after acute myocardial infarction - severe liver failure - shock - simultaneous use with aliskiren in patients with diabetes mellitus or renal dysfunction (GFR less than 60 ml / min / 1.73 m2) - fructose intolerance and glucose / galact absorption disorder syndrome ose or sucrase / isomaltase deficiency - pregnancy - breastfeeding period - age up to 18 years (efficacy and safety not established) - hypersensitivity to active ingredients or auxiliary substances - hypersensitivity to other dihydropyridine derivatives. The drug should be prescribed with caution in abnormal liver function, renovascular arterial hypertension, primary aldosteronism, aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy, heart failure, heart failure, heart rate, heart rate, heart rate, heart rate, heart, time, time, time, heart rate, time, time, time, time, size, time,, time, time, time, time, time, time, time, time, time, time, and time, will be a time to be a time to begin, about the heart of the world, the heart of heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, heart, and the heart will not be used to be used by the heart, if you are using a time factor, if you are a time, or to leave the distance, it is a time to time to, in the color, it is a time, time, time, time, status, time, time, time, value, time, temperature,,,,,,,,,,,, and, will be used as a purpose; BCC and / or hyponatremia, hyperkalemia, other conditions characterized by RAAS activation.
Use during pregnancy and lactation
Special studies on the use of the drug Twynsta during pregnancy and lactation has been conducted. The effects associated with the individual components of the drug are described below. Pregnancy Telmisartan The use of angiotensin II receptor antagonists is contraindicated in pregnancy.When pregnancy occurs, the use of the drug should be immediately stopped. If necessary, an alternative therapy should be prescribed. Preclinical studies of telmisartan did not reveal teratogenic properties, but established the presence of fetotoxicity. It is known that the use of angiotensin II receptor antagonists in the II and III trimesters of pregnancy has a fetotoxic effect (reduced kidney function, oligohydramnion, delayed ossification of the fetal skull), and neonatal toxicity (renal failure, arterial hypotension and hyperkalemia) is also observed. In patients planning pregnancy, angiotensin II receptor antagonists should be replaced with other antihypertensive drugs that have an established safety profile when used in pregnant women (unless continued treatment with angiotensin II receptor antagonists is considered necessary). If angiotensin II receptor antagonists are used during pregnancy, then, starting from the second trimester of pregnancy, an ultrasound scan of the kidneys and bones of the fetal skull is recommended. Newborns whose mothers received angiotensin II receptor antagonists should be carefully monitored for the development of arterial hypotension. Amlodipine Limited data available on the effects of amlodipine or other calcium channel blockers do not indicate a negative effect on the fetus. However, there is a risk of slowing down the process of childbirth The period of breastfeeding Special studies on the allocation of telmisartan and / or amlodipine with breast milk in women have not been conducted. Experimental studies on animals revealed that telmisartan is excreted in milk from lactating animals. Given the possible adverse reactions, the decision to continue breastfeeding or to cancel therapy should be made taking into account its importance to the mother. Studies of the effect of the drug on human fertility has not been conducted.
Dosage and administration
Tvinsta drug is taken orally 1 time / day, regardless of the meal. Tvinsta drug can be prescribed to patients receiving the same dose of telmisartan and amlodipine in the form of separate dosage forms, for ease of therapy and increased adherence to treatment.Tvinsta drug can be prescribed to patients in whom the use of amlodipine or telmisartan as monotherapy does not lead to adequate control of blood pressure. Patients taking amlodipine at a dose of 10 mg, in which adverse reactions that restrict the use of the drug (for example, peripheral edema) are noted, can be transferred to the use of the drug Twynsta at a dose of 40 mg / 5 mg 1 time / day, which will reduce will not reduce the overall expected antihypertensive effect. Treatment of arterial hypertension in a patient can begin with the use of the drug Twynsta in the case when it is assumed that the achievement of BP control with the help of any one drug is unlikely. The recommended initial dose of Twynsta is 40 mg / 5 mg 1 time / day. In patients who need a more significant reduction in blood pressure, the initial dose of Twynsta can be increased to 80 mg / 5 mg 1 time / day. If, at least after 2 weeks of treatment, an additional reduction in blood pressure is required, the dose of the drug can be gradually increased to a maximum of 80 mg / 10 mg 1 time / day. Tvinsta drug can be used with other antihypertensive drugs. In patients with impaired renal function, incl. in patients on hemodialysis, dose adjustment is not required. Amlodipine and telmisartan are not removed from the body during hemodialysis. In patients with mild or moderately impaired liver function, Twynsta should be used with caution. The dose of telmisartan should not exceed 40 mg 1 time / day. Elderly patients Dosage and dose does not require changes. Peculiarities of the drug action at the first dose or when it is canceled After taking the first dose of telmisartan, the antihypertensive effect develops gradually during the first 3 hours, lasts for 24 hours and remains significant until 48 hours. development of withdrawal syndrome.
Side effects
The frequency of side effects is classified as follows: very often (1/10); often (1/100, less than 1/10); infrequently (1/1000, less than 1/100); rarely (1/10 000, less than 1/100); very rarely (less than 1/10 000); frequency unknown (cannot be calculated from available data).Unwanted adverse reactions are classified by organ and system according to the terms of MedDRA. Side effect Frequency of infection and invasion: Urinary tract infection1), upper respiratory tract infection1) Infrequently Sepsis, incl. fatal outcome1), cystitis3) Rarely Mental disorders: Depression3), anxiety3), insomnia3) Rarely Lability of mood2), confusion2) Frequency unknown Nervous system: Dizziness3) Often Drowsiness3), migraine3), headache3), paresthesia3) Nastomas Decreased sensitivity or resistance to external factors3), a violation of taste3), fainting3), tremor3), peripheral neuropathy3) Rarely Extrapyramidal disorders2) Frequency unknown From the immune system: Anaphylactic reaction1) Rarely Elevated sensitivity1), 2) Rarely1), Frequency unknown 2) On the part of the organ of vision: Visual disorders1) Rarely Reduced vision2) Frequency is unknown On the part of the organ of hearing and vestibular apparatus: Vertigo3) Infrequently Tinnitus2) Frequency is unknown On the part of the cardiovascular system: Bradycardia3 ), palpitations3), marked reduction of AD3), orthostatic hypotension3) Infrequently Tachycardia1) Rarely Myocardial infarction2, arrhythmia2), ventricular tachycardia2), atrial fibrillation2) Frequency unknown From the respiratory system: Cough3) Infrequently Dyspnea1), 2) Infrequently1), frequency is unknown2) Rhinitis2) Frequency is unknown On the part of the digestive system: Abdominal Pain3), diarrhea3), nausea3), flatulence1), increased activity of liver enzymes3) Infrequently Vomiting3), dyspepsia3), discomfort in the area stomach1), abnormal liver function1) Rarely, Hepatitis2), jaundice2), changes in defecation rhythm2), pancreatitis2), gastritis2), increased activity of hepatic transaminases (mainly reflecting cholestasis) 2) Frequency unknown Skin and subcutaneous tissue: Pruritus 3) Eczema3), erythema3 ), rash3), drug rash1), toxic rash1) Rarely Hyperhidrosis1), 2), Infrequently1), frequency unknown2) Angioedema 1), 2), urticaria 1), 2) Rarely1), Unknown frequency2) Alopecia2), purpura2) , discoloration of the skin2), erythema multiforme2), exfoliative dermatitis2), Stevens-Johnson syndrome2), photosensitization reaction2), vasculitis2) Frequency is unknown From the musculoskeletal system: Arthralgia3), muscle spasms (convulsions of calf muscles) 3), myalgia3) Infrequently: Pain in the lower extremities3), pain in the tendons (symptoms resembling tendonitis) 1)pain spine3) Rarely Urinary system: Nikturiya3) Rarely impaired renal function, including acute renal nedostatochnost1) mocheispuskaniya2 disorders), rapid mocheispuskanie2) Frequency unknown Reproductive system and breast Erectile disfunktsiya3) Infrequently General disorders: Peripheral oteki3) Often Asthenia (weakness) 3), chest pain3), increased fatigue3), edema3), feeling of a rush of blood to the face3) Infrequently Malaise3), flu-like syndrome1), hypertrophy of the gum mucous membrane3 ), dry mucous membranes of the oral cavity3) Rarely Pain2), weight gain2), weight loss2), gynecomastia2) Frequency unknown From laboratory indicators: Hyperkalemia1), anemia1), increased concentration of creatinine in the blood1) Infrequently Increasing the concentration of uric acid in the blood3 ), increased CK1 activity), decreased hemoglobin1), hypoglycemia (in patients with diabetes mellitus) 1), eosinophilia1) Rarely Thrombocytopenia1), 2) Rarely1), frequency unknown 2) Leukopenia2), hyperglycemia2) Frequency unknown 1) expected on the basis experience with telmisartan 2) expected based on experience with amlodipine 3) expected with simultaneous use of telmisartan and amlodipine Additional information on individual components Side effects that were previously reported when using one of the components of the drug (amlodipine or telmisartan) may increase with the use of the drug Twynsta, even if they were not observed in clinical studies or during the post-marketing period. Additional information regarding the combination of components Peripheral edema (dose-dependent side effect of amlodipine) was less common in patients who received the combination of telmisartan and amlodipine than in patients who received only amlodipine.
Overdose
No overdose cases have been identified. Possible symptoms consist of symptoms of overdose of individual components of the drug. Symptoms of telmisartan overdose: tachycardia, possibly bradycardia, dizziness, increased serum creatinine concentration, acute renal failure. Symptoms of amlodipine overdose: excessive reduction in blood pressure with the possible development of reflex tachycardia and symptoms of excessive peripheral vasodilation (the risk of severe and persistent arterial hypotension, including the development of shock and death).Treatment: conducting symptomatic and supportive therapy, monitoring the patient's condition. Such treatments as induction of vomiting, gastric lavage, the use of activated carbon can be used. In the case of a pronounced decrease in blood pressure of the patient should be transferred to a horizontal position with a low head; recommended administration of plasma-substituting solutions. In order to counter the blockade of calcium channels shown in / in the introduction of calcium gluconate. Hemodialysis is ineffective.
Interaction with other drugs
The interaction between the two active ingredients that are included in fixed doses in the composition of this drug in clinical studies was not observed. Special studies of drug interactions drug Twynsta with other drugs have been conducted. The combination of active ingredients If used simultaneously with other antihypertensive drugs, the hypotensive effect of Twynsta may increase. Some drugs (such as baclofen and amifostine), due to their pharmacological properties, can be expected to enhance the hypotensive effect of all anti-hypertensive drugs, including Twint. In addition, orthostatic hypotension may be enhanced by ethanol, barbiturates, narcotic drugs or antidepressants. With simultaneous use with corticosteroids (for systemic use), it is possible to reduce the antihypertensive effect. Based on the experience of using other drugs that affect the RAAS, simultaneous use of the drug Tvinsta and potassium-sparing diuretics, potassium supplements, potassium containing edible salt, other drugs that increase the content of potassium in the blood (for example, heparin) can lead to hyperkalemia. Therefore, the use of such combinations requires caution and control of the potassium content in the blood. Telmisartan With simultaneous use with other antihypertensive drugs may increase the anti-hypertensive effect. In one study, the combined use of telmisartan and ramipril showed an increase in AUC0-24 and Cmax of ramipril and ramiprilat by a factor of 2.5. The clinical significance of this interaction has not been established.Double blockade of the RAAS (for example, the simultaneous use of an ACE inhibitor or aliskiren, a direct inhibitor of renin with angiotensin II receptor antagonists) is not recommended due to possible impairment of renal function (including acute renal failure). It was noted a reversible increase in the concentration of lithium in the blood, accompanied by toxic effects when used simultaneously with ACE inhibitors. In rare cases, such changes have been reported with the appointment of angiotensin II receptor antagonists, in particular, telmisartan. With simultaneous use of lithium preparations and angiotensin II receptor antagonists, it is recommended to determine the content of lithium in the blood. NSAIDs, including acetylsalicylic acid (in doses used as an anti-inflammatory agent), COX-2 inhibitors and non-selective NSAIDs can cause the development of acute renal failure in patients with reduced BCC. Drugs affecting the activity of the RAAS, incl. telmisartan may have a synergistic effect. In patients receiving NSAIDs and telmisartan, at the beginning of treatment, BCC should be compensated and renal function should be investigated. With the simultaneous use of NSAIDs and antihypertensive drugs like telmisartan, a decrease in the antihypertensive effect was reported by inhibiting the vasodilating effect of prostaglandins. No clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin, ibuprofen, paracetamol and amlodipine was detected. An increase in the average concentration of digoxin in the blood plasma was noted on average by 20% (in one case by 39%). With simultaneous use of telmisartan and digoxin, it is advisable to periodically determine the concentration of digoxin in the blood. Amlodipine The simultaneous use of the drug Twynsta with grapefruit or grapefruit juice is not recommended, because In some patients, as a result of the increased bioavailability of amlodipine, its antihypertensive effect may be enhanced. In a study in elderly patients, diltiazem was shown to inhibit amlodipine metabolism, probably affecting CYP3A4 (amlodipine plasma concentrations increase by about 50% and the effect of amlodipine increases).It is possible that more active inhibitors of CYP3A4 (such as ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine more than diltiazem. Simultaneous use with CYP3A4 isoenzyme inducers (anticonvulsant drugs (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone), rifampicin, and St. John's wort (Hypericum perforatum) can reduce the concentration of amlodipine in blood plasma. Regular medical surveillance is indicated. It is recommended (if possible) to change the dose of amlodipine during the use of CYP3A4 inducers, as well as after their cancellation. The simultaneous use of simvastatin in a dose of 80 mg with amlodipine, regardless of the dose, helps to increase the exposure of simvastatin to 77% compared with simvastatin monotherapy. Therefore, the dose of simvastatin should not exceed 20 mg / day. With simultaneous use, amlodipine can increase the systemic exposure of cyclosporine or tasonermine. In such cases, it is recommended to regularly monitor the concentration of cyclosporine or tasonermine in the blood and dose adjustment, if necessary. The safety of simultaneous use of amlodipine with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin (used sublingually), NSAIDs, antibiotics and hypoglycemic drugs for oral administration has been established. With simultaneous use of amlodipine and sildenafil, it was shown that each drug had an independent antihypertensive effect. Additional information Simultaneous use of 240 ml of grapefruit juice with a single dose of amlodipine 10 mg taken orally in 20 healthy volunteers did not lead to a significant effect on the pharmacokinetic properties of amlodipine. The simultaneous use of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine. The simultaneous use of amlodipine with atorvastatin, digoxin or warfarin did not significantly affect the pharmacokinetics or pharmacodynamics of these drugs.
special instructions
During treatment with drugs that affect the RAAS, especially in the presence of impaired renal function and / or heart failure, hyperkalemia may occur.In these patients, it is recommended to regularly monitor the content of potassium in the serum. Periodic monitoring of serum creatinine is also recommended for patients with impaired renal function. In some patients, due to the suppression of the RAAS, especially when using a combination of agents acting on this system (for example, adding an ACE inhibitor or aliskiren, a direct renin inhibitor, to angiotensin II receptor antagonists), renal function is impaired (including acute renal failure). Therapy, accompanied by a similar double blockade of the RAAS, is not recommended and therefore should be limited and carried out strictly individually with careful monitoring of renal function. In cases of dependence of the vascular tone and kidney function, mainly on the activity of the RAAS (for example, in patients with chronic heart failure or kidney disease, including stenosis of the renal arteries), the administration of drugs affecting this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria, and, in rare cases, acute renal failure. In patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney, taking medications that affect the RAAS, there is an increased risk of severe arterial hypotension and renal failure. In patients with primary aldosteronism, antihypertensive drugs, whose mechanism of action is to inhibit the RAAS, are generally not effective. Thus, the use of telmisartan in such cases is not recommended. In patients with aortic or mitral stenosis, or in obstructive hypertrophic cardiomyopathy, the use of the drug Twynsta, as well as other vasodilators, requires special care. A clinical study found that the use of amlodipine in patients with heart failure of non-ischemic etiology of III and IV functional class (according to the NYHA classification) was accompanied by more frequent development of pulmonary edema (despite the absence of significant differences in the frequency of deterioration of heart failure compared with placebo).In patients with diabetes, IHD may be asymptomatic, as a result of which it may be undiagnosed. Patients with diabetes need to undergo an appropriate examination for the diagnosis and treatment of coronary artery disease (for example, an exercise test) before starting treatment with Tvinst. In patients with diabetes mellitus with concomitant IHD, the likelihood of a fatal myocardial infarction and sudden cardiovascular death may be increased by treating such antihypertensive drugs as angiotensin II receptor antagonists and ACE inhibitors. There is no data on the use of the drug Twynsta in patients with unstable angina, in the acute period and within one month after myocardial infarction. Limiting salt intake, intensive diuretic therapy, diarrhea or vomiting can lead to a decrease in BCC and / or hyponatremia, as a result of which symptomatic arterial hypotension may develop, especially after taking the first dose of the drug. Before using the drug Twynsta such conditions require correction. Experience with the use of the drug Twynsta in patients who have recently received a kidney transplant is absent. Amlodipine and telmisartan are not removed during hemodialysis. Periodic monitoring of serum potassium and creatinine is recommended for patients with impaired renal function. Recommendations regarding the dosing of the drug in patients with impaired liver function have not been developed, so care should be taken. Twynsta is effective in treating patients of the Negroid race (renin activity in the blood is usually reduced in this population). Impact on the ability to drive motor vehicles and control mechanisms No impact studies on the ability to drive motor vehicles and control mechanisms have been conducted. However, it should be taken into account that during treatment such undesirable effects as syncope, drowsiness or dizziness may occur. Therefore, care should be taken or to avoid the implementation of potentially dangerous activities such as driving a motor vehicle or operating machinery.