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Instruction for use: Brimonidine (Brimonidinum)

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Chemical rational name: 5-Bromo-N- (4,5-1H-imidazol-2-yl) quinoxalin-6-amine (as the L-tartrate)

Pharmacotherapeutic group:

Alpha-adrenoceptor agonists

Ophthalmic agents

The nosological classification (ICD-10)

H40.0 Suspected glaucoma

Marked rise in intraocular pressure, Hypertension eyes, ocular hypertension, Measurement of intraocular pressure, ophthalmohypertension, Elevated IOP, Elevated intraocular pressure, Elevated intraocular pressure in infectious diseases of the eye, Elevated intraocular pressure, Increased, ophthalmotonus, Spontaneous blockade angle opposite eye, Narrow chamber angle, Iatrogenic blockade angle opposite eye

H40.1 Primary open-angle glaucoma

open-angle glaucoma, Open-angle glaucoma, Primary glaucoma, pseudoexfoliation glaucoma, Elevated IOP

L53 Other erythematous conditions

variable eythrokeratodermia, Malignant exudative erythema, Erythema, erythematosus, erythroderma, Erythema of the diaper

L71 Rosacea

rosacea, Acne red, Acne pink, Red acne

CodeCAS 59803-98-4

Characteristics substance of Brimonidine

Brimonidine tartrate - powder white to slightly yellowish color, is soluble in water. Molecular Weight - 442.24.

Pharmacological Properties of BrimonidinePharmachologic effect
Mode of action - alpha adrenomimeticheskoe, lowering intraocular pressure.

pharmacodynamics

Brimonidine is an agonist highly selective alpha2-adrenergic receptors: its affinity for alpha2-adrenergic receptors in 1000 times the affinity for alpha1-adrenergic receptors.

When used in the form of eye drops drug 0.15-0.2% maximum IOP reduction achieved in 2 hours. The antihypertensive effect of brimonidine is provided by reducing the formation and increase the outflow of intraocular fluid by uveoscleral path.

Drawing on the skin (in the form of a gel for external use), a highly selective agonist of the alpha2-adrenergic receptors leads to a decrease in erythema due to direct vasoconstriction of skin vessels.

Pharmacokinetics

eye drops

When instillation 0.15-0.2% brimonidine eye drops Cmax plasma levels achieved through 0.5-2.5 h, T1 / 2 is about 2 hours. Systemic absorption of brimonidine slowly. It is metabolized primarily in the liver. Brimonidine and its derived metabolites kidneys.

Absorption. In a pharmacokinetic study in 14 healthy volunteers (4 men and 10 women) were used 0.15% ophthalmic solution of brimonidine topically once, in a single drop in one eye. Plasma Cmax and AUC0-inf were (73 19) pg / ml (375 89) pg h / ml, respectively. Tmax -. (1,7 0,7) h system a half-life was approximately 2.1 hours.

Metabolism. Brimonidine is metabolized primarily in the liver. Metabolism in vitro data obtained using microsomal fractions of human liver slices and show that brimonidine undergoes extensive hepatic metabolism.

Withdrawal. Excretion through the kidneys - the main route of elimination of brimonidine and its metabolites. Approximately 87% of the orally administered dose excreted radiolabelled brimonidine for 120 hours, with 74% of the radioactivity detected in urine.

Gel for external use

Suction. The absorption of brimonidine in the form of a gel for topical application was studied in a clinical study in 24 adult patients with facial erythema in rosacea. With once-daily application to the skin for 29 days, the accumulation of plasma brimonidine was not observed.

Absorption. The absorption of brimonidine in the form of a gel for topical application was evaluated in a clinical study in 24 adult patients with facial erythema in rosacea. All patients once daily 1 g of gel was applied to the entire face for 29 days. Pharmacokinetic evaluation was performed in the 1 st, 15 th and 29 th day. The values of Cmax and AUC in plasma was highest in the 15-day mean values of Cmax and AUC were and ( standard deviation) (46 62) pg / ml (417 264) pg h / ml, respectively. Systemic exposure was slightly below the 29-day, indicating no further accumulation.

Metabolism. Brimonidine is extensively metabolised in the liver.

Withdrawal. Brimonidine and its metabolites are excreted primarily through the kidneys.

Indications for Brimonidine
Eye drops: open-angle glaucoma; ocular hypertension (as monotherapy or in combination with other drugs that lower the IOP).

Gel for external use: Treatment of facial erythema in rosacea.

Contraindications for Brimonidine

Eye drops: Hypersensitivity to brimonidine; Simultaneous therapy MAO inhibitors and tricyclic antidepressants; Children under 2 years of age, low body weight (20 kg); lactation.

Gel for external use: Hypersensitivity to brimonidine; concomitant use with MAO inhibitors (eg selegiline or moclobemide), tricyclic (imipramine) and tetracyclic (maprotiline, mianserin and mirtazapine) antidepressants influencing the noradrenergic transmission; Children up to age 18 years (safety and efficacy has not been established for this age group).

Restrictions on the use

Eye drops: patients with renal (Cl creatinine less than 40 ml / min) or hepatic failure. In patients with orthostatic hypotension, congestive heart failure and cerebrovascular insufficiency, depression, Raynaud's syndrome, thromboangiitis obliterans brimonidine may exacerbate the severity of the diseases caused by vascular insufficiency. While 0.2% brimonidine in clinical studies to have a minimal impact on blood pressure and heart rate in patients with severe cardiovascular disease, as well as patients with unstable and uncontrolled cardiovascular disease course, care must be taken. In children aged 2 to 7 years.

Gel for external use: pregnancy; liver and kidney function.

Pregnancy and breast-feeding

Drops eye. Preclinical studies revealed no effects on reproductive function. However it found that brimonidine crosses the placental barrier and is contained in small quantities in the fetal blood plasma. The damaging effect on the fetus has been established. Controlled studies in pregnant women have been conducted. During pregnancy brimonidine eye drops should be used with extreme caution, only in cases where the expected benefit to the mother is significantly greater than the potential risk to the fetus.

In animal studies have shown that brimonidine tartrate into breast milk. At the time of application of lactation the drug should be discontinued.

Gel for external use. Data on the use of brimonidine in pregnancy limited or absent. Reproductive toxicity studies in animals did not reveal any direct or indirect adverse effects of the drug. As a precaution it is recommended to avoid application of the gel during pregnancy.

It is unknown whether brimonidine and its metabolites in breast milk. In this connection, it is impossible to eliminate the risk for newborns and infants. Brimonidine as a gel for topical use should not be used during breastfeeding.

Category effects on the fetus by FDA - B.

Adequate and well-controlled studies of brimonidine in a 0.1 or 0.15% ophthalmic solution or as a gel in pregnant women is not carried out. In animal studies found that brimonidine crossed the placenta and enters the fetal circulation to a limited extent. Brimonidine as a 0.1 or 0.15% ophthalmic solution or as a gel to be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

It is not known whether brimonidine tartrate is excreted into breast milk, although in animal studies have shown that brimonidine tartrate is excreted into breast milk. Because of the potential for serious adverse reactions in infants of women in the application of brimonidine in a 0.1 or 0.15% ophthalmic solution or as a topical gel should stop breastfeeding or to discontinue the application of the gel, taking into account the importance of the treatment to the mother.

Side effects of Brimonidine

eye drops

The most commonly observed adverse reactions on the part of the organ of vision are allergic conjunctivitis, conjunctival hyperemia, mucosal itching eye and eyelid skin. Most of the adverse reactions had a transient in nature and mild (not requiring discontinuation of treatment). According to clinical studies, the symptoms of allergic reactions have been observed by the eye in 12.7% of cases (causing cessation of treatment 11.5% of the cases), with the majority of patients are manifested after 3-6 months using brimonidine (according to current information about experience of using brimonidine at a concentration of 0.2%).

The incidence of adverse effects identified in the studies was assessed as follows: very common (> 10%); frequent (> 1% and <10%); uncommon (> 0.1% and <1%); rarely (> 0.01% and <0.1%).

The following side effects identified in clinical studies:

From a sight organ: very often - allergic conjunctivitis, conjunctival hyperemia, itching, eye irritation and skin of eyelids, blurred vision; often - burning sensation, conjunctival folliculosis or follicular conjunctivitis, local allergic reactions on the part of the eye (including keratoconjunctivitis), blurred vision, blepharitis, Blepharoconjunctivitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, epiphora, epiphora, mucous discharge from the eyes, dryness and eye irritation, eye pain, eyelid edema, redness of the eyelids, foreign body sensation in eyes, keratitis, destruction age, photosensitivity, stabbing sensation in the eye, superficial punctate keratopathy, lacrimation, loss of visual fields, detachment vitreous hemorrhage in the vitreous floaters in the vitreous, and decreased visual acuity; infrequently - corneal erosion and barley.

CNS: often - headache, drowsiness, insomnia, dizziness.

From the CCC: often - increase or decrease in blood pressure.

From the respiratory system: often - bronchitis, pharyngitis, cough, shortness of breath; rare - dryness of the nasal mucosa; apnea.

On the part of the digestive tract: often - gastrointestinal disorders (dyspepsia, dry oral mucosa).

Skin and subcutaneous tissue: often - a rash.

Infectious and parasitic diseases: often - grippopodobnuy syndrome, infectious disease (fever and respiratory infection), rhinitis, sinusitis, including infectious.

Laboratory tests: often - hypercholesterolemia.

Other: often - a common allergic reaction, asthenia, fatigue, taste disturbance; infrequently - dysgeusia.

Children (including neonates and infants) observed apnea, bradycardia, decreased blood pressure, hypothermia, muscular hypotension, pallor, drowsiness, decreased attention. Individual serious adverse reactions, such as the occurrence of coma, lethargy and respiratory depression in the neonate and infant, ie in an age in which the use of drugs not approved, have been reported with the use of a concentration of 0.2%, exceeding the recommended concentration.

In post-marketing period, further received reports of the following side effects:

From a sight organ: the frequency is unknown - iritis, keratoconjunctivitis sicca, cramps.

CNS: depression, syncope.

From the CCC: bradycardia, tachycardia.

On the part of the digestive tract: nausea.

Skin and subcutaneous tissue: local skin reactions (erythema, itching of the eyelids, swelling of the face, rash and vasodilatation of skin vessels eyelids and face), hypersensitivity.

Experience in clinical research

As the clinical trials conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not be directly compared with the frequency of other clinical trials and to predict the occurrence of side effects in clinical practice.

Adverse reactions identified in approximately 10-20% of the subjects who used ophthalmic solution (0.1-0.2%) brimonidine included allergic conjunctivitis, conjunctival hyperemia and itching in the eye. Adverse reactions were observed in approximately 5-9% of the participants included the burning sensation, folliculosis conjunctiva, increased blood pressure, eye allergies, dryness of the oral mucosa, impaired vision.

Adverse reactions were marked at approximately 1-4% of the subjects who used ophthalmic solution (0.1-0.2%) brimonidine included taste disturbance, allergic reaction, asthenia, blepharitis, Blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival edema, hemorrhage conjunctiva, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, epiphora, discharge from the eyes, dry mucous membranes of the eyes, eye irritation, eye pain, eyelid edema, erythema of eyelid, fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation in eye, gastrointestinal disorders, headache, hypercholesterolemia, lowering blood pressure, infection (primarily colds and respiratory infections), insomnia, keratitis, defeated century, pharyngitis, photophobia, rash, rhinitis, sinusitis, sinusitis, sleepiness, feeling tingling sensations in the eyes, superficial punctate keratopathy, lacrimation increased, visual field loss, vitreous detachment, vitreous loss, deterioration of visual acuity.

The following reactions were reported in less than 1% of cases: corneal erosion, barley, dry nasal mucosa, taste perversion.

Post-marketing experience

Since the reports of these reactions have been reported voluntarily from a population of uncertain size, as it is not usually possible to reliably estimate their frequency or establish a causal relationship to drug action. The reactions have been chosen for inclusion due to their seriousness, frequency and possible causal relationship to the use of ophthalmic solutions of brimonidine or a combination of these factors include: bradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, cramps, nausea, skin reactions (in including erythema, itching of the eyelids, rash and vasodilatation), syncope, tachycardia. Children who used brimonidine ophthalmic solutions have been reported apnea, bradycardia, coma, decreased blood pressure, hypothermia, hypotension, lethargy, pallor, respiratory depression and drowsiness.

Gel for external use

The most common adverse reactions, including redness, itching, hyperemia and burning sensation of the skin were noted in patients 1,2-3,3% of the cases in clinical trials. As a rule, it was the reaction of mild or moderate severity, which did not lead to treatment discontinuation. Significant differences in the safety profiles in elderly patients and in patients aged 18 to 65 years have been identified. The Post-registration period was marked by frequent gain redness, flushing and burning sensation of the skin. Cases of swelling of the face, and urticaria have been marked as infrequent.

Adverse reactions obtained in clinical trials are classified according to organ system and frequency of development. The frequency of adverse reactions were classified as follows: very common (> 1/10); often (> 1/100 to <1/10); uncommon (> 1/1000 to <1/100); rare (> 1/10000 to <1/1000); very rare (<1/10000); Frequency not known (can not be estimated from the available data).

From the nervous system: rarely - headache, paresthesia.

From a sight organ: rare - swelling of the eyelids.

On the part of the vessels: common - redness.

The respiratory system, organs, thoracic and mediastinal disorders: uncommon - nasal congestion.

On the part of the digestive tract: rarely - dry mouth.

Skin and subcutaneous tissue disorders: common - redness, itching, burning sensation of the skin; infrequently - Rosacea, dermatitis, skin irritation, feeling of warmth on the skin, contact dermatitis, allergic contact dermatitis, dry skin, sore skin, skin discomfort, papular rash, acne, swelling of the face *, urticaria *.

General disorders and administration site at: Infrequent - feeling hot, feeling cold in the extremities.

experience in clinical research

As the clinical trials conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not be directly compared with the frequency of other clinical trials and to predict the occurrence of side effects in clinical practice.

During clinical trials, 1210 participants had used brimonidine in the form of a gel for topical use. A total of 833 people were treated resistant (imperishable), erythema associated with rosacea, and 330 of them used the gel once a day for 29 days in a controlled trial (control - the basis of the gel).

Adverse reactions that have been observed in at least 1% of patients treated with the gel once a day for 29 days, and the frequency at which the gel exceeded background incidence of side effects on the control of the background (the base gel) are shown below.

Next to the name indicates the number of patients in patients receiving brimonidine as a gel for topical application experienced this side effect, in brackets - the frequency of adverse effects as a percentage, a comma - similar findings in a group of patients treated with control. Brimonidine as a gel for topical application used 330 subjects, control group was 331 people.

Subjects with at least one adverse event, the number (%) 109 subjects (33), 91 (28).

Erythema 12 (4%), 3 (1%).

Hyperemia 9 (3%), 0.

Burning sensation of the skin 5 (2%), 2 (1%).

Contact dermatitis: 3 (1%) 1 (<1%).

Dermatitis 3 (1%) 1 (<1%).

Feeling of warmth on the skin: 3 (1%), 0.

Paresthesia: 2 (1%) 1 (<1%).

Acne: 2 (1%) 1 (<1%).

Soreness of the skin: 2 (1%) 0.

Blurring: 2 (1%), 0.

nasal congestion: 2 (1%), 0.

Open long-term study

Open study of brimonidine in the form of a gel when applied once a day for up to 1 year was conducted in patients with persistent (imperishable), facial erythema associated with rosacea. Participants were allowed to use a different treatment of rosacea. A total of 276 participants applied brimonidine in gel form for at least 1 year. The most common adverse events (≥ 4% of subjects) during the study were flushing (10%), erythema (8%), rosacea (5%), nasopharyngitis (5%), burning of the skin (4%), increased IOP (4 %) and headache (4%).

Contact type allergy

On the development of allergic contact dermatitis when using brimonidine in the form of a gel for topical application was reported in approximately 1% of the participants throughout the clinical trial program. Two of the subjects carried out a test with the individual components of the preparation. One participant was found sensitivity to brimonidine tartrate, the other - to phenoxyethanol (preservative).

Post-marketing experience

Since the reports of these reactions have been reported voluntarily from a population of uncertain size, as it is not usually possible to reliably estimate their frequency or establish a causal relationship to drug action.

From the CCC: bradycardia, hypotension (including orthostatic hypotension).

Immune system: angioneurotic edema, hypersensitivity, swelling of the lips, tongue, throat, rash.

From the nervous system: dizziness.

Skin and subcutaneous tissue disorders: pallor.

Interaction

Research for the study of the interaction of brimonidine in the form of eye drops or gel for topical use with other drugs have not been conducted. However, when the simultaneous application should be considered an opportunity to enhance the effect of drugs which depress the central nervous system (alcohol, barbiturates, opiates, sedatives, general anesthetics).

Patients taking MAO inhibitors, and patients taking tricyclic and tetracyclic antidepressants that affect noradrenergic transmission, the use of brimonidine is not recommended (see. "Contraindications" and "Restrictions on the use").

Data on the effect of brimonidine on the level of circulating catecholamines absent. However, caution is recommended in patients receiving drugs that can affect the metabolism of amines and increase their concentration in the blood. It is recommended to be careful at simultaneous application with other brimonidine ophthalmic drug or changing the dose in the treatment of ophthalmic diseases.

Caution is recommended at the beginning of the treatment or change the dose prescribed together systemic drugs (regardless of the dosage form) which may interact with agonists of alpha-adrenergic receptors or to influence their activity, i.e. They are agonists or antagonists of adrenergic receptors (such as isoprenaline, prazosin).

Some patients brimonidine can cause clinically significant reductions in blood pressure, so be careful when using drugs such as antihypertensives and / or cardiac glycosides, together with brimonidine.

Overdose

eye drops

Overdosing the local application

Symptoms of overdose by topical application submitted previously marked adverse reactions.

Overdose Accidental ingestion

Reported cases of drug overdose in adults is sufficiently small.

Today registered one adverse reaction associated with a reduction in blood pressure. With the development of arterial hypotension was observed subsequently rebound hypertension.

If you accidentally taking the drug inside you have the following symptoms: CNS depression, drowsiness, depression, and loss of consciousness, decreased blood pressure, bradycardia, decreased body temperature, skin cyanosis, apnea, fatigue, vomiting, seizures, arrhythmias, miosis.

If any symptoms of overdose symptomatic therapy is necessary, control the airway.

Overdose in children

The symptoms of brimonidine overdose have been observed in the treatment of congenital glaucoma or accidental ingestion in younger children. In case of overdose of required maintenance and symptomatic therapy, as well as may be required intensive care with intubation. Complete relief of symptoms of brimonidine overdose in all reported cases occurred within 6-24 hours.

Gel for external use

Information on overdose with topical brimonidine in adults missing patients.

In case of accidental application of such phenomena into possible overdose alpha2 receptor agonists, as hypotension, weakness, vomiting, drowsiness, lethargy, bradycardia, arrhythmias, miosis, apnea, hypotonia, hypothermia, respiratory depression and convulsions.

In the clinical study, it was noted 2 cases of serious adverse events caused by accidental ingestion of the gel younger children. Observed in children symptoms consistent with the known symptoms of overdose alpha2 receptor agonists in young children and within 24 hours had completely disappeared.

Treatment of overdose ingestion includes supportive and symptomatic therapy, a patent airway should be maintained.

Routes of administration

Locally, externally.

Precautions of Brimonidine

eye drops

Brimonidine as eye drops may be used with other ophthalmic agents to reduce IOP. When using two or more medications to do a 5-minute break between the instillation.

Contact lenses should be removed before use of the drug. The time interval between the use of the drug and re-installation of contact lenses must be at least 15 minutes.

The use of brimonidine in the form of eye drops have not studied in patients with impaired hepatic or renal function; in the treatment of these patients need to be careful.

Use in children. The 3-month Phase 3 study in children aged 2-7 years with glaucoma and poor control of the disease with beta-blockers have noted a high incidence of somnolence (55%) when using 0.2% brimonidine as adjunctive therapy. Drowsiness was strongly expressed in 8% of the children was the reason for discontinuation of treatment in 13% of cases. Drowsiness frequency decreased with increasing age and was minimal in the 7-year-old children (25%) but mainly determined by weighing drowsiness frequently observed in children weighing ≤20 kg (63%) compared to children weighing> 20 kg (25%).

Careful observation and monitoring of patients aged 2 to 7 years (especially with a body weight up to 20 kg) due to the high frequency of occurrence and severity of sleepiness.

Safety and efficacy in children younger than 2 years of age have not been established.

Applications in Pediatrics

In a well-controlled clinical trial in patients with glaucoma (ages 2 to 7 years), the most commonly observed adverse reactions in the application of 0.2% ophthalmic solution of brimonidine tartrate three times a day on a daily basis were somnolence (50-83% in patients between the ages of 2 to 6 years) and decreased alertness. In pediatric patients 7 years of age (> 20 kg) appeared less drowsiness (25%). Approximately 16% of children who used the ophthalmic solution of brimonidine tartrate, were excluded from the study because of sleepiness.

The use in the elderly. In elderly people not observed differences in safety or efficacy as compared to other adult patients. Cmax and T1 / 2 of brimonidine were similar in elderly (65 years and older) and younger patients the adult population that shows no significant effect of age on the systemic absorption and excretion of brimonidine.

With the development of allergic reactions should stop treatment and seek medical advice.

Perhaps the increased IOP in the event of delayed hypersensitivity reactions.

Reported cases of bacterial keratitis when using multidose vials ophthalmic agent for topical application, the infected patients, who in most cases had concomitant disease of the cornea or the concomitant loss of the corneal epithelium and conjunctiva.

If not handled properly, or if the vial-dropper tip comes into contact with the eye or surrounding structures eye, ophthalmic preparations may be infected with the bacteria that cause eye infections. Using infected solution may cause serious damage to the eyes, followed by loss of sight.

If was moved ophthalmic surgery or arose accompanying eye disease (such as trauma or infection), you should immediately consult a doctor regarding the continued use of the multidose vial-dropper.

Effects on ability to drive vehicles and mechanisms. Use of brimonidine as eyedrops episodes may be accompanied by sleepiness and weakness in some patients. In that case, if the work of the patient associated with potentially hazardous activities, driving motor vehicles, it is necessary to warn in advance about the possible reduction of the concentration of attention and speed of psychomotor reactions, and to recommend to refrain from such activities.

Gel for external use

The gel should not be applied to irritated skin or open wounds, the area around the eyes. In the case of express irritation or allergy is necessary to interrupt treatment.

After the application must be sure to wash your hands. Brimonidine in the form of a gel may be used in conjunction with other drugs used for the treatment of inflammatory rosacea elements. They can be applied to the skin only after the gel has dried, but not simultaneously. After application and drying, the gel is possible to use cosmetics.

Erythema and hyperemia. Action brimonidine as a gel begins to subside after a few hours after application. Some patients have been described renewed transient redness and erythema in more severe than before treatment. Most cases of erythema was observed during the first 2 weeks after initiation of treatment.

Some patients had transient hyperemia. Start Time hyperemia after application of the gel was varied from 30 minutes to several hours.

In most cases, erythema and redness took place after discontinuation of the drug.

In case of worsening of erythema use gel should be discontinued. Symptomatic measures, such as cooling, intake of NSAIDs and antihistamines can alleviate the symptoms.

Upon the resumption of the use of brimonidine in the form of a gel recurrent exacerbations observed erythema and hyperemia. However, if necessary, treatment can be resumed after recovery of the skin barrier function, starting with a trial application of the gel on a small area of a person not less than 1 day prior to the resumption of full treatment of all skin.

Erythema. As the post-marketing reports, some patients noted the resumption of erythema involving the areas of the face that have not been affected, as well as skin outside of treatment (such as the neck and décolletage).

Pallor and excessive white. In post-marketing reports indicate that some patients had pallor or excessive white in the place of application of the gel or outside brimonidine after treatment in the form of a gel.

It is necessary to strictly observe the recommended dose and frequency of application: once a day, a very thin layer.

It is necessary to avoid increasing the maximum daily dose and / or frequency of application, because security higher daily doses or repeated daily use has not been established.

Concomitant use with systemic alpha-adrenergic agonists receptor may potentiate the side effects of this class of drugs in patients with:

- Severe or uncontrolled or unstable cardiovascular disease;

- Depression, cerebral or coronary insufficiency blood circulation, Raynaud's disease, orthostatic hypotension, thromboangiitis obliterans, scleroderma or Sjögren's syndrome.

Effects on ability to drive and use machines. The drug has no effect or little effect on the ability to drive vehicles or to engage in other potentially hazardous activities that require high concentration and psychomotor speed reactions.

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