Symptoms of overdose
In the few cases of overdose that have been reported, a dose of 19.6 mg was ingested acutely without fatality. Signs and symptoms reported included: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. Based on the pharmacodynamic properties of Физиотенз, the following reactions may be expected in adults: headache, sedation, somnolence, hypotension, orthostatic dysregulation, dizziness, asthenia, bradycardia, dry mouth, fatigue and upper abdominal pain. In rare cases, emesis and a transient paradoxical increase in blood pressure can occur. In case of a severe overdose close monitoring of especially consciousness disturbances and respiratory depression is recommended.
In addition, based on a few high dose studies in animals, transient hypertension, tachycardia and hyperglycaemia may also occur.
Treatment of overdose
In the case of a severe overdose, in particular the observation of disorders of consciousness and respiratory depression is advisable. Treatment consists of absorption-reducing measures such as gastric lavage (if shortly after ingestion), administration of activated charcoal and laxatives, and otherwise is symptomatic.
No specific antidote is known.
In case of hypotension, circulatory support such as fluids and dopamine administration may be considered. Bradycardia may be treated with atropine. Alpha-receptor antagonists may diminish or abolish the paradoxical hypertensive effects of a Физиотенз overdose.
Paediatric population
The following case of inadvertent overdose in a 2-year old child has been described:
The child ingested an unknown quantity of Физиотенз. The maximum dose that could have been taken was 14 mg. The child exhibited the following symptoms: Sedation, coma hypotension, miosis and dyspnoea. Gastric lavage, glucose infusions, mechanical ventilation and rest resulted in the symptoms completely disappearing over the course of 11 hours.
Symptoms of overdose
In the few cases of overdose that have been reported, a dose of 19.6 mg was ingested acutely without fatality. Signs and symptoms reported included: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. Based on the pharmacodynamic properties of Физиотензidine, the following reactions may be expected in adults: headache, sedation, somnolence, hypotension, orthostatic dysregulation, dizziness, asthenia, bradycardia, dry mouth, fatigue and upper abdominal pain. In rare cases, emesis and a transient paradoxical increase in blood pressure can occur. In case of a severe overdose close monitoring of especially consciousness disturbances and respiratory depression is recommended.
In addition, based on a few high dose studies in animals, transient hypertension, tachycardia and hyperglycaemia may also occur.
Treatment of overdose
In the case of a severe overdose, in particular the observation of disorders of consciousness and respiratory depression is advisable. Treatment consists of absorption-reducing measures such as gastric lavage (if shortly after ingestion), administration of activated charcoal and laxatives, and otherwise is symptomatic.
No specific antidote is known.
In case of hypotension, circulatory support such as fluids and dopamine administration may be considered. Bradycardia may be treated with atropine. Alpha-receptor antagonists may diminish or abolish the paradoxical hypertensive effects of a Физиотензidine overdose.
Paediatric population
The following case of inadvertent overdose in a 2-year old child has been described:
The child ingested an unknown quantity of Физиотензidine. The maximum dose that could have been taken was 14 mg. The child exhibited the following symptoms: Sedation, coma hypotension, miosis and dyspnoea. Gastric lavage, glucose infusions, mechanical ventilation and rest resulted in the symptoms completely disappearing over the course of 11 hours.
Физиотенз is contraindicated in patients with:
- sick sinus syndrome
- bradycardia (resting HR <50 beats/minute)
- 2nd or 3rd degree atrioventricular block
- cardiac insufficiency
Физиотензidine is contraindicated in patients with:
- sick sinus syndrome
- bradycardia (resting HR <50 beats/minute)
- 2nd or 3rd degree atrioventricular block
- cardiac insufficiency
Not applicable.
Most frequent side effects reported by those taking Физиотенз include dry mouth, dizziness, asthenia and somnolence. These symptoms often decrease after the first few weeks of treatment. Undesirable Effects by System Organ Class (observed during placebo-controlled clinical trials with n=886 patients exposed to Физиотенз resulted in frequencies below):
*there was no increase in frequency compared to placebo
| Very common (>1/10) | Common (>1/100, <1/10) | Uncommon (>1/1,000, <1/100) | Very rare (<1/10,000) | |
| Endocrine disorders | Gynaecomastia, impotence and loss of libido | |||
| Psychiatric disorders | Altered thought processes, insomnia | Anxiety, nervousness, anorexia | ||
| Nervous system disorders | Sleep disturbances, headache*, dizziness, vertigo, somnolence | Sedation, syncope* | ||
| Eye disorders | Dry, itching or burning sensation of the eye | |||
| Ear and labyrinth disorders | Tinnitus | |||
| Cardiac disorders | Bradycardia | |||
| Vascular disorders | Vasodilatation | Hypotension (including orthostatic), paraesthesia of extremities, peripheral circulation disorders | ||
| Gastrointestinal disorders | Dry mouth | Diarrhoea, nausea / vomiting / dyspepsia*, constipation and other gastrointestinal disorders | ||
| Hepatobiliary disorders | Hepatic reactions | |||
| Skin and subcutaneous tissue disorders | Rash / Pruritus, | Angioedema | ||
| Musculosketal and connective tissue disorders | Back pain | Neck pain | ||
| General disorders and administration site conditions | Asthenia | Oedema of different location, leg weakness, fluid retention, parotid pain |
*there was no increase in frequency compared to placebo
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Most frequent side effects reported by those taking Физиотензidine include dry mouth, dizziness, asthenia and somnolence. These symptoms often decrease after the first few weeks of treatment. Undesirable Effects by System Organ Class (observed during placebo-controlled clinical trials with n=886 patients exposed to Физиотензidine resulted in frequencies below):
*there was no increase in frequency compared to placebo
| Very common (>1/10) | Common (>1/100, <1/10) | Uncommon (>1/1,000, <1/100) | Very rare (<1/10,000) | |
| Endocrine disorders | Gynaecomastia, impotence and loss of libido | |||
| Psychiatric disorders | Altered thought processes, insomnia | Anxiety, nervousness, anorexia | ||
| Nervous system disorders | Sleep disturbances, headache*, dizziness, vertigo somnolence | Sedation, syncope* | ||
| Eye disorders | Dry, itching or burning sensation of the eye | |||
| Ear and labyrinth disorders | Tinnitus | |||
| Cardiac disorders | Bradycardia | |||
| Vascular disorders | Vasodilatation | Hypotension (including orthostatic), paraesthesia of extremities, peripheral circulation disorders | ||
| Gastrointestinal disorders | Dry mouth | Diarrhoea, nausea / vomiting / dyspepsia*, constipation and other gastrointestinal disorders | ||
| Hepatobiliary disorders | Hepatic reactions | |||
| Skin and subcutaneous tissue disorders | Rash / Pruritus, | Angioedema | ||
| Musculosketal and connective tissue disorders | Back pain | Neck pain | ||
| General disorders and administration site conditions | Asthenia | Oedema of different location, leg weakness, fluid retention, parotid pain |
*there was no increase in frequency compared to placebo
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Preclinical data reveal no special hazard for humans based on conventional studies of repeated toxicity, genotoxicity and carcinogenic potential.
Reproductive toxicity studies revealed no effects on fertility and no teratogenic potential. Embryotic effects were seen in rats and in rabbits. In a perinatal and postnatal study in rats the development as well as the viability of the offspring was affected. All effects were seen at maternal toxic dosages above the human exposure.
Физиотенз is indicated in adults for treatment of mild to moderate essential hypertension.
Физиотензidine is indicated in adults for treatment of mild to moderate essential hypertension.
Pharmacotherapeutic group: Antihypertensives, antiadrenergic agents, centrally acting
ATC code: C02AC05
In various animal models it has been shown that Физиотенз has a strongly hypotensive effect. Available experimental data indicate that the site of action of Физиотенз is located in the central nervous system (CNS).
In the brain stem, Физиотенз binds selectively to I1-imidazoline receptors. These imidazoline-sensitive receptors are predominantly found in the rostral ventrolateral medulla, an area which plays an important role in central control of the sympathetic nervous system. The effect of this interaction with these I1-imidazoline receptors appears to be a reduction in the activity of the sympathetic nerves. This has been demonstrated for cardiac, splanchnic and renal sympathetic nerves.
Физиотенз differs from other centrally acting antihypertensives in the fact that it has only a weak affinity for the central α2-adrenergic receptors compared to the affinity for I1-imidazoline receptors. Alpha2-adrenergic receptors are considered to be the intermediate pathway that causes sedation and dry mouth, the most commonly observed undesirable effects of centrally acting antihypertensives.
Mean systolic and diastolic blood pressure is reduced both at rest and during exercise. The effects of Физиотенз on mortality and cardiovascular morbidity are currently unknown.
In humans, Физиотенз leads to a reduction of systemic vascular resistance and consequently in arterial blood pressure.
Pharmacotherapeutic group: Antihypertensives, antiadrenergic agents, centrally acting
ATC code: C02AC05
In various animal models it has been shown that Физиотензidine has a strongly hypotensive effect. Available experimental data indicate that the site of action of Физиотензidine is located in the central nervous system (CNS).
In the brain stem, Физиотензidine binds selectively to I1-imidazoline receptors. These imidazoline-sensitive receptors are predominantly found in the rostral ventrolateral medulla, an area which plays an important role in central control of the sympathetic nervous system. The effect of this interaction with these I1-imidazoline receptors appears to be a reduction in the activity of the sympathetic nerves. This has been demonstrated for cardiac, splanchnic and renal sympathetic nerves.
Физиотензidine differs from other centrally acting antihypertensives in the fact that it has only a weak affinity for the central α2-adrenergic receptors compared to the affinity for I1-imidazoline receptors. Alpha2-adrenergic receptors are considered to be the intermediate pathway that causes sedation and dry mouth, the most commonly observed undesirable effects of centrally acting antihypertensives.
Mean systolic and diastolic blood pressure is reduced both at rest and during exercise. The effects of Физиотензidine on mortality and cardiovascular morbidity are currently unknown.
In humans, Физиотензidine leads to a reduction of systemic vascular resistance and consequently in arterial blood pressure.
Absorption
Физиотенз is rapidly absorbed after oral administration. In humans, approximately 90% of an oral dose is absorbed. Ingestion of food has no effect on the pharmacokinetics of Физиотенз. There is no first-pass metabolism and bioavailability is 88 %.
Distribution
Only about 7% of Физиотенз is bound to human plasma proteins (Vdss = 1.8 ± 0.4 l/kg). Peak plasma levels of Физиотенз are reached 30-180 minutes after administration of a film-coated tablet.
Biotransformation
Физиотенз is 10-20% metabolised, predominantly to 4,5-dehydroФизиотенз and to an aminomethanamidine derivative by opening of the imidazoline ring. The hypotensive effect of 4,5-dehydroФизиотенз is only 1/10, and that of the aminomethanamidine derivative less than 1/100, of that of Физиотенз.
Elimination
Физиотенз and its metabolites are almost entirely eliminated via the kidney. More than 90% of the dose is eliminated in the first 24 hours via the kidney, while approximately 1% is eliminated in the faeces. The cumulative excretion of unchanged Физиотенз is approximately 50-75%. The mean plasma elimination half-life is 2.2-2.3 hours and the renal half-life 2.6-2.8 hours.
Characteristics in patients with renal impairment
In patients with moderately impaired renal function (GFR 30 - 60 ml/min), the AUC increased by 85% and the clearance decreased by 52%. In such patients the hypotensive effect of Физиотенз should be closely monitored, especially at the start of treatment. The dose must be adapted in these patients so that the maximum daily dose is not more than 0.4 mg and the maximum single dose is 0.2 mg.
In patients with severely impaired renal function (GFR < 30 ml/min) the clearance is reduced by 68 % and the elimination half live is prolonged up to 7 hours. In these patients Физиотенз dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.3 mg daily, if clinically indicated and well tolerated. In such patients the hypotensive effect of Физиотенз should be closely monitored, especially at the start of treatment.
Paediatric population
No pharmacokinetic studies in children have been performed.
Absorption
Физиотензidine is rapidly absorbed after oral administration. In humans, approximately 90% of an oral dose is absorbed. Ingestion of food has no effect on the pharmacokinetics of Физиотензidine. There is no first-pass metabolism and bioavailability is 88 %.
Distribution
Only about 7% of Физиотензidine is bound to human plasma proteins (Vdss = 1.8 ± 0.4 l/kg). Peak plasma levels of Физиотензidine are reached 30-180 minutes after administration of a film-coated tablet.
Biotransformation
Физиотензidine is 10-20% metabolised, predominantly to 4,5-dehydroФизиотензidine and to an aminomethanamidine derivative by opening of the imidazoline ring. The hypotensive effect of 4,5-dehydroФизиотензidine is only 1/10, and that of the aminomethanamidine derivative less than 1/100, of that of Физиотензidine.
Elimination
Физиотензidine and its metabolites are almost entirely eliminated via the kidney. More than 90% of the dose is eliminated in the first 24 hours via the kidney, while approximately 1% is eliminated in the faeces. The cumulative excretion of unchanged Физиотензidine is approximately 50-75%. The mean plasma elimination half-life is 2.2-2.3 hours and the renal half-life 2.6-2.8 hours.
Characteristics in patients with renal impairment
In patients with moderately impaired renal function (GFR 30 - 60 ml/min), the AUC increased by 85% and the clearance decreased by 52%. In such patients the hypotensive effect of Физиотензidine should be closely monitored, especially at the start of treatment. The dose must be adapted in these patients so that the maximum daily dose is not more than 0.4 mg and the maximum single dose is 0.2 mg.
In patients with severely impaired renal function (GFR < 30 ml/min) the clearance is reduced by 68 % and the elimination half live is prolonged up to 7 hours. In these patients Физиотензidine dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.3 mg daily, if clinically indicated and well tolerated. In such patients the hypotensive effect of Физиотензidine should be closely monitored, especially at the start of treatment.
Paediatric population
No pharmacokinetic studies in children have been performed.
Cases of varying degrees of AV block have been reported in the post-marketing setting in patients undergoing Физиотенз treatment. Based on these case reports, the causative role of Физиотенз in delaying atrioventricular conduction cannot be completely ruled out. Therefore, caution is recommended when treating patients with a possible predisposition to developing an AV block.
When Физиотенз is used in patients with 1st degree AV block special care should be exercised to avoid bradycardia. Физиотенз must not be used in higher degree AV blocks.
When Физиотенз is used in patients with severe coronary artery disease or unstable angina pectoris special care should be exercised due to the fact that there is limited experience in this patient population.
Due to lack of clinical evidence supporting safe use in patients with co-existing moderate cardiac insufficiency, Физиотенз should be administered with caution in these patients.
Caution is advised in the administration of Физиотенз to patients with renal impairment as Физиотенз is excreted primarily via the kidneys. In these patients careful titration of the dose is recommended, especially at the start of therapy. Dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.4 mg daily for patients with moderate renal impairment (GFR>30 ml/min but < 60 ml/min) and to a maximum of 0.3 mg daily for patients with severe renal impairment (GFR<30 ml/min) if clinically indicated and well tolerated.
If Физиотенз is used in combination with a β-blocker, and both treatments have to be discontinued the β-blocker should be discontinued first, and, then Физиотенз after a few days.
So far, no rebound effect on blood pressure has been observed after the discontinuation of treatment with Физиотенз. However, it is advisable not to stop taking Физиотенз abruptly, but to reduce it gradually over a period of two weeks.
The elderly population may be more susceptible to the CV effects of blood pressure lowering drugs. Therefore therapy should be started with the lowest dose and dose increments should be introduced with caution to prevent the serious consequences these reactions may lead to.
Физиотенз contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Cases of varying degrees of AV block have been reported in the post-marketing setting in patients undergoing Физиотензidine treatment. Based on these case reports, the causative role of Физиотензidine in delaying atrioventricular conduction cannot be completely ruled out. Therefore, caution is recommended when treating patients with a possible predisposition to developing an AV block.
When Физиотензidine is used in patients with 1st degree AV block special care should be exercised to avoid bradycardia. Физиотензidine must not be used in higher degree AV blocks.
When Физиотензidine is used in patients with severe coronary artery disease or unstable angina pectoris special care should be exercised due to the fact that there is limited experience in this patient population.
Due to lack of clinical evidence supporting safe use in patients with co-existing moderate cardiac insufficiency, Физиотензidine should be administered with caution in these patients.
Caution is advised in the administration of Физиотензidine to patients with renal impairment as Физиотензidine is excreted primarily via the kidneys. In these patients careful titration of the dose is recommended, especially at the start of therapy. Dosing should be initiated with 0.2 mg daily and can be increased to a maximum of 0.4 mg daily for patients with moderate renal impairment (GFR>30 ml/min but < 60 ml/min) and to a maximum of 0.3 mg daily for patients with severe renal impairment (GFR<30 ml/min) if clinically indicated and well tolerated.
If Физиотензidine is used in combination with a β-blocker, and both treatments have to be discontinued the β-blocker should be discontinued first, and, then Физиотензidine after a few days.
So far, no rebound effect on blood pressure has been observed after the discontinuation of treatment with Физиотензidine. However, it is advisable not to stop taking Физиотензidine abruptly, but to reduce it gradually over a period of two weeks.
The elderly population may be more susceptible to the CV effects of blood pressure lowering drugs. Therefore therapy should be started with the lowest dose and dose increments should be introduced with caution to prevent the serious consequences these reactions may lead to.
Физиотензidine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
No studies on the effects on the ability to drive and use machines have been performed. However, somnolence and dizziness have been reported. This should be taken into account when performing these tasks.
Posology
Adults
Treatment must be instituted with the lowest dosage of Физиотенз. This means a daily dose of 0.2 mg Физиотенз in the morning. If the therapeutic effect is insufficient, the dose can be increased after three weeks to 0.4 mg. This dose can be given as a single dose (to be taken in the morning) or as a divided daily dose (morning and evening). If the results are still insufficient after a further three weeks, the dosage can be increased further to a maximum of 0.6 mg given divided in the morning and evening. A single dose of 0.4 mg Физиотенз and a daily dose of 0.6 mg Физиотенз should not be exceeded.
Special populations
Elderly
Provided that renal function is not impaired, dosage recommendation is the same as for adults.
Paediatric population
Физиотенз should not be given to children and adolescents under 18 years of age as insufficient safety and therapeutic data are available for this.
Method of administration
As concomitant ingestion of food does not affect the pharmacokinetics of Физиотенз, Физиотенз can be taken before, during or after meals. The tablets should be taken with sufficient fluid.
Posology
Adults
Treatment must be instituted with the lowest dosage of Физиотензidine. This means a daily dose of 0.2 mg Физиотензidine in the morning. If the therapeutic effect is insufficient, the dose can be increased after three weeks to 0.4 mg. This dose can be given as a single dose (to be taken in the morning) or as a divided daily dose (morning and evening). If the results are still insufficient after a further three weeks, the dosage can be increased further to a maximum of 0.6 mg given divided in the morning and evening. A single dose of 0.4 mg Физиотензidine and a daily dose of 0.6 mg Физиотензidine should not be exceeded.
Special populations
Elderly
Provided that renal function is not impaired, dosage recommendation is the same as for adults.
Paediatric population
Физиотензidine should not be given to children and adolescents under 18 years of age as insufficient safety and therapeutic data are available for this.
Method of administration
As concomitant ingestion of food does not affect the pharmacokinetics of Физиотензidine, Физиотензidine can be taken before, during or after meals. The tablets should be taken with sufficient fluid.
No special requirements.
