Composition, form of production and packaging
Eye drops in the form of a clear, colorless or almost colorless, slightly viscous solution.
dorzolamide hydrochloride 22.26 mg,
which corresponds to the content of dorzolamide 20 mg
timolol maleate 6.84 mg,
which corresponds to the content of timolol 5 mg
Auxiliary substances: hyetylose - 1 mg, citric acid monohydrate - 4 mg, sodium hydroxide solution 1M - 0.066 ml, mannitol - 20 mg, benzalkonium chloride - 0.075 mg, sodium hydroxide solution 1M / hydrochloric acid solution 1M - to a pH of 5.6 В± 0.1, purified water - up to 1 ml.
5 ml - a bottle-droppers polymer (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
The antiglaucoma preparation contains two active substances: dorzolamide and timolol, each of which reduces the increased intraocular pressure due to a decrease in the secretion of the intraocular fluid. Joint action of these substances in the combined preparation Dorzopt Plus leads to a more pronounced decrease in intraocular pressure.
Dorzolamide is a selective inhibitor of type II carbonic anhydrase. Inhibition of the carbonic anhydrase of the ciliary body leads to a decrease in the secretion of the aqueous humor, presumably due to a decrease in the formation of bicarbonate ions, which in turn leads to a slowing down of sodium transport and intraocular fluid.
Timolol is a non-selective beta-blocker. Although the exact mechanism of action of timolol in reducing intraocular pressure has not yet been established, a number of studies have shown a predominant decrease in the formation of intraocular fluid, as well as a slight increase in its outflow.
Decrease in intraocular pressure occurs 20 minutes after instillation, reaches a maximum after 2 hours and lasts at least 24 hours.
Suction and distribution
It penetrates the eye mainly through the cornea (to a lesser extent through the sclera or limbus). With topical application, dorzolamide penetrates the systemic circulation. With prolonged use, dorzolamide accumulates in erythrocytes as a result of selective binding to type II carbonic anhydrase, maintaining extremely low concentrations of free drug in plasma. Binding to plasma proteins is about 33%.
Metabolism and excretion
As a result of metabolism, it is transformed into an N-desethylated metabolite, less active with respect to carbonic anhydrase II, but capable of blocking type I carbonic anhydrase. The metabolite also accumulates in red blood cells, where it binds mainly to type I carbonic anhydrase. It is excreted by the kidneys in the unmodified form and in the form of metabolites. After discontinuing the use of the drug, dorzolamide is washed out of the erythrocytes nonlinearly, which first leads to a rapid decrease in its concentration, then the elimination slows down. T 1/2 is about 4 months.
When dorsolamide was taken internally in order to simulate the maximum systemic exposure during its topical application, the equilibrium state was achieved after 13 weeks. At the same time, free dorzolamide or its metabolites were practically free of plasma in the blood plasma. Inhibition of erythrocyte carbonic anhydrase was insufficient to achieve a pharmacological effect on the function of the kidneys and respiration. Similar pharmacological results were observed with prolonged local application of dorzolamide. Nevertheless, in some elderly patients with renal failure (CK 30-60 ml / min), higher concentrations of metabolite in erythrocytes were detected, but this was not clinically significant.
With topical application timolol penetrates into the systemic bloodstream. The concentration of timolol in the plasma was studied in 6 patients with topical administration of timolol in the form of eye drops 0.5% 2 times / day. The average C max after application in the morning was 0.46 ng / ml, after application in the afternoon - 0.35 ng / ml.
- increased intraocular pressure with open-angle glaucoma and pseudoexfoliation glaucoma with insufficient monotherapy effectiveness.
The drug Dorzopt Plus is recommended to instill 1 drop into the conjunctival sac of the eye (or both eyes) 2 times / day.
If the drug Dorzopt Plus is prescribed as a replacement for another ophthalmic drug for the treatment of glaucoma, the latter must be canceled 1 day before the start of therapy with Dorzopt Plus.
In case of joint application with other local ophthalmic preparations, the preparation of Dorzopt Plus should be administered at an interval of 10 minutes.
With nasolacrimal occlusion (closing of the eyelids) for 2 min after instillation of the drug, its systemic absorption decreases, which may lead to an increase in local action.
The drug Dorzopt Plus is a sterile solution, so patients should be instructed how to properly use the bottle.
The duration of treatment is determined by the doctor depending on the clinical condition of the patient.
In clinical trials, the drug, in general, was well tolerated. Undesirable reactions were limited to already known adverse reactions with the use of dorzolamide and timolol. Systemic adverse reactions were mild and did not lead to withdrawal of the drug. Approximately in 1.2% of patients the drug was canceled due to local allergic reactions. Among the most frequent unwanted local reactions were burning sensation or itching in the eyes, corneal erosion, injection of vessels of the sclera conjunctiva, blurred vision, lacrimation, distortion of taste.
During the post-marketing period, the following undesirable reactions were observed with dorsolamide + timolol combination: dyspnea, respiratory insufficiency, bradycardia, AV blockade, choroidal detachment of the eye, nausea, contact dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. Cases of edema and irreversible destruction of the cornea have been reported in patients with chronic corneal defects and / or undergoing intraocular surgery.
The following possible undesirable reactions of the active components of the preparation are known.
From the nervous system: headache, asthenia / fatigue, paresthesia.
From the side of the organ of vision: inflammation of the eyelids, lacrimation, irritation and peeling of the eyelid, iridocyclitis, acupuncture, transitory myopia (after the drug is withdrawn).
Allergic reactions: angioedema, bronchospasm, urticaria, pruritus, rash.
From the respiratory system: nosebleeds.
Timolol (topical application)
Mental disorders: depression.
On the part of the immune system: anaphylaxis, angioedema, urticaria, localized or generalized rash.
From the side of the nervous system: ringing in the ears, paresthesia, headache, asthenia, fatigue, dizziness, insomnia, nightmares, memory loss, myasthenia symptoms.
On the part of the respiratory system: bronchospasm (mainly in patients with previous bronchial obstructive pathology), cough, chest pain.
From the side of the organ of vision: conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity, dry eye syndrome; visual disturbances, including changes in the refractive power of the eye (in some cases because of the cancellation of miotics), diplopia, ptosis.
From the cardiovascular system: arrhythmia, cardiac arrest, lowering blood pressure, fainting, Raynaud's syndrome, lowering the temperature of the hands and feet.
On the part of the digestive system: diarrhea, dyspepsia, dry mouth, throat irritation, abdominal pain.
From the skin and subcutaneous tissues: alopecia, psoriasis-like rash or exacerbation of psoriasis.
From the osteomuscular system and connective tissue: lameness, systemic lupus erythematosus.
On the part of the reproductive system: decreased libido, Peyronie's disease.
General disorders and disorders at the injection site: edema.
Timolol (systemic application)
On the part of the blood and lymphatic system: netrombotsitopenicheskaya purpura.
From the nervous system: weakness, dizziness, increased drowsiness, decreased concentration of attention.
On the part of the endocrine system: hyperglycemia, hypoglycemia.
From the respiratory system: pulmonary edema, wheezing.
From the cardiovascular system: decreased tolerance to physical activity, AV-blockade II-III degree, sinotrial blockade, decompensation of heart failure, progression of angina pectoris, vasodilation.
On the part of the digestive system: vomiting.
From the skin and subcutaneous tissues: exfoliative dermatitis, skin itching, increased sweating.
From the side of the kidneys and urinary tract: disturbances of urination.
From the musculoskeletal system: pain in the extremities, arthralgia.
On the part of the reproductive system: impotence.
Laboratory and instrumental data: rarely - a slight increase in the concentration of residual nitrogen, potassium, uric acid and triglycerides of blood plasma; a slight decrease in the concentration of hemoglobin, hematocrit, cholesterol, HDL. These changes were not clinically manifested and did not progress.
- airway hyperreactivity;
- bronchial asthma (including in the anamnesis);
- Severe chronic obstructive pulmonary disease (COPD);
- sinus bradycardia;
- Sinoatrial blockade;
- AV-blockade of II-III degree;
- severe heart failure;
- cardiogenic shock;
- renal failure of severe degree (QC less than 30 ml / min);
- hyperchloremic acidosis;
- dystrophic processes in the cornea;
- lactation (breastfeeding);
- children's and adolescents under 18 years of age (because efficiency and safety have not been adequately studied);
- Hypersensitivity to the components of the drug.
With caution should prescribe the drug for cardiovascular disease in history, including heart failure; AV-blockade of the I degree; COPD of mild and moderate severity;severe violations of peripheral circulation (severe forms of Raynaud's disease or Reynaud's syndrome); hepatic insufficiency; diabetes mellitus; urolithiasis (including in the anamnesis); hyperthyroidism; violations of the cornea; patients of advanced age.
PREGNANCY AND LACTATION
The drug Dorzopt Plus is contraindicated for use during pregnancy and lactation (breastfeeding).
Data on the use of dorzolamide in pregnancy is not enough. In studies on rats, the teratogenic effect of dorzolamide in doses toxic to pregnant females was revealed.
It is not known whether dorsolamide penetrates the breast milk of lactating women. Young lactating female rats treated with dorsolamide showed a decrease in body weight gain.
Data on the use of timolol in pregnancy is not enough. In epidemiological studies, the effect of beta-adrenoblockers on ingestion on the formation of congenital malformations was not detected, but intrauterine growth retardation was detected. In addition, the neonates had signs and symptoms of blockade of? -adrenoceptors (bradycardia, arterial hypotension, respiratory failure, hypoglycemia) in the case when beta-blockers were used before delivery.
Beta-blockers penetrate into breast milk. In the period of breastfeeding, it is necessary to cancel the use of Dorzopt Plus or to stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated in renal insufficiency of severe degree (CC less than 30 ml / min);
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution in liver failure.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS
Caution should be given to elderly patients.
Dorzopt Plus, like other ophthalmic drugs for topical use, can penetrate into the systemic bloodstream. Since the drug timolol is a beta-adrenoblocker, the undesirable reactions that develop with the systemic application of beta-blockers can be noted with topical application of Dorzopt Plus.
Reactions from the cardiovascular and respiratory systems
Before using Dorsopt Plus, you need to ensure adequate control of the cardiovascular system.
Patients with a history of cardiovascular disease, including heart failure, should be closely monitored for signs of worsening of these diseases (HR and BP control).
Reported cases of heart failure with a fatal outcome against the background of the use of timolol in the form of eye drops.
With the appearance of the first signs or symptoms of heart failure, the drug Dorzopt Plus should be discontinued.
Patients with grade I blockade should be prescribed beta-blockers with caution because of their ability to slow the pulse.
Reported cases of bronchospasm with fatal outcome in patients with bronchial asthma on the background of the use of timolol in the form of eye drops.
In patients with COPD of mild to moderate severity, Dorsopt Plus should be used with caution and only if the perceived benefit of treatment exceeds the potential risk.
The drug should be used with caution in patients with severe impairment of peripheral circulation (severe illness or Raynaud's syndrome).
The drug should be used with caution in patients with spontaneous hypoglycemia or in patients with diabetes mellitus (especially with labile course) on the background of the use of insulin or oral hypoglycemic drugs, since beta-adrenoblockers can mask the symptoms of hypoglycemia.
Beta-blockers may mask some clinical signs of hyperthyroidism (eg, tachycardia). If there is a suspected development of hyperthyroidism, patients should be closely monitored. It is necessary to avoid a sharp abolition of beta-blockers due to the risk of thyrotoxic crisis.
Anesthesia in surgery
The need to abolish beta-blockers in the case of the forthcoming extensive surgical intervention has not been proven. The effects of beta-adrenoblockers during surgery, if necessary, can be eliminated by applying sufficient doses of adrenomimetics.
Impaired liver function
Studies of the use of Dorzopt Plus in patients with hepatic insufficiency have not been carried out, so the drug should be used with caution in such patients.
Allergies and hypersensitivity reactions
Like other ophthalmic drugs for topical use, the drug Dorzopt Plus can penetrate into the systemic bloodstream. The dorsolamide included in the preparation is sulfonamide. Undesirable reactions revealed in the systemic application of sulfonamides can be noted with topical application of the drug (Stevens-Johnson syndrome and toxic epidermal necrolysis). If signs of severe hypersensitivity reactions appear, the drug should be discontinued.
In the treatment of beta-adrenergic blockers of patients with atopy or severe anaphylactic reactions to various allergens in a history, it is possible to strengthen the response with repeated contact with these allergens. In this group of patients, the use of epinephrine in a standard therapeutic dose to stop allergic reactions may not be effective.
When using Dorzopt Plus in patients taking systemic beta-blockers, it is necessary to take into account the possible mutual enhancement of the pharmacological action of the drugs both with respect to the known systemic effects of beta-blockers and with respect to reducing intraocular pressure. The combined use of Dorzopt Plus with other beta-blockers is not recommended.
Discontinuation of therapy
If it is necessary to cancel the local administration of timolol, as in the case of abolition of systemic beta-blockers, discontinuation of therapy in patients with IHD should be gradual.
Disturbances from the cornea
Used in ophthalmology, beta-blockers can cause dry eye mucosa. The drug should be used with caution in patients with corneal disorders. In patients with a low number of endothelial cells, there is an increased risk of developing corneal edema.
The use of systemic inhibitors of carbonic anhydrase can lead to a violation of acid-base balance and is accompanied by urolithiasis, especially in patients with a history of urolithiasis.
The composition of the drug Dorzopt Plus includes an inhibitor of carbonic anhydrase, which, when applied topically, can be absorbed and enter the systemic bloodstream, so the risk of developing urolithiasis in patients with urolithiasis in an anamnesis with Dorzopt Plus may increase.
Use in elderly patients
In clinical studies, the difference in the efficacy and safety of dorsolamide + timolol combination in patients older than 65 years compared with younger patients was not detected. Nevertheless, the possibility of higher sensitivity to the drug in some elderly patients should not be ruled out.
Use of contact lenses
Dorzopt Plus contains a preservative of benzalkonium chloride, which can cause irritation of the eye. Therefore, patients before using the drug should take out soft contact lenses and install them back no earlier than 15 minutes after instillation of the drug. Benzalkonium chloride is capable of discoloring soft contact lenses.
Impact on the ability to drive vehicles and mechanisms
During the period of application of Dorzopt Plus it is necessary to refrain from managing vehicles and mechanisms and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.
There is no evidence of accidental or intentional drug overdose.
There are cases of unintentional overdose of timolol eye drops with the development of systemic symptoms of beta-blocker overdose when administered systemically: dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest.
Most anticipated symptoms of overdosage of dorzolamide are electrolyte imbalance, development of acidosis, headache, asthenia / fatigue, paresthesia.
Treatment: symptomatic and supportive therapy. It should control the concentration of electrolytes (especially sodium) and the pH of the blood plasma. Timolol is not displayed during dialysis.
Research Plus Dorzopt drug interactions with other drugs was conducted.
However, it is possible to enhance the hypotensive effect and / or development of bradycardia in the combined use ophthalmic solution of timolol and blockers, slow calcium channels, sympatholytics, beta-blockers, antiarrhythmics (including amiodarone), cardiac glycosides, parasympathomimetics, opioid analgesics and MAO inhibitors .
When the joint application of timolol and isozyme CYP2D6 inhibitors (e.g., quinidine or selective serotonin reuptake inhibitors) reported potencies systemic blockade effect? -adrenoceptor (e.g., reduced heart rate, depression).
Despite the fact that part of the Dorzopt plus carbonic anhydrase inhibitor dorzolamide is used topically, it can penetrate into the systemic circulation. In clinical studies, dorzolamide application ophthalmic solution showed no disorders of acid-base equilibrium. However, when systemic administration of carbonic anhydrase inhibitors, these disorders are known and in some cases they may have an impact on the interaction with other drugs (e.g., amplify toxic reactions when used in high doses of salicylates).
Systemic beta-blockers may increase the effects of hypoglycemic agents.
Systemic beta-blockers may exacerbate the severity of hypertension, is the effect of clonidine.
There are individual data on the development of mydriasis with concomitant use of timolol and epinephrine.
There is a possibility amplification known systemic effects of inhibiting carbonic anhydrase in the combined use of local and systemic carbonic anhydrase inhibitors.Because data on the use of such a combination is absent, the combined use of the drug Dorzopt Plus and systemic carbonic anhydrase inhibitors are not recommended.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, dry, protected from light at a temperature of no higher than 25 В° C. Shelf life - 2 years.
After opening the bottle of drops should be used within 4 weeks.