Ketamine-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETAMIN-ZN (KETAMIN-ZN)

Composition:

Active substance: ketamine;

1 ml of solution contains ketamine hydrochloride equivalent to 50 mg of ketamine;

Excipients: benzethonium chloride, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or almost colorless liquid.

Pharmacotherapeutic group. Agents for general anesthesia. ATC code N01AX03.

Pharmacological Properties

Pharmacodynamics

Ketamine is an anesthetic agent with pronounced analgesic properties. The drug induces so-called dissociative anesthesia, described as a functional dissociation between the thalamo-neocortical and limbic systems. The analgesic effect of ketamine is already evident at subdissociative doses and lasts longer than the anesthetic effect. Sedative and hypnotic effects are less pronounced. Ketamine exerts local anesthetic action in the spinal cord and peripheral nerves.

With ketamine administration, muscle tone remains unchanged or may even increase. Therefore, protective reflexes are generally preserved. The seizure threshold is not reduced. During spontaneous respiration, intracranial pressure may increase; this phenomenon can be avoided with controlled ventilation.

Since ketamine induces sympathicotonia, arterial pressure and heart rate may rise. Along with increased coronary blood flow in the myocardium, oxygen demand also increases. Ketamine has a negative inotropic effect and antiarrhythmic action (direct cardiac effect). Due to its antagonistic action, peripheral vascular resistance remains unchanged.

After ketamine administration, pronounced hyperventilation occurs without significant deviations in blood gas parameters. Ketamine relaxes bronchial smooth muscle.

Pharmacokinetics

Ketamine is lipid-soluble. Maximum plasma concentration is observed one minute after intravenous administration and 20 (5–30) minutes after intramuscular injection. Following intramuscular administration, the bioavailability of the drug is 93%. Approximately 47% of ketamine is protein-bound in the blood. The first phase of action (alpha phase) lasts approximately 45 minutes, with a half-life (T½) of 10–15 minutes. Clinically, the first phase is characterized by the anesthetic effect of the drug. Ketamine rapidly distributes into well-vascularized tissues (e.g., the brain). The tissue concentration of ketamine follows a biphasic open model. Termination of the anesthetic effect results from redistribution from the CNS to peripheral tissues with lower blood supply and from hepatic biotransformation into active metabolites. Among ketamine metabolites, one exhibits sedative effects. The elimination half-life of the second phase (beta phase) is approximately 2.5 hours. About 90% of metabolites are excreted via the kidneys. Ketamine crosses the placenta.

Clinical characteristics.

Indications.

Used as an anesthetic agent (monotherapy) for short-term diagnostic procedures and surgical interventions in children and in certain special cases in adults: induction and maintenance of anesthesia.

For general anesthesia in combination with other drugs (especially benzodiazepines), a lower dose of the drug is administered.

Specific indications for ketamine use (alone or in combination with another drug):

• painful procedures (dressing changes in burn patients);
• neurodiagnostic procedures (pneumoencephalography, ventriculography, myelography);
• endoscopy;
• certain ophthalmological procedures;
• diagnostic and surgical interventions in the neck or oral cavity; dental procedures;
• otolaryngological interventions;
• gynecological extraperitoneal interventions;
• obstetric interventions, induction of anesthesia for cesarean section;
• orthopedic and trauma surgery;
• anesthesia in patients in shock or with hypotension, due to ketamine's specific effects on the heart and circulation;
• anesthesia in patients where intramuscular administration is preferred (e.g., in children).

Contraindications.

Hypersensitivity to the active substance or other components of the drug.

Pre-eclampsia, eclampsia.

The drug is contraindicated in patients with severe cardiovascular diseases, in whom elevated arterial pressure (in adults, BP > 180/100 mm Hg at rest, poorly controlled), congestive heart failure, patients with head trauma, brain tumors, intracranial hemorrhage, stroke, or cerebral circulation disorders.

Untreated or inadequately treated hyperthyroidism.

History of seizures; psychiatric disorders (schizophrenia, acute psychosis).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of barbiturates and/or other anesthetic agents with ketamine prolongs awakening time after anesthesia.

Ketamine in combination with atracurium and tubocurarine may enhance neuromuscular blockade, including respiratory depression and apnea.

Simultaneous use of halogenated anesthetics with ketamine may prolong ketamine's elimination half-life and increase awakening time after anesthesia. Concomitant administration of ketamine (especially at high doses or rapid infusion) with halogenated anesthetics may increase the risk of bradycardia, hypotension, or reduced cardiac output.

Use of ketamine with other medicinal products that depress central nervous system (CNS) activity (e.g., ethanol, phenothiazines, antihistamines, or muscle relaxants) may enhance CNS depression and/or increase the risk of respiratory insufficiency. Dose reduction of ketamine may be necessary when used concomitantly with hypnotics, sedatives, and tranquilizers. Ketamine has been reported to be an antagonist of the hypnotic effect of thiopental.

When thyroid hormones are used, increased arterial pressure and tachycardia may occur.

Concomitant use of antihypertensive drugs and ketamine increases the risk of hypotension.

Combination with aminophylline (theophylline) may lower the seizure threshold. Cases of unpredictable extensor muscle seizures associated with simultaneous use of these drugs have been reported.

Drugs that inhibit CYP3A4 enzyme activity generally reduce hepatic clearance, resulting in increased plasma concentrations of CYP3A4 substrate drugs such as ketamine. When ketamine is administered concomitantly with drugs that inhibit CYP3A4 enzyme, a lower dose of ketamine may be required to achieve the desired clinical effect. Drugs that induce CYP3A4 enzyme activity generally increase hepatic clearance, resulting in decreased plasma concentrations of CYP3A4 substrate drugs such as ketamine. When ketamine is used concomitantly with drugs that induce CYP3A4 enzyme activity, an increased dose of ketamine may be required to achieve the desired clinical effect.

Special precautions for use.

Ketamine may be combined with any type of local anesthesia.

The drug must be administered by a specialist—anesthesiologist.

As with other agents used for general anesthesia, equipment and instruments for resuscitation must be prepared prior to ketamine administration.

Since respiratory depression may occur during administration of the drug, a device for artificial ventilation of the lungs must be available. Use of such a device should be combined with administration of analeptics.

Intravenous ketamine must be administered slowly (over 1 minute). Rapid injection may lead to respiratory depression and a sharp increase in arterial blood pressure.

Since pharyngeal reflexes are generally preserved during ketamine therapy, mechanical stimulation of the pharynx should be avoided. For procedures involving the larynx, pharynx, or trachea, ketamine must be combined with muscle relaxants and careful monitoring of respiration.

For surgical procedures involving visceral pain pathways, administration of additional analgesics may be required.

When ketamine is used in outpatient settings, the patient may be discharged only after full recovery of consciousness and under the supervision of an adult.

For obstetric procedures requiring complete uterine muscle relaxation, ketamine monotherapy is not recommended.

For diagnostic or therapeutic procedures on the organs of vision, the use of local analgesics is not indicated.

Ketamine should be used with special caution in the following conditions:

• Chronic alcoholism and acute alcohol intoxication;

Ketamine is metabolized in the liver, and complete hepatic elimination leads to termination of clinical effects. Prolonged duration of action may occur in patients with liver cirrhosis or other forms of hepatic insufficiency. Therefore, the dose of ketamine should be reduced in such patients. Abnormal liver function tests have been reported in association with prolonged use of the drug, particularly in patients treated for more than 3 days or in individuals with a history of substance dependence. With repeated use, dilatation of the biliary tract has also been reported, with or without signs of obstruction.

• Increased intracranial pressure;
• In patients with penetrating eye injury and/or elevated intraocular pressure (e.g., glaucoma), since pressure may increase significantly even after a single dose of ketamine;
• In patients with acute intermittent porphyria;
• In patients receiving thyroid hormone replacement therapy (increased risk of elevated arterial pressure and heart rate);
• In patients with infectious diseases of the upper respiratory tract and lungs (since ketamine increases sensitivity of the pharyngeal reflex, which may trigger laryngospasm);
• In patients with elevated intracranial pressure;
• Within 6 months after an episode of unstable angina or myocardial infarction.

Reactions and features that may occur during emergence from anesthesia.

Psychological disturbances may range from mild to severe, including dream-like experiences, vivid imagery, hallucinations, nightmares, post-anesthetic delirium (often manifesting as dissociative sensations and feelings of "free-floating"), and in some cases, confusion, psychomotor agitation, and irrational behavior.

Acute delirium may occur during emergence from anesthesia. This reaction may be prevented by administration of benzodiazepines or by reducing verbal, tactile, and visual stimuli. However, monitoring of vital functions remains essential.

Since ketamine increases myocardial oxygen consumption, it should be used cautiously in patients with hypovolemia, dehydration, or cardiac disease, particularly in ischemic heart disease (e.g., congestive heart failure, ischemic state, or myocardial infarction). Ketamine should also be used cautiously in patients with mild to moderate pulmonary arterial hypertension and tachyarrhythmias.

Patients with hypertension or heart failure require continuous monitoring of cardiac function during anesthesia. Premedication with diazepam reduces the hypertensive response. Maximum increase in arterial pressure (20–25%) occurs several minutes after intravenous administration, but blood pressure returns to baseline values within 15 minutes. Depending on the patient's condition, the rise in arterial pressure may be considered either a beneficial effect or an adverse reaction. The cardiostimulatory effect of ketamine can be prevented by prior intravenous administration of diazepam at a dose of 0.2–0.25 mg/kg body weight.

Ketamine is not intended or recommended for long-term use. Cases of cystitis, including hemorrhagic cystitis, have been reported in patients receiving prolonged ketamine treatment (from 1 month to several years).

There have also been reports of ketamine abuse. Data indicate that ketamine may cause symptoms such as dysphoria, hallucinations, "flashback" phenomena, fear, anxiety, insomnia, or disorientation, as well as cases of cystitis or hemorrhagic cystitis. Daily use of ketamine over several weeks may lead to dependence, particularly in individuals with current or past substance dependence. Therefore, the drug should be used under close medical supervision and with caution in the aforementioned conditions and diseases.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Ketamine crosses the placenta. This should be taken into account during obstetric surgical procedures. Controlled clinical studies during pregnancy have not been conducted. Use during pregnancy has not been studied and is not recommended, except for administration during cesarean section or vaginal delivery.

Intravenous doses of ketamine ≥ 1.5 mg/kg may cause respiratory depression and low Apgar scores in newborns, which may require resuscitation.

Significant increases in arterial pressure and uterine tone have been observed when intravenous doses exceed 2 mg/kg.

There are no data on intramuscular injections or maintenance infusions in pregnant women.

Lactation

The safety of ketamine use during breastfeeding has not been established, and such use is not recommended.

Ability to affect reaction speed when driving or operating machinery.

Patients must be warned that driving a vehicle, operating machinery, or engaging in any other potentially hazardous activities is prohibited for 24 hours or longer after anesthesia.

Ketamine may impair cognitive function, which could affect the ability to drive a vehicle.

Dosage and Administration.

Individual response to the drug, as with other systemically acting anesthetics, depends on the dose, route of administration, and patient's age. Therefore, the dosage should be individually adjusted.

When used in combination, the dose of ketamine should be reduced.

The following doses are recommended for adults, elderly patients (over 65 years of age), and children.

Intravenous administration.
The drug should be administered slowly over 1 minute.

Initial dose – 0.7–2 mg/kg body weight, providing surgical anesthesia within approximately 30 seconds after administration, lasting for 5–10 minutes (in high-risk patients, elderly patients, or patients in shock, the recommended dose is 0.5 mg/kg body weight).

Intramuscular administration.

Initial dose – 4–8 mg/kg body weight, providing surgical anesthesia within several minutes after administration, lasting for 12–25 minutes.

Intravenous infusion.

Add 500 mg of ketamine to 500 mL of 5% glucose solution or 0.9% sodium chloride solution. Initial dose: 80–100 drops per minute.

Maintenance dose: 20–60 drops per minute (2–6 mg/kg body weight per hour).

The dose for adults is 2–6 mg/kg body weight per hour.

Maintenance anesthesia.

If necessary, half of the initial dose or the full initial dose may be repeated intramuscularly or intravenously.

The appearance of nystagmus or motor response to stimulation indicates inadequate depth of anesthesia, and therefore, administration of a repeat dose may be required. However, involuntary limb movements may occur regardless of the depth of anesthesia.

Children. The drug is used in pediatric practice.

Overdose.

Ketamine has a wide therapeutic index.

Rapid intravenous administration or administration of large doses may result in respiratory depression or apnea. In such cases, artificial ventilation of the lungs should be performed until adequate spontaneous respiration is restored.

Side effects.

Immune system disorders: anaphylactic reactions.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: confusion, inappropriate behavior, fear, anxiety, "flashback" sensation, dysphoria, insomnia, disorientation.

During the recovery period, vivid dreams, visual hallucinations, emotional disturbances, delirium, psychomotor agitation, and confusion may occur. These phenomena are less common in patients under 15 years of age and over 65 years of age.

Nervous system disorders: nystagmus, increased skeletal muscle tone, and tonic-clonic movements, which do not indicate reduced depth of anesthesia and therefore do not require administration of an additional dose of the drug.

Eye disorders: diplopia, moderate increase in intraocular pressure.

Cardiovascular system disorders: transient increase in arterial blood pressure (BP) and heart rate is frequently observed. Maximum increase in arterial blood pressure (20–25%) occurs several minutes after intravenous administration of the drug, but BP returns to baseline values within 15 minutes. The cardiostimulatory effect of ketamine can be prevented by prior intravenous administration of diazepam at a dose of 0.2–0.25 mg/kg body weight.

Bradycardia, arterial hypotension, and arrhythmia may also occur.

Respiratory system disorders: increased respiratory rate; with rapid administration or overdose, respiratory depression, airway obstruction, or respiratory arrest are common. Laryngospasm has been reported rarely.

Hepatobiliary disorders: changes in liver function laboratory parameters, dilation of biliary passages with or without signs of obstruction upon repeated administration.

Gastrointestinal disorders: loss of appetite, nausea, vomiting, salivation.

Skin and subcutaneous tissue disorders: urticaria, transient erythema and/or morbilliform rash.

Renal and urinary disorders: cystitis, hemorrhagic cystitis.

General disorders and administration site reactions: reactions at the site of administration, including pain and/or rash at the injection site.

With repeated administration over a short period, particularly in young children, tolerance to the drug may develop. In such cases, the desired effect can be achieved by appropriate dose escalation.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibility.

Barbiturates, due to chemical incompatibility with ketamine, must not be administered in the same syringe as ketamine.

If simultaneous administration of ketamine and diazepam is necessary, the drugs should be administered separately; they must not be mixed in the same syringe or infusion solution.

Packaging.

2 ml in an ampoule; 10 ampoules in a cardboard box.

2 ml in an ampoule; 5 ampoules in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

Manufacturer's address and place of business.

41 Kuilikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.