Zaldiar tab. p/o. 37.5 mg/325 mg No. 20 Farmaceutici Formenti/Italy/Grunenthal/Germany

Pharmacodynamics and pharmacokinetics

Tramadol is opioid analgesic Stimulates opioid receptors on the pre- and postsynaptic walls of the afferent processes of cells of the nociceptive system in the digestive tract and in the brain. It has the following effects on the brain and spinal cord: hyperpolarizes membranes and blocks the conduction of pain impulses, helps open sodium and calcium channels. Enhances the effects of sedatives.

Paracetamol lowers the temperature and relieves pain. Suppresses cyclooxygenase in the nervous system, acting on the centers of thermoregulation and pain. Does not irritate the mucous membranes of the stomach and intestines, does not affect mineral metabolism, because it does not affect the synthesis of prostaglandins in the tissues of peripheral organs.

Paracetamol provides a rapid onset of analgesic effect, and tramadol prolongs this effect. The synergism of the analgesic effect of these components reduces the risk of developing undesirable effects.

Pharmacokinetics

After consumption, the active components are immediately absorbed from the intestines. Tramadol absorption occurs more slowly than paracetamol . The highest concentration of paracetamol in the blood is recorded after an hour and does not change when used simultaneously with tramadol .

The bioavailability of tramadol reaches 75%; with repeated use it can reach up to 90%. Plasma protein binding for tramadol is 20%; for paracetamol binding values ​​are approximately the same.

Tramadol undergoes metabolism in the liver to form 11 metabolites, only one of which ( mono-O-desmethyltramadol ) demonstrates pharmacological activity. paracetamol component is also metabolized mainly in the liver. The half-life of tramadol reaches five hours, and paracetamol is three hours. Tramadol, paracetamol and their metabolites are excreted primarily by the kidneys.

Zaldiar is a new combination drug for the treatment of pain syndromes

Pain is a general biological adaptive reaction that signals the presence of pathological abnormalities, warns and protects the body from damage. Often this protective meaning of pain is lost and it becomes a serious medical problem. The resulting pain sensation leads to the activation of stress-limiting systems that have central, autonomic and humoral components. But when pain becomes excessive and prolonged, it can lead to regulatory maladaptation. Pain increases the load on almost all vital systems of the body. Tachycardia, hypertension, arrhythmia occur, breathing becomes more frequent and its depth decreases, vital capacity and FRC decrease, motor activity decreases, the patient assumes a forced position, and a depressive state may develop. Subjectively felt pain is difficult to objectively quantify, and is perceived by the consciousness of the victim to varying degrees in intensity and character. These differences are a consequence not only of different susceptibility to painful effects, but also of the location and nature of the causes - from short-term pathogenic effects to a condition accompanied by persistent chronic pain. In clinical practice, the types of pain shown in Figures 1-3 are distinguished. The division of pain into somatic superficial, arising from irritation of nociceptors of the skin and subcutaneous layers, somatic deep, the source of which is muscles, fascia, ligaments, joints, periosteum and visceral, which reflects diseases or dysfunction of the chest and abdominal organs, is of practical importance in diagnostics and pharmacotherapy. Pain occurs when pain receptors (nociceptors, algoreceptors), pathways, or directly the nuclei of the nociceptive analyzer are irritated. Signals arising in nerve endings during the action of painful stimuli are conducted to the cerebral cortex, where they are perceived, along a three-neuron pathway (Fig. 4). To suppress pain, primarily peripheral and thalamo-cortical neurons are available, and only occasionally influence on spinothalamic neurons is possible. The mechanism of pain is multifactorial, and its formation involves physical (mechanical and temperature) and chemical influences. Among the chemical agents, the most effective endogenous algic substances are: bradykinin and kalidin, histamine, serotonin, prostaglandins, hydrogen and potassium ions. Prostaglandins play a significant role in the mechanism of pain. Algogenic substances have an irritating effect, forming a pain syndrome; in addition, they can mutually enhance each other’s actions and reduce the threshold of sensitivity of nociceptors to the action of other pathogenic factors. Currently, taking into account the multifactorial mechanism of pain development, general principles for the treatment of pain syndromes have been developed: 1. Treatment of pain should be, if possible, etiopathogenetic (i.e., aimed at eliminating the causes of pain), and not symptomatic. 2. A unified tactics for the treatment of pain syndromes is used, based on strict compliance of the prescribed painkillers depending on their intensity. The intensity of pain is established on a simple scale: The division of pain into 4 stages is of great importance for the choice of analgesics. Mild pain (1 point) should be eliminated with non-narcotic analgesics. For moderate pain (2 points), it is advisable to prescribe non-narcotic opioid analgesics in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and/or non-narcotic analgesics. Indications for the prescription of potent narcotic drugs (morphine, promedol, etc.) should be established only for severe and very severe (3–4 points) acute pain syndrome. This tactic of prescribing pain medications helps prevent the unjustified prescription of potent drugs to patients who do not need them and avoid possible complications and side effects. In addition to the digital scale, a visual analog scale in the form of a ruler can be used:

No pain Moderate pain Severe pain

3. The pain reliever prescribed by the doctor must be adequate to the intensity of the pain and safe for the patient, i.e. should relieve pain without causing serious side effects. If an analgesic is prescribed that is insufficient to eliminate pain, the pain persists and begins to rapidly increase due to the summation of painful stimuli and overexcitation of the pain-conducting nerve structures; As a result, a pain syndrome that is difficult to eliminate is formed, sometimes becoming chronic. It is unjustified to prescribe too strong a narcotic for mild or moderate pain. There are known cases of severe complications in young patients in the early stages after minor surgical interventions as a result of the prescription of morphine and other powerful opiates for pain relief, which led to deep drug-induced depression of the central nervous system, depression of breathing and circulation. 4. Monotherapy with drugs for any pain syndrome (including severe pain) should not be used. In order to increase the effectiveness and safety of pain relief, the drug should always be combined with non-narcotic analgesics, selected in accordance with the pathogenesis of a particular pain syndrome. A number of authors recommend the use of combination therapy with various groups of drugs, in particular a combination of narcotic and non-narcotic analgesics, which avoids addiction, slows down the formation of drug dependence, allows the use of smaller doses of drugs and achieve a good analgesic effect. Recently, in the treatment of pain syndromes, much attention has been paid to the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs in this group (acetylsalicylic acid, indomethacin, diclofenac, ketoprofen, ketorolac, ibuprofen, piroxicam, etc.) have long been used in medicine due to their ability to suppress inflammation, reduce body temperature and pain intensity. Their mechanism of action is that they block the synthesis of prostaglandins by inhibiting the enzyme cyclooxygenase, which catalyzes the conversion of arachidonic acid and the formation of a number of prostaglandin precursors. Prostaglandins are algogenic substances, but, in addition, they are mediators of the inflammatory reaction in tissues and cause tissue swelling, vasodilation, and fever. The administration of NSAIDs helps to inhibit or completely eliminate the inflammatory response. When used, consciousness, hemodynamics and breathing are not depressed, and autonomic reactions are stabilized. Unfortunately, taking non-steroidal anti-inflammatory drugs is associated with the development of NSAID-induced gastropathy, manifested by erosions (often multiple) and ulcers of the antrum of the stomach and/or duodenum. The main risk factors for their development are the elderly age of patients, a history of peptic ulcer disease, combined therapy with NSAIDs and glucocorticoids, long-term treatment with high doses of NSAIDs or simultaneous use of two or more drugs in this group. For the prevention and treatment of NSAID-induced gastropathy, the entire arsenal of antiulcer drugs is used: proton pump inhibitors (omeprazole 20–40 mg/day, lansoprazole 30–60 mg/day, etc.), H2-histamine receptor blockers (famotidine), synthetic analogue of PGE1 - misoprostol, etc. One of the safest non-narcotic analgesics is paracetamol (acetaminophen). Paracetamol blocks cyclooxygenase only in the central nervous system, affecting the centers of pain and thermoregulation. In inflamed tissues, the effect of paracetamol on cyclooxygenase is neutralized by cellular peroxidases, which explains the almost complete absence of anti-inflammatory effect. An important advantage of paracetamol over other non-narcotic drugs and NSAIDs is the lack of influence on the synthesis of prostaglandins in peripheral tissues, which results in the absence of a negative effect on water-salt metabolism (sodium and water retention) and, most importantly, on the mucous membrane of the gastrointestinal tract (GIT) ), therefore the drug does not cause erosion of the gastrointestinal tract. Paracetamol does not have an inhibitory effect on the synthesis of thromboxane A, so the drug has virtually no effect on the hemostatic system. Side effects when using paracetamol are very rare. With long-term use and in large doses, hepatotoxicity may develop. The indication for the use of paracetamol is pain of mild to moderate intensity. The drug is widely used for postoperative pain relief during various interventions. An effective combination of paracetamol and opiates has been noted. For example, the combined use of paracetamol and morphine can reduce the daily dose of morphine by 46%, reduce the incidence of side effects and achieve a good analgesic effect in 87% of patients undergoing orthopedic surgery. According to statistics, in medical practice the most common pain syndromes are of moderate intensity, in which non-narcotic analgesics are no longer effective enough, and narcotic ones are not yet indicated or are not readily available [Osipova N.A., 2006]. The main drugs for the treatment of such pain syndromes are opioids of medium analgesic potency - codeine and tramadol, which have a number of important positive properties. In particular, unlike codeine, it is not a narcotic analgesic. Tramal (tramadol) is a synthetic opioid analgesic with central action. At the level of the brain and spinal cord, it causes hyperpolarization of neuron membranes and inhibits the conduction of pain impulses. Tramal destroys catecholamines, which have a depressing effect on nociception, and stabilize the content of catecholamines in the central nervous system. Tramal is a selective agonist of m-opioid receptors, selectively inhibits the reuptake of serotonin and norepinephrine. Tramal's affinity for opioid receptors is 10 times weaker than codeine and 6000 times weaker than morphine. In terms of analgesic effect, Tramal is 4–5 times weaker than morphine. In therapeutic doses, Tramal has virtually no effect on hemodynamics and respiration, slightly slows down intestinal motility, without causing constipation. Has some sedative effect. The indication for the use of Tramal is acute and chronic pain syndrome of severe and moderate intensity, including postoperative pain syndrome. Compared to pure agonists (morphine, promedol), side effects are rare and manifest themselves in the form of dizziness, weakness, some lethargy, dry mouth, nausea, and allergic reactions. Tramal has high bioavailability through various routes of administration (68–100%), surpasses codeine in analgesic action and is the safest of all opioids [Osipova N.A., 2006]. In medicine, combinations of various analgesics with different mechanisms of action have long been used in order to increase their analgesic effects without increasing the number of side effects. One of the most successful modern combined analgesics is Zaldiar, produced by a pharmaceutical company (Germany), which contains 325 mg of paracetamol and 37.5 mg of tramadol. This rational combination allows you to achieve high-quality pain relief, while the analgesic effect is more pronounced than with a double dose of each of these drugs, with a significant reduction in side effects. Paracetamol and Tramal (tramadol) are effective analgesics that have different complementary mechanisms and have different pharmacotherapeutic properties. Tramadol is characterized by a long-lasting effect with a delayed onset, while paracetamol has an effect that occurs fairly quickly. The combination of paracetamol and Tramal allows you to achieve a more pronounced, longer-lasting analgesic effect in a short time [Langford R., 2006]. Zaldiar is indicated for acute and chronic pain syndrome of moderate and severe intensity. The drug is a film-coated tablet. When taken orally, the drug is quickly and almost completely absorbed from the gastrointestinal tract; the expected effect begins within a few minutes. Zaldiar has no side effects of NSAIDs, and it can be used in patients with gastropathy, gastric and duodenal ulcers. A single dose for adults is 1–2 tablets, the maximum daily dose is up to 8 tablets. Studies have shown that Zaldiar provides adequate pain relief for various acute and chronic pain syndromes. For example, in the treatment of postoperative pain, chronic cancer pain syndrome, for perioperative analgesia, including preoperative pain syndrome, pain syndrome in osteoarthritis and osteoarthritis, in the treatment of moderate and severe pain in neurology, various fields of surgery, dentistry, traumatology and orthopedics and gynecology . In addition, according to the conclusion of the Russian Anti-Doping Center, this drug does not contain prohibited doping agents and/or their metabolites and can be used in sports medicine. Zaldiar is well tolerated by patients at the indicated therapeutic doses. It is also important that Zaldiar is not included in the lists of the Permanent Drug Control Committee and is not subject to subject-quantitative registration, which greatly facilitates its acquisition, storage and use. Zaldiar expands the possibilities of pain therapy using non-narcotic analgesics. It is used to treat various types of pain syndromes of moderate and severe intensity and deserves wide introduction into clinical practice.

Literature 1. Sviridov S.V. “Rationale for the use of prostaglandin and kininogenesis inhibitors in the complex of general anesthesia and postoperative pain relief” //Anesthesiology and Reanimatology. –1992, – No. 2, – p. 3–9. 2. Shvets P., Shvets A. “Pain and pharmacotherapy of pain” // Slovakofarma review. T.IV., 1994, No. 2–3. 3. Lebedeva R.N., Nikoda V.V. “Pharmacotherapy of acute pain” – M., – 1998. 4. Voznesensky A.G. “Clinical pharmacology of non-steroidal anti-inflammatory drugs” – Volgograd, –1999. 5. Osipova N.A. “Procedure and timing of prescribing narcotic analgesics” Guidelines. M. 1999. 18 p. 6. Osipova N.A., Abuzarova G.R., Khoronenko V.E., Sergeeva I.E. “Zaldiar: new opportunities in the treatment of pain syndromes” // Consilium-medicum. Extra release. 2006. 7. Nasonov E.L. “Non-steroidal anti-inflammatory drugs. Prospects for use in medicine” – M.: – Anko, – 2000, –143 p. 8. Ovechkin A.M., Morozov D.V., Zharkov I.P. “Analgesia and controlled sedation in the postoperative period: realities and possibilities” // Bulletin of Intensive Care. – 2001. – No. 4. 9. Smolnikov P.V. "Pain. Choice of protection” // Moscow, – 2001. 10. Belyakov V.A., Soloviev I.K. “Non-narcotic analgesics” - N. Novgorod, - 2001. 11. Ekstrem A.V., Popov A.S., Kondrashenko E.N. “Mechanisms and treatment of postoperative pain” - Volgograd, - 2003. 12. Langford R. “Tramadol and paracetamol: pharmacological and clinical aspects of a new combination of analgesics” // Consilium-Medicum. Extra release. 2006 13. V.V. Nikoda, V.V. Makarova, A.P. Nikolaev, A.V. Bondarenko “Clinical aspects of the use of analgesics based on tramadol and paracetamol in the treatment of postoperative pain” // Consilium-Medicum No. 6. Volume 06. 2004 14. Butrov A.V., Borisov A.Yu. “Modern approaches to pharmacotherapy of postoperative pain with the use of synthetic opioids and non-narcotic analgesics” // Russian Medical Journal No. 24. Volume 12. – 2004.

Contraindications

• Sensitization to the components of the drug;
• acute intoxication with drugs that suppress the nervous system ( hypnotics, opioids or psychotropic drugs) or alcohol;
• severe liver or kidney damage;
• simultaneous administration with MAO inhibitors and a two-week period after their discontinuation;
• uncontrolled epilepsy ;
• age less than 14 years;
• withdrawal syndrome .

Zaldiar should be used with caution in patients with traumatic brain injury , in a state of shock , with intracranial hypertension , a tendency to convulsions , cryptogenic confusion, impaired respiratory function, simultaneous use with psychotropic drugs, other painkillers of central and local action, benign hyperbilirubinemia , diseases hepatobiliary system, viral hepatitis , deficiency of glucose-6-phosphate dehydrogenase , alcoholism , alcoholic changes in the liver, drug addiction , with symptoms of “ acute abdomen ” of unknown origin, in the elderly.

Side effects

• From the nervous system: increased fatigue, headache, dizziness, weakness, nervousness, anxiety, spasms , emotional lability, euphoria, hallucinations, lethargy, sleep disturbance, incoordination , confusion, depression , deterioration of cognitive function, amnesia , gait instability, paresthesia , blurred vision or taste;
• allergic reactions: itching , urticaria , angioedema ;
• reactions from the digestive system: vomiting or nausea, dry mouth, flatulence , constipation , abdominal pain, diarrhea , activation of liver enzymes, difficulty swallowing;
• reactions from the hormonal system: hypoglycemia ;
• reactions from the circulatory system: fainting, orthostatic hypotension, tachycardia, collapse ;
• reactions from the respiratory system: dyspnea ;
• reactions from the genitourinary system: dysuria , urinary retention, possible nephrotoxicity if recommended doses are exceeded for a long time;
• skin reactions: bullous rash, exanthema, erythema multiforme, Lyell's syndrome;
• reactions from hematopoiesis: sulfhemoglobinemia , possible appearance of pancytopenia, aplastic anemia, agranulocytosis with prolonged excess of recommended doses;
• other reactions: increased sweating, changes in the menstrual cycle.

Zaldiar®

More than 10% of patients who are prescribed a combination of tramadol and paracetamol experience nausea, dizziness and drowsiness.

The frequency of occurrence of side effects is classified as follows: very often (≥1/10); often (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000); unknown frequency - cannot be estimated from available data.

In each group, adverse reactions are presented in descending order of severity.

Mental disorders:

often - confusion, mood changes, anxiety, nervousness, euphoria, sleep disturbances; infrequently - depression, hallucinations, nightmares; rarely - delirium, drug dependence.

Post-marketing observations

Very rare (<1/10000): abuse.

Nervous system disorders:

very often - dizziness, drowsiness; often - headache, tremor; infrequently - involuntary muscle contractions, paresthesia, amnesia; rarely - ataxia, convulsions, fainting, speech disorders.

Visual disorders:

rarely - blurred vision, miosis, mydriasis.

Hearing and labyrinth disorders:

infrequently - ringing in the ears.

Heart disorders

: uncommon - palpitations, tachycardia, arrhythmia.

Gastrointestinal disorders:

very often - nausea; often - vomiting, constipation, dry mouth, diarrhea, abdominal pain, dyspepsia, flatulence; infrequently - dysphagia, melena.

General disorders and disorders at the injection site:

infrequently - chills, chest pain.

Laboratory and instrumental data:

infrequently - increased transaminase activity, unknown frequency - hypoglycemia.

Renal and urinary tract disorders:

uncommon - albuminuria, urinary disorders (dysuria and urinary retention).

Respiratory, thoracic and mediastinal disorders

: infrequently - shortness of breath.

Disorders of the track and subcutaneous tissues:

often - sweating, itching; uncommon - skin reactions (rash, urticaria).

Vascular disorders:

infrequently - arterial hypertension, hot flashes.

The occurrence of the following adverse reactions, known to be associated with the use of tramadol or paracetamol, cannot be excluded, although this was not observed during the clinical use of Zaldiar®.

Tramadol

:

- orthostatic hypotension, bradycardia, collapse;

-changes in the warfarin effect, including an increase in prothrombin time;

- allergic reactions with respiratory symptoms (such as shortness of breath, bronchospasm, wheezing, angioedema) and anaphylaxis;

- changes in appetite, motor weakness, respiratory depression;

-mental disorders of varying severity and nature (depending on the type of personality and duration of treatment). They include changes in mood (usually euphoria, sometimes dysphoria), changes in activity (usually increased fatigue, less often increased physical activity), disturbances in cognition and perception (eg, decision-making, perceptual disturbances);

-possible worsening of asthma symptoms has been reported, although a cause-and-effect relationship has not been established;

-signs of withdrawal syndrome can manifest themselves in the form of restlessness, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders. Other symptoms that have been observed extremely rarely with abrupt cessation of tramadol treatment include: panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus, unusual central nervous system symptoms.

Paracetamol

:

- side effects are rare, hypersensitivity reactions to the drug are possible, including skin rash; hematopoietic disorders, including thrombocytopenia and agranulocytosis, a cause-and-effect relationship with the use of paracetamol has not been established;

- there is evidence that the simultaneous use of paracetamol with indirect anticoagulants (for example, warfarin) can lead to hypoprothrombinemia; in other studies, prothrombin time did not change;

-In very rare cases, serious skin reactions have been reported.

Instructions for use of Zaldiar (Method and dosage)

Instructions for use of Zaldiar recommend swallowing the tablets whole, without chewing and drinking water, and does not advise connecting the use of the drug with food intake. If you missed taking the next pill, you should not double the dosage the next time you take it.

The dosage regimen is set individually, as is the duration of treatment, depending on the degree of pain and the patient’s condition.

For adults and children over 14 years of age, the initial single dose is set at 1-2 tablets, the time between doses of such doses is six hours. The highest daily dose is 8 tablets, which corresponds to 2.6 g of paracetamol and 300 mg of tramadol.

Overdose

Signs of tramadol : vomiting, miosis, collapse, depression of the respiratory center, convulsions, coma, apnea.

Signs of paracetamol : diarrhea , loss of appetite; if recommended doses are exceeded for 2-4 days - hypocoagulation, cerebral edema, disseminated intravascular coagulation syndrome, metabolic acidosis, hypoglycemia, arrhythmia, collapse . Rarely, fulminant development of liver dysfunction, including renal failure .

Therapy: gastric lavage, administration of enterosorbents , control and normalization of parameters of the cardiovascular and respiratory systems.

In case of respiratory depression (as a symptom of tramadol ), administration of naloxone ; for convulsions - use diazepam . Hemodialysis or hemofiltration are ineffective for the removal of tramadol .

If signs of paracetamol , it is recommended to administer precursors for glutathione and SH-group donors ( methionine ).

Zaldiar

Allergic reactions to the components of the drug: urticaria, itching, Quincke's edema, exanthema, bullous rash.

From the nervous system: dizziness, headache, lethargy, paradoxical stimulation of the central nervous system (nervousness, agitation, anxiety, tremors, muscle spasms, euphoria, emotional lability, hallucinations), drowsiness, sleep disturbance, confusion, impaired motor coordination, convulsions of central origin (with simultaneous prescription of antipsychotic drugs), depression, amnesia, impaired cognitive function, paresthesia, gait instability.

From the digestive system: dry mouth, nausea, vomiting, flatulence, abdominal pain, constipation, diarrhea, difficulty swallowing; increased activity of liver enzymes, usually without the development of jaundice.

From the cardiovascular system: tachycardia, orthostatic hypotension, syncope, collapse.

From the endocrine system: hypoglycemia, up to hypoglycemic coma.

From the urinary system: difficulty urinating, dysuria, urinary retention. With long-term use in doses significantly higher than recommended - nephrotoxicity (interstitial nephritis, papillary necrosis).

From the senses: impaired vision, taste.

From the respiratory system: dyspnea.

From the skin: exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

From the hematopoietic organs: sulfhemoglobinemia. With long-term use in doses significantly higher than recommended - aplastic anemia, pancytopenia, agranulocytosis.

Other: sweating, weakness, increased fatigue, menstrual irregularities.

With long-term use - the development of drug dependence (irritability, phobias, nervousness, sleep disturbances, psychomotor activity, tremor, discomfort in the stomach or intestines). If you stop taking it abruptly, you may develop a “withdrawal” syndrome.

Overdose.

Symptoms of tramadol overdose: miosis, vomiting, collapse, coma, convulsions, depression of the respiratory center, apnea.

Symptoms of paracetamol overdose: (acute overdose develops 6-14 hours after taking paracetamol, chronic - after 2-4 days if the dose is exceeded). Symptoms of acute overdose: diarrhea, loss of appetite. Symptoms of chronic overdose: cerebral edema, hypocoagulation, development of disseminated intravascular coagulation syndrome, hypoglycemia, metabolic acidosis, arrhythmia, collapse; rarely - impaired liver function, which develops at lightning speed and can be complicated by renal failure (renal tubular necrosis).

Treatment: gastric lavage and taking enterosorbents (activated carbon, polyphepan), maintaining cardiovascular function, ensuring airway patency.

For respiratory depression (a symptom of tramadol overdose) - naloxone, for convulsions - diazepam. Hemodialysis or hemofiltration are ineffective for tramadol intoxication.

If symptoms of paracetamol overdose appear: administration of SH-group donors and precursors for the synthesis of glutathione - methionine 8-9 hours after the overdose and N-acetylcysteine ​​- 12 hours later. The need for further administration of methionine and intravenous administration of N-acetylcysteine ​​is determined depending on the concentration paracetamol in the blood, as well as the time elapsed after taking it.

Interaction

When used together with other drugs that depress the nervous system ( hypnotics or tranquilizers ), as well as with ethanol , undesirable effects may occur.

When used simultaneously with opioid agonists-antagonists ( nalbuphine, buprenorphine, pentazocine ), the analgesic effect is reduced due to a competing effect and there is a risk of withdrawal syndrome . This combination is not desirable.

Inducers of microsomal oxidation ( phenytoin, carbamazepine, phenylbutazone, ethanol, rifampicin, barbiturates, tricyclic antidepressants ) weaken the analgesic effect of the drug and its duration.

Naloxone activates breathing and eliminates the analgesia caused by Zaldiar.

Inhibitors of microsomal oxidation, when used together, reduce the likelihood of developing hepatotoxic effects from taking Zaldiar.

Long-term use of barbiturates reduces the effectiveness of paracetamol.

Use with tricyclic antidepressants , selective serotonin reuptake blockers, and antipsychotics may increase the risk of seizures.

Long-term combined use with other non-steroidal anti-inflammatory drugs increases the risk of nephropathy and papillary necrosis of the kidneys , the onset of the final stage of renal failure .

Simultaneous long-term administration of high doses of paracetamol and salicylates increases the risk of bladder or kidney cancer .

Diflunisal increases the concentration of paracetamol in the blood by 50%, while simultaneously increasing the risk of hepatoxicity.

With simultaneous long-term use with indirect anticoagulants , their effects are enhanced, which increases the likelihood of bleeding.