Zaldiar^® (Tablets) Instructions for Use

Marketing Authorization Holder

Stada Arzneimittel, AG (Germany)

Manufactured By

Farmaceutici Formenti, S.p.A. (Italy)

Labeled By

GRUNENTHAL, GmbH (Germany)

Quality Control Release

Stada Arzneimittel, AG (Germany)

Contact Information

NIZHPHARM group of companies (Russia)

ATC Code

N02AJ13 (Tramadol and Paracetamol)

Active Substances

Paracetamol (Rec.INN registered by WHO)

Tramadol (Rec.INN registered by WHO)

Dosage Form

Zaldiar®

Film-coated tablets, 325 mg+37.5 mg: 10, 20, 30, or 50 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, capsule-shaped, biconvex, with an engraving “T5” on one side and the “Grünenthal” company logo on the other; on the cross-section, the core is almost white.

Excipients: microcrystalline cellulose – 26 mg, pregelatinized starch – 6.5 mg, sodium carboxymethyl starch (type A) – 6.5 mg, corn starch – 26 mg, magnesium stearate – 2.5 mg.

Coating composition: hypromellose (hydroxypropyl methylcellulose 6 mPa.s) – 3.69 mg, lactose monohydrate – 1.878 mg, titanium dioxide – 2.86 mg, macrogol 6000 – 0.915 mg, yellow iron oxide dye – 0.132 mg, propylene glycol – 0.305 mg, talc – 1.22 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.

Clinical-Pharmacological Group

Combined drug with analgesic action

Pharmacotherapeutic Group

Analgesics; opioids; opioids in combination with non-opioid analgesics

Pharmacological Action

Combined drug with analgesic action.

Tramadol is a synthetic opioid analgesic, an agonist of opioid receptors. It activates opioid receptors (mu-, delta-, kappa-) on pre- and postsynaptic membranes of afferent fibers of the nociceptive system in the brain and gastrointestinal tract. It has an effect on the brain and spinal cord: it promotes the opening of K⁺ and Ca²⁺ channels, causes membrane hyperpolarization and inhibits the conduction of pain impulses. It enhances the effect of sedatives.

Paracetamol is an analgesic-antipyretic. It blocks cyclooxygenase in the central nervous system, affecting pain and thermoregulation centers. It does not cause irritation of the gastric and intestinal mucosa, does not affect water-salt metabolism, as it does not affect the synthesis of prostaglandins in peripheral tissues.

Paracetamol provides a rapid onset of the analgesic effect, while tramadol provides a prolongation of analgesia. The synergism of the analgesic action of the two components reduces the risk of side effects.

Pharmacokinetics

Absorption

After oral administration, the active components are rapidly and almost completely absorbed from the gastrointestinal tract. The absorption of tramadol occurs more slowly than that of paracetamol.

C_max of paracetamol in blood plasma is reached within 1 hour and does not change with concomitant use with tramadol. The bioavailability of tramadol is approximately 75%, with repeated use it increases to 90%.

Distribution

Plasma protein binding of tramadol is about 20%, V_d is about 0.9 l/kg. A relatively small part (up to 20%) of paracetamol binds to plasma proteins.

Metabolism

Tramadol is metabolized in the liver by N- and O-demethylation followed by conjugation with glucuronic acid. Eleven metabolites have been identified, of which mono-O-desmethyltramadol (M₁) is pharmacologically active.

Paracetamol is metabolized mainly in the liver.

Excretion

The mean T_1/2 of the tramadol metabolite is 4.7-5.1 hours, T_1/2 of paracetamol is 2-3 hours.

Tramadol (about 30%) and its metabolites (about 60%) are excreted mainly in the urine. Paracetamol and its conjugates are also excreted in the urine.

Indications

• Moderate to severe intensity pain syndrome of various etiologies (including inflammatory, traumatic, vascular origin);
• Pain relief during painful diagnostic or therapeutic procedures.

ICD codes

Dosage Regimen

The dosage regimen and duration of treatment are set individually depending on the severity of the pain syndrome and the patient’s sensitivity. The drug should not be prescribed beyond the period justified from a therapeutic point of view.

For adults and children over 14 years of age, the initial single dose is 1-2 tablets, the interval between single doses is at least 6 hours. The maximum daily dose is 8 tablets (300 mg of tramadol and 2.6 g of paracetamol).

The tablets should be taken regardless of meals, swallowed whole, without breaking or chewing, with liquid. If the patient forgot to take the next tablet, the dose should not be doubled at the next dose.

In elderly patients (aged 75 years and older), there is no need to adjust the single dose. However, due to the possibility of delayed excretion, the interval between single doses may be increased.

In patients with impaired renal function (CC 30-10 ml/min), the interval between single doses should be at least 12 hours. Since tramadol is excreted very slowly during hemodialysis or hemofiltration, post-dialysis administration to maintain the analgesic effect is usually not required.

In moderate hepatic impairment, the interval between doses of the drug should be increased. In severe hepatic impairment, the drug should not be used.

Adverse Reactions

Allergic reactions urticaria, itching, angioedema.

From the central and peripheral nervous system dizziness, headache, weakness, increased fatigue, lethargy, paradoxical stimulation of the central nervous system (nervousness, agitation, anxiety, tremor, muscle spasms, euphoria, emotional lability, hallucinations), drowsiness, sleep disturbance, confusion, impaired coordination of movements, seizures of central origin (with simultaneous administration of antipsychotic drugs), depression, amnesia, impaired cognitive function, paresthesia, unsteady gait, visual impairment, taste disturbance.

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, fainting, 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 exceeding the recommended ones – nephrotoxicity (interstitial nephritis, papillary necrosis).

From the respiratory system dyspnea.

Dermatological reactions exanthema, bullous rash, multiforme erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

From the hematopoietic organs sulfhemoglobinemia. With long-term use in doses significantly exceeding the recommended ones – aplastic anemia, pancytopenia, agranulocytosis.

Other increased sweating, menstrual cycle disorder.

Contraindications

• Acute intoxication with alcohol or drugs that depress the central nervous system (hypnotics, opioid analgesics and psychotropic drugs);
• Simultaneous use of MAO inhibitors and the period within 2 weeks after their withdrawal;
• Severe hepatic and/or renal failure (CC less than 10 ml/min);
• Epilepsy, uncontrolled by therapy;
• Withdrawal syndrome from narcotic drugs;
• Children under 14 years of age;
• Hypersensitivity to the components of the drug.

With caution should be used in patients in a state of shock, with traumatic brain injury, intracranial hypertension, a tendency to convulsive syndrome (with epilepsy, controlled therapeutically, Zaldiar^® is prescribed only for vital indications), confusion of unknown etiology, impaired respiratory function, simultaneous use of psychotropic drugs, other centrally acting analgesics and local anesthetics, diseases of the biliary tract, benign hyperbilirubinemia, viral hepatitis, glucose-6-phosphate dehydrogenase deficiency, alcoholic liver damage, alcoholism, drug addiction, with the symptom complex “acute” abdomen of unclear genesis, in elderly patients (over 75 years old).

Use in Pregnancy and Lactation

Zaldiar^® should not be used during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

In moderate hepatic impairment, the interval between doses of the drug should be increased. In severe hepatic impairment, the drug should not be used.

Use in Renal Impairment

In patients with impaired renal function (CC 30-10 ml/min), the interval between single doses should be at least 12 hours. Since tramadol is excreted very slowly during hemodialysis or hemofiltration, post-dialysis administration to maintain the analgesic effect is usually not required.

Special Precautions

Patients should be informed about the need to strictly adhere to the dosage regimen. During the period of taking Zaldiar^®, other drugs containing tramadol or Paracetamol should not be used without a doctor’s prescription.

With long-term uncontrolled use of Zaldiar^®, symptoms of drug dependence may appear (irritability, phobias, nervousness, sleep disorders, psychomotor activity, tremor, gastrointestinal discomfort). With abrupt withdrawal of the drug, signs of withdrawal syndrome may appear.

In patients prone to abuse or dependence, treatment should be carried out under careful medical supervision for a short period of time.

During treatment with Zaldiar^®, alcohol consumption is prohibited. The risk of liver dysfunction increases in patients with alcoholic hepatosis.

During long-term use of Zaldiar^®, monitoring of the peripheral blood picture and functional state of the liver is necessary.

Effect on the ability to drive vehicles and mechanisms

During treatment with Zaldiar^®, you should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

In case of acute overdose of Zaldiar^®, symptoms may include signs and symptoms of tramadol and/or paracetamol overdose.

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

Symptoms of paracetamol overdose acute – diarrhea, loss of appetite; chronic – cerebral edema, hypocoagulation, development of DIC syndrome, hypoglycemia, metabolic acidosis, arrhythmia, collapse (acute overdose develops 6-14 hours after taking paracetamol, chronic – after 2-4 days in case of overdose). Rarely, liver dysfunction develops rapidly, which may be complicated by renal failure (renal tubular necrosis).

Treatment gastric lavage, intake of enterosorbents (activated charcoal, polyphepan), maintenance of the function of the cardiovascular system, ensuring airway patency.

If respiratory depression occurs (as a symptom of tramadol overdose), the administration of naloxone is indicated; convulsions can be eliminated by the use of diazepam. Tramadol is minimally removed from the blood serum by hemodialysis or hemofiltration, so performing only these measures for the treatment of overdose is ineffective.

If symptoms of paracetamol overdose appear, the administration of SH-group donors and precursors of glutathione synthesis (methionine – 8-9 hours after overdose and N-acetylcysteine – after 12 hours) is indicated. The need for additional measures (further administration of methionine, intravenous administration of N-acetylcysteine) is determined depending on the concentration of paracetamol in the blood, as well as on the time elapsed after its intake.

Drug Interactions

When Zaldiar^® is used concomitantly with opioid agonist-antagonists (buprenorphine, nalbuphine, pentazocine), the analgesic effect is reduced due to competing action on the receptors and there is a risk of withdrawal syndrome, so the use of this combination is not recommended.

When Zaldiar^® is used in therapy together with other drugs that have a depressant effect on the central nervous system (for example, sleeping pills or tranquilizers), as well as with the simultaneous use of ethanol, the side effects characteristic of tramadol may be more pronounced.

Naloxone, being an opioid receptor antagonist, activates respiration, eliminating the analgesia caused by Zaldiar^®.

Inducers of microsomal oxidation (including carbamazepine, phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) reduce the analgesic effect of Zaldiar^® and its duration.

Inhibitors of microsomal oxidation (including cimetidine) with simultaneous use reduce the risk of hepatotoxic effects of Zaldiar^®.

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

Long-term combined use of paracetamol and NSAIDs increases the risk of nephropathy and renal papillary necrosis, and the onset of end-stage renal failure. Simultaneous long-term administration of paracetamol in high doses and salicylates increases the risk of kidney or bladder cancer.

Concomitant use of Zaldiar^® with drugs that lower the seizure threshold (for example, with selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics) may increase the risk of seizures.

Zaldiar^® with simultaneous long-term use enhances the effect of indirect anticoagulants (warfarin and other coumarins), which increases the risk of bleeding.

Drugs that inhibit the CYP3A4 isoenzyme, such as ketoconazole and erythromycin, may slow down the metabolism of tramadol (N-demethylation) and the active O-demethylated metabolite.

Diflunisal increases the plasma concentration of paracetamol by 50%, while the risk of hepatotoxicity increases.

Quinidine increases the plasma concentration of tramadol and reduces the concentration of the M₁ metabolite due to competitive inhibition of the CYP2D6 isoenzyme.

The absorption rate of paracetamol may be increased with simultaneous use of metoclopramide or domperidone and decreased with simultaneous use of cholestyramine.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.