Ramlepsa® (Ramlepsa)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspfilm-coated tablets
Composition:

1 tablet, film-coated:

Active substances:

Paracetamol 325.0 mg

Tramadol hydrochloride 37.5 mg

Excipients:

Pregelatinized starch - 21.8 mg

Carboxymethyl starch sodium - 18.0 mg

Microcrystalline cellulose - 25.6 mg

Magnesium stearate 2.1 mg

Film sheath:

Fade yellow 15B82958 * - 9.14 mg **

* Fell yellow 15B82958:

hypromellose 3 mPas = 2.916 mg

hypromellose 6 mPas - 2.916 mg

Macrogol-400 - 0.731 mg

polysorbate-80 - 0.091 mg

titanium dioxide - 2.358 mg

coloring agent iron oxide yellow (E 172) 0.128 mg

* Theoretical amount: due to process losses during the film coating process, it is possible to use more (up to 20%) Decaying yellow 15B82958.

Description:

Oval, slightly biconvex tablets covered with a film coat of light yellow with a slight brownish hue.

Pharmacotherapeutic group:analgesic agent combined (analgesic with a mixed mechanism of action + analgesic non-narcotic agent)
Pharmacodynamics:

Tramadol - narcotic synthetic analgesic, acting on the central nervous system (CNS). Is a non-selective agonist of opioid receptors (μ-, δ-, κ-) on the pre- and postsynaptic membranes of the afferent fibers of the nociceptive system in the brain and gastrointestinal tract (GIT), has a higher affinity for μreceptors.

Other mechanisms of analgesic action are inhibition of norepinephrine reuptake in neurons and increased release of serotonin. Tramadol has antitussive effect. In contrast to morphine, tramadol in analgesic doses does not suppress the function of respiration and does not affect the motility of the gastrointestinal tract. The effects of tramadol on the cardiovascular system are usually easily expressed. The severity of analgesic action is 6-10 times weaker than morphine.

Paracetamol: the exact mechanism of analgesic action is not known, possibly includes central and peripheral effects.

In the WHO guidelines for pain management, Ramlepsa® refers to analgesics of stage II; should be applied in accordance with the recommendations.

Pharmacokinetics:

Tramadol is a racemic mixture of two enantiomers: dextrorotatory (+) and levorotatory (-). Monobasic mono-O-desmethyltramadol (M1). The absorption of tramadol is slower than paracetamol, while the half-life (T1/2) tramadol longer.

With a single ingestion of paracetamol / tramadol tablets (37.5 mg / 325 mg), the maximum concentrations in the blood plasma (Cmax) - 64.3 / 55.5 ng / ml of [(+) - tramadol / (-) - tramadol] and 4.2 μg / ml of paracetamol are achieved after 1.8 hours for [(+) - tramadol / (-) - tramadol] and 0.9 hours for paracetamol, respectively.

Significant changes in the pharmacokinetic parameters when taking paracetamol / tramadol are not detected by mouth as compared with the intake of each active substance.

With a single ingestion of paracetamol / tramadol tablets (37.5 mg / 325 mg), the maximum concentrations in the blood plasma (Cmax) - 64.3 / 55.5 ng / ml of [(+) - tramadol / (-) - tramadol] and 4.2 μg / ml of paracetamol are achieved after 1.8 hours for [(+) - tramadol / (-) - tramadol] and 0.9 hours for paracetamol, respectively.

Significant changes in the pharmacokinetic parameters when taking paracetamol / tramadol are not detected by mouth as compared with the intake of each active substance.

Suction

The racemate tramadol quickly and almost completely absorbed when ingested. Absolute bioavailability of a single dose of 100 mg is approximately 75%, with repeated application - increases to about 90%.

After ingestion paracetamol in the small intestine rapid and almost complete. FROMmax paracetamol in blood plasma is achieved after 1 hour and does not change with simultaneous application with tramadol.

Eating does not have a significant effect on Cmax or the degree of absorption of tramadol and paracetamol, so the drug can be taken regardless of food intake.

Distribution

Tramadol has a high affinity for tissues (Vd,ß=203 ± 40 L). Binding to plasma proteins is about 20%.

Paracetamol well distributed in most body tissues, except fat. The apparent volume of distribution is approximately 0.9 l / kg. A relatively small part (~ 20%) of paracetamol binds to plasma proteins.

Metabolism

Tramadol after ingestion is actively metabolized by O-demethylation (catalyzed by isoenzyme CYP2D6) before the metabolite M1, and then - A-demethylation (catalyzed by isoenzyme CYP3A) to metabolite M2 followed by conjugation with glucuronic acid. T1/2 M1 from the blood plasma is 7 hours. Metabolite M1 has an analgesic effect and has a more pronounced effect than itself tramadol. Concentration M1 in blood plasma is several times lower than the concentration of tramadol.

Paracetamol metabolized primarily in the liver in two main ways: glucuronization and sulfation. The latter way is quickly saturated, if the dose exceeds the therapeutic dose. A small portion of the dose (less than 4%) is metabolized by cytochrome P450 to the active metabolite (N-acetylbenzoquinonimine),which is normally rapidly neutralized by glutathione and excreted by the kidneys after conjugation with cysteine ​​and mercapturic acid. However, the concentration of this metabolite increases with a severe overdose.

Excretion

Tramadol and its metabolites are excreted mainly by the kidneys: 30% unchanged, and 60% - in the form of metabolites.

T1/2 paracetamol in adults it is from 2 to 3 hours. In children, it is slightly shorter, and in newborns and patients with cirrhosis of the liver - lengthened. Paracetamol is derived, mainly in the form of glucuronic and sulfone conjugates, the formation of which depends on the dose of paracetamol. Less than 9% of paracetamol is excreted by the kidneys unchanged.

With renal insufficiency, T1 / 2 of both active components of the drug is lengthened.

Indications:

- Symptomatic treatment of pain syndrome of medium and strong intensity of various etiologies, including inflammatory, traumatic,vascular origin (if necessary combined therapy of tramadol and paracetamol).

- Anesthesia when performing painful diagnostic or therapeutic manipulations.

Contraindications:

- Hypersensitivity to the active substances or auxiliary components of the drug;

- conditions accompanied by respiratory depression or severe CNS depression (including acute intoxication with alcohol, hypnotic drugs (LS), narcotic analgesics and other psychoactive drugs);

- simultaneous use with monoamine oxidase (MAO) inhibitors and within 2 weeks after their cancellation;

- severe hepatic and / or renal insufficiency (creatinine clearance (CC) less than 10 ml / min);

- epilepsy, uncontrolled by treatment;

- syndrome of "cancellation" of narcotic drugs;

- children's age (up to 14 years) (efficiency and safety not established);

- pregnancy, the period of breastfeeding.

Carefully:

Hepatic insufficiency of moderate severity; renal failure of moderate severity (QC 10-30 ml / min), patients with opioid dependence, craniocerebral trauma,prone to the development of convulsive syndrome or patients with controlled epilepsy, or simultaneously taking drugs that reduce the threshold of convulsive readiness (especially selective serotonin reuptake inhibitors, tricyclic antidepressants, neuroleptics, central action analgesics or topical anesthetics); with dysfunction of the bile ducts, patients in shock, with a violation of the consciousness of unknown etiology, with a violation of the respiratory center function or with respiratory failure; with intracranial hypertension; simultaneous use with agonist-antagonists or partial agonists of opioid receptors (buprenorphine, nalboufine, pentazocine), by means of local anesthesia; before surface general anesthesia (eg, enflurane and dinitrogen oxide).

Pregnancy and lactation:

The drug Ramlepsa ® should not be used during pregnancy and during breastfeeding.

Dosing and Administration:

Inside, regardless of food intake. Ramleps ® ® tablets should be swallowed whole, with a sufficient amount of liquid. Do not chew or divide into pieces.The drug Ramlepsa ® is used under the supervision of a doctor. The dose of the drug is selected individually, depending on the severity of the pain syndrome and the effect of the therapy. For the purpose of anesthesia, the minimum effective dose is usually prescribed. If you need a repeated and prolonged use of Ramlepsa®, treatment should be performed under close medical supervision. If possible, take intermittent treatment to assess the need for continued therapy.

Adults and adolescents over 14 years of age

The recommended initial dose is 1 -2 tablets of the drug Ramlepsa® with an interval between doses of the drug for at least 6 hours. The maximum daily dose of Ramleps is 8 tablets (equivalent to 300 mg of tramadol and 2600 mg of paracetamol).

Children

Children under 14 years of age should not take Ramlepsa ®, efficacy and safety of the drug in children younger than 14 years are not established.

Patients elderly (75 years and older)

Correction of the dose of Ramleps ® is not required. However, in connection with the possibility of delayed excretion of tramadol, the interval between doses of the drug may be increased.

Renal impairment

In patients with impaired renal function, excretion of tramadol slows down. Patients with severe renal insufficiency (CC less than 10 ml / min) should not be used. In patients with impaired renal function (QC 10-30 ml / min), the interval between doses should be at least 12 hours.

Since hemodialysis or hemofiltration tramadol is very slow, the use of the drug after the dialysis procedure is usually not required. Dysfunction of the liver

In patients with impaired liver function, excretion of tramadol slows down. Patients with severe impairment of liver function, Ramlepsa® should not be used. In the case of moderately severe violations of the liver, it is necessary to increase the interval between doses of the drug.

Side effects:

Classification of the frequency of development of side effects of the World Health Organization (WHO):

very often - ≥1 / 10

often from ≥1/100 to <1/10

infrequently - from ≥1/1000 to <1/100

rarely from ≥1/10000 to <1/1000

very rarely - from <1/10000

the frequency is not known - can not be estimated from the available data.

In each group, undesirable effects are presented in order of decreasing severity.

The most frequent adverse events noted during clinical trials were: nausea, dizziness and drowsiness, which were observed in more than 10% of patients.

Disorders of the psyche:

often: confusion, lability of mood (anxiety, nervousness, euphoria), sleep disturbances;

infrequently: depression, hallucinations, "nightmarish" dreams, amnesia; rarely: drug dependence;

Post-marketing surveillance:

very rarely: abuse.

Impaired nervous system:

very often: dizziness, drowsiness;

often: headache, tremor;

infrequently: involuntary muscle contractions, paresthesia;

rarely: ataxia, convulsions.

Disorders from the side of the organ of vision:

rarely: blurred vision.

Hearing disorders and labyrinthine disturbances:

infrequently: ringing in the ears.

Heart Disease:

infrequently: arrhythmia, tachycardia, palpitation.

Vascular disorders:

infrequently: increased blood pressure (BP), a sensation of "tides" of blood to the skin of the face.

Disturbances from the respiratory system, chest and mediastinal organs:

infrequently: shortness of breath.

Disorders from the gastrointestinal tract:

very often: nausea;

often: vomiting, constipation, dryness of the oral mucosa, diarrhea, abdominal pain, indigestion, flatulence;

infrequently: dysphagia, melena.

Disturbances from the skin and subcutaneous tissues:

often: increased sweating, itchy skin;

infrequently: skin rash, hives.

Disorders from the kidneys and urinary tract:

infrequent: urination disorders (dysuria and urinary retention), albuminuria.

General disorders and disorders at the site of administration:

infrequently: fever, chest pain (Organism as a whole: rarely: a shiver, a sensation of "tides" of blood to the skin of the face, pain in the chest)

Laboratory and instrumental data:

infrequently: increased activity of transaminases.

Undesirable effects that did not occur in clinical trials, but their association with tramadol or paracetamol can not be excluded

Tramadol:

- Orthostatic hypotension, bradycardia, collapse;

- In clinical practice, with simultaneous use with warfarin, there was rarely a change in the effect of warfarin, including prolongation of prothrombin time;

- rarely: allergic reactions with respiratory symptoms (eg, dyspnea, bronchospasm, wheezing, angioedema) and anaphylactic shock;

- rarely: changes in appetite, muscle weakness and respiratory depression; mental disorders that differ in intensity and nature (depending on the type of personality and duration of treatment): mood changes (usually euphoria, sometimes dysphoria), changes in motor activity (usually increased fatigue, less increased activity), and changes in cognitive functions and sensitivity (ie, violation of perception and behavior);

- cases of exacerbation of the course of bronchial asthma are described. Causal link is not established.

- signs of the syndrome of "withdrawal", similar to those for the abolition of narcotic analgesics: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and reactions from the gastrointestinal tract. Very rarely, with a sharp reversal of tramadol, there were other symptoms: panic attacks, severe anxiety, hallucinations, paresthesia, ringing in the ears, and uncharacteristic symptoms from the CNS.

Paracetamol:

- Undesirable reactions with paracetamol have been observed in rare cases, hypersensitivity reactions, including skin rash, are possible. Cases of violations by hemopoietic organs, including thrombocytopenia and agranulocytosis, are described. Causal relationship with the use of paracetamol is not established.

- there are several reports that simultaneous use of paracetamol with indirect anticoagulants can cause hypoprothrombinemia.

Overdose:

Symptoms of an overdose of Ramlepsa® may include symptoms of an overdose of tramadol or paracetamol, as well as of both active components.

Symptoms of an overdose of tramadol (typical for narcotic analgesics): miosis, vomiting, collapse, impaired consciousness right up to the development of coma, convulsions, respiratory depression before apnea.

Symptoms of an overdose of paracetamol:

Acute overdose of paracetamol (develops within 24 hours after taking paracetamol): pallor of the skin, nausea, vomiting, decreased appetite before anorexia, abdominal pain.

Chronic overdose with paracetamol (develops 12-48 hours after paracetamol administration): in case of severe poisoning, liver failure may occur progress to the development of encephalopathy, coma and death; cerebral edema, hypocoagulation, development of DIC syndrome, glucose metabolism disorders (hypoglycemia) and metabolic acidosis; possible the development of cardiac arrhythmias and pancreatitis, collapse. Acute renal failure (acute tubular necrosis) can develop even in the absence of severe liver damage.

Liver involvement is possible in adults with 4 g or more of paracetamol. Excess amount of toxic metabolite (which is inactivated by adequate dosing of paracetamol with glutathione) irreversibly binds to liver tissue.

Treatment

Emergency hospitalization in a specialized department. If the patient is conscious, vomiting or gastric lavage should be performed and absorbants taken (Activated carbon). Before the start of treatment, it is necessary, as soon as possible, to determine plasma concentrations of paracetamol and tramadol, and assess liver function (at the beginning and in the dynamics (every 24 hours)). Usually, an increase in the activity of "hepatic" enzymes (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)), which is then normalized after one or two weeks. The functions of the respiratory and cardiovascular systems should be maintained; ensure airway patency; when oppression of respiration (with an overdose of tramadol) is administered naloxone, with convulsions - intravenous diazepam. Adults or adolescents who have taken about 4 g or more of paracetamol during the last 4 hours and a child who has taken 150 mg / kg of paracetamol within the last 4 hours will be rinsed. After 4 hours after an overdose, the concentration of paracetamol in the blood plasma should be determined for risk assessment development of liver damage (through the nomogram Rumacq-Matthew). It may be necessary to use methionine inside or acetylcysteine ​​intravenously, which may have a beneficial effect, at least within the first 48 hours after an overdose.

The most effective use of acetylcysteine ​​(intravenous administration) in the first 8 hours after taking paracetamol. If more than 8 hours have passed after taking paracetamol, you should also use it orally or intravenously acetylcysteine during the entire treatment period. If a severe overdose is suspected, treatment with acetylcysteine ​​should be started immediately. Hemodialysis or hemofiltration is not effective.

Regardless of the dose of paracetamol taken, the antidote (acetylcysteine) should be administered orally or intravenously as soon as possible, if possible, within the first 8 hours after an overdose.

Interaction:

Tramadol can cause seizures and promote the development of seizures when applied selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors and norepinephrine, tricyclic antidepressants, antipsychotics and other drugs that reduce the threshold of convulsive activity (such as: bupropion, mirtazapine).

Simultaneous use of tramadol and serotonergic drugs (SSRIs, serotonin reuptake inhibitors and norepinephrine, MAO inhibitors, tricyclic antidepressants, and mirtazapine) may cause serotonin toxicity. Serotonin syndrome should be assumed in the presence of one of the following symptoms:

- spontaneous clone,

- an induced or ocular clone with agitation or sweating,

- tremor and hyperreflexia,

- arterial hypertension, an increase in body temperature> 38 ° C, an induced or ocular clonus.

The abolition of serotinergic drugs usually leads to a rapid improvement. Treatment depends on the type of severity of the symptoms.

Contraindicated simultaneous use with the following drugs:

- nonselective MAO inhibitors, selective MAO A inhibitors (reversible) and selective MAO B inhibitors (irreversible): risk of developing serotonin syndrome (diarrhea, tachycardia, sweating, tremor, confusion, up to coma) or symptoms of CNS excitation, which resemble it. The drug Ramlepsa ® should be taken no earlier than 2 weeks after the abolition of MAO inhibitors.

It is not recommended simultaneous use with the following drugs:

- alcohol: increased sedative effect of tramadol, weakened attention. Avoid taking alcoholic beverages or alcohol-containing medications.

- carbamazepine and other inducers of microsomal liver enzymes (for example, phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants): possible decrease in efficiency (decrease analgesic effect and its duration) due to a decrease in the concentration of tramadol in the blood plasma.

- agonists-antagonists or partial agonists of opioid receptors (buprenorphine, nalboufine, pentazocine): possible a decrease in efficiency (decrease in analgesic effect) due to competitive blocking of receptors; risk of withdrawal syndrome.

Simultaneous use requires caution:

- Cases of serotonin syndrome (confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhea) that have been chronologically associated with tramadol at the same time as others serotonergic drugs (selective serotonin reuptake inhibitors and tryptanes).

- Other narcotic analgesics (including antitussives and drugs used as substitution therapy for opioid dependence), benzodiazepines and barbiturates: the threat of respiratory depression, which in case of an overdose can be fatal.

- Other drugs that depress the central nervous system: narcotic analgesics (including antitussives and agents used as substitution therapy for opioid dependence), barbiturates, benzodiazepines, anxiolytic, hypnotic, sedative antidepressants, H1 blockers-gistaminovyh receptors with sedative properties, antipsychotics, central antihypertensives, thalidomide and baclofen - additional CNS depression caused by tramadol.

- Indirect anticoagulants (for example, warfarin): Since there are reports of an increase in the International Normalized Ratio (INR), prothrombin time should be monitored periodically.

- Other isoenzyme inhibitors CYP3A4, eg, ketoconazole and erythromycin, can inhibit the metabolism of tramadol (N-detylation) and active O-demethylated (M1) metabolite. The clinical significance of this interaction has not been studied.

- Drugs that reduce the threshold of convulsive alertness, such as bupropion, serotonin reuptake inhibitors (antidepressants), tricyclic antidepressants and antipsychotics: risk of seizures.

- The rate of absorption of paracetamol is increased by the action of metoclopramide or domperidone, and suction is reduced by action colestyramine.

- Pre- or postoperative use of an anti-emetic drug ondansetron (blocker of 5-HTZ-serotonin receptors) requires the use of higher doses of tramadol in patients with postoperative pain syndrome.

Special instructions:

In adults and children aged 14 years and older, the maximum daily dose of Ramlepsa® should not exceed 8 tablets. Patients should be informed that the recommended dose should not be exceeded or at the same time other drugs containing tramadol and paracetamol (including those sold without a prescription) without consulting a doctor.

The drug Ramlepsa® is not recommended in cases of severe renal failure (CC less than 10 ml / min). In patients with severe hepatic insufficiency, Ramlepsa® should not be used. The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver damage.At moderately expressed violations of the liver function, it is necessary to increase the interval between doses of the drug. In severe respiratory failure, the use of Ramlepsa ® is not recommended.

In patients with opioid dependence tramadol as a replacement therapy is not applied. Tramadol does not stop the "withdrawal" syndrome of morphine.

Patients who are prone to develop convulsive syndrome or who are taking drugs simultaneously, reduce the threshold of convulsive readiness (especially selective serotonin reuptake inhibitors, tricyclic antidepressants, neuroleptics, central action analgesics or topical anesthetics), the development of seizures was observed with tramadol. The risk of seizures increases with the use of tramadol in doses exceeding the maximum recommended. In patients with controlled epilepsy and in patients prone to developing convulsive syndrome, Ramlepsa ® can be used only for vital signs. Simultaneous use of agonist antagonists or partial agonists of opioid receptors (buprenorphine, nalboufine, pentazocine) is not recommended.

The Ramleps® drug should be used with caution in patients with opioid dependence, a history of the history of the cranial trauma, susceptible to developing convulsive syndrome, bile duct disease in shock, with a violation of the unknown etiology, respiratory insufficiency and intracranial hypertension.

Paracetamol is hepatotoxic in high doses.

With the cancellation of tramadol, used in therapeutic doses, there may be signs of withdrawal syndrome. In rare cases, with prolonged uncontrolled use, it is possible to develop drug dependence.

Perhaps the appearance of symptoms of the syndrome of "withdrawal", identical with those for the abolition of narcotic analgesics.

The use of tramadol during the general surface anesthesia of dinitrogen with an oxide, which promoted awakening during the operation, is described. It is recommended to avoid the use of tramadol during surface anesthesia (eg, enflurane and dinitrogen oxide) until further information is obtained.

Effect on the ability to drive transp. cf. and fur:The Ramleps® preparation has a pronounced effect on the ability to drive and work with moving machinery. Tramadol can cause drowsiness and dizziness, which can be exacerbated by alcohol and other CNS depressant medications, so during treatment should refrain from driving and practicing potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
Form release / dosage:

The film-coated tablets are 325 mg + 37.5 mg.

Packaging:

For 10 tablets in a blister of the combined material PVC / PVDH white film - aluminum foil.

1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 blisters are placed in a cardboard pack together with an instruction for use.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

The drug belongs to the list of 1 potent substances of the Standing Committee on Drug Control M3 RF.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription
Registration number:LP-002103
Date of registration:17.06.2013
The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO
Manufacturer: & nbsp
KRKA, d.d. Slovenia
Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO
Information update date: & nbsp11.08.2015
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