Universal reference book for medicines
Product name: RAMLEPSA ® (RAMLEPSA ® )

Active substance: paracetamol, tramadol

Type: Combined drug with analgesic action

Manufacturer: KRKA (Slovenia)
Composition, form of production and packaging
The tablets covered with a film membrane of
light yellow color, with a weak brownish tinge, oval, slightly biconcave.

1 tab.

paracetamol 325 mg

tramadol hydrochloride 37.5 mg

[PRING] pregelatinized starch - 21.8 mg, sodium carboxymethyl starch - 18 mg, microcrystalline cellulose - 25.6 mg, magnesium stearate - 2.1 mg.

The composition of the film shell: opadray yellow 15B82958 - 9.14 mg (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, iron dye oxide yellow (E172) - 0.128 mg)

10 pieces.
- blisters of PVC / PVDC / aluminum foil (1) - packs of cardboard.
10 pieces.
- blisters from PVC / PVDH / aluminum foil (2) - packs cardboard.
10 pieces.
- blisters made of PVC / PVDH / aluminum foil (3) - packs cardboard.
10 pieces.
- blisters from PVC / PVDH / aluminum foil (4) - packs cardboard.
10 pieces.
- blisters of PVC / PVDC / aluminum foil (5) - packs of cardboard.
10 pieces.
- blisters of PVC / PVDC / aluminum foil (6) - packs of cardboard.
10 pieces.
- blisters from PVC / PVDH / aluminum foil (7) - packs cardboard.
10 pieces.
- blisters from PVC / PVDH / aluminum foil (8) - packs cardboard.
10 pieces.
- blisters of PVC / PVDC / aluminum foil (9) - packs of cardboard.
10 pieces.
- blisters from PVC / PVDC / aluminum foil (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

Tramadol is a narcotic synthetic analgesic that acts on the central nervous system.
Is a non-selective agonist of opioid receptors (? -,? -,? -) on the pre- and postsynaptic membranes of the afferent fibers of the nociceptive system in the brain and GI tract, has a higher affinity for? -receptors.
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 the analgesics of stage II;
should be applied in accordance with the recommendations.
PHARMACOKINETICS

Tramadol is a racemic mixture of two enantiomers: dextrorotatory (+) and levorotatory (-).
In the blood mono-O-desmethyltramadol (M1) metabolite is determined.The absorption of tramadol is slower than paracetamol, while T 1/2 of tramadol is longer.
With a single oral take of paracetamol / tramadol tablets (37.5 mg / 325 mg), Cmax is 64.3 / 55.5 ng / ml of [(+) - tramadol / (-) tramadol] and 4.2 μg / ml paracetamol is achieved 1.8 hours later for [(+) - tramadol / (-) - tramadol] and after 0.9 hours for paracetamol, respectively.

Significant changes in the pharmacokinetic parameters when taking paracetamol / tramadol orally were not detected as compared with the administration of each of the active substances of the preparation.

Suction

The racemate of tramadol is quickly and almost completely absorbed when taken orally.
Absolute bioavailability of a single dose of 100 mg is approximately 75% with repeated application - increases to about 90%.
After ingestion, the absorption of paracetamol in the small intestine is rapid and almost complete.
C max 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 C max 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 (V ?,? = 203 ± 40 L).
Binding to plasma proteins is about 20%.
Paracetamol is well distributed in most body tissues, except for 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 oral administration is actively metabolized by O-demethylation (catalyzed by the isoenzyme CYP2D6) to the metabolite M1 and then - N-demethylation (catalyzed by the CYP3A isoenzyme) to the metabolite M 2 , followed by conjugation with glucuronic acid.
T 1/2 M 1 from the blood plasma is 7 hours.Metabolite M 1 has analgesic effect and has a more pronounced effect than tramadol itself. The M 2 concentration of the blood plasma is several times lower than the concentration of tramadol.
Paracetamol is metabolized predominantly 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 with 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.

T 1/2 of paracetamol in adults 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 excreted, 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 failure, T 1/2 of both active components of the drug is lengthened.

INDICATIONS

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

- Anesthesia when performing painful diagnostic or therapeutic manipulations.

DOSING MODE

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 Ramleps ® 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 long-term treatment with Ramleps ®, 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 Ramleps ® with an interval between doses of the drug 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 Ramleps ® as it does not.
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 of the drug should be at least 12 hours.
Since during hemodialysis or haemofiltration, 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 Ramleps ® 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 EFFECT

Classification of the incidence of adverse events 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; frequency is unknown - 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.

Violation of the central nervous system:

very often: dizziness, drowsiness;

often: headache, tremor;

infrequent: involuntary contraction of the mouse, 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, 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 digestive 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 chest ( Organism as a whole: rarely: trembling, 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 hyiotension, 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, a violation of perception and behavior);

- cases of exacerbation of the course of bronchial asthma are described.
Causal link is not established.
- signs of the "withdrawal" syndrome, 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, other symptoms are noted: 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 the simultaneous use of paracetamol with indirect anticoagulants can cause hypoprothrombinemia.

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 (drugs), 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.

With caution: hepatic insufficiency of moderate severity;
renal failure of moderate severity (CK 10-30 ml / min), patients with opioid dependence, craniocerebral trauma, inclined to develop convulsive syndrome or patients with controlled epilepsy, or simultaneously taking drugs that reduce the threshold of convulsive readiness (especially selective inhibitors reuptake of serotonin, tricyclic antidepressants, antipsychotics, central action analgesics or topical anesthetics); with dysfunction of the biliary tract, 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 application with agonist-antagonists or partial agonists of opioid receptors (buprenorphine, nalbuphine, pentazocine), local anesthesia; before surface general anesthesia (eg, euflurane and dinitrogen oxide).
PREGNANCY AND LACTATION

The drug is contraindicated in pregnancy and during breastfeeding.

APPLICATION FOR FUNCTIONS OF THE LIVER

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 of the drug should be at least 12 hours.
Since during hemodialysis or haemofiltration, tramadol is very slow, the use of the drug after the dialysis procedure is usually not required.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with impaired liver function, excretion of tramadol slows down.
Patients with severe impairment of liver function Ramleps ® 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.
APPLICATION FOR CHILDREN

Children under 14 years of age should not take Ramleps ® as it does not.
efficacy and safety of the drug in children younger than 14 years are not established.
APPLICATION IN ELDERLY PATIENTS

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.
SPECIAL INSTRUCTIONS

In adults and children aged 14 years and older, the maximum daily dose of Ramleps ® should not exceed 8 tablets.
Patients should be informed that they should not exceed the recommended dose or simultaneously take other drugs containing tramadol and paracetamol (including over-the-counter products) without consulting a doctor.
Ramleps ® is not recommended in cases of severe renal failure (CC less than 10 ml / min).
In patients with severe hepatic insufficiency, Ramleps ® should not be used.The risk of paracetamol overdose is higher in patients with non-cirrhotic alcoholic liver damage. With moderately severe violations of liver function, it is necessary to increase the interval between doses of the drug. In severe respiratory failure, the use of Ramleps ® is not recommended.
In patients with opioid dependence, tramadol is not used as a substitution therapy.
Tramadol does not stop the "withdrawal" syndrome of morphine.
Patients who are prone to develop convulsive syndrome or who are taking drugs at the same time reduce the threshold of convulsive readiness (especially selective serotonin reuptake inhibitors, tricyclic antidepressants, neuroleptics, central action analgesics or local anesthetic agents), 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 the development of convulsive syndrome, Ramleps ® can be used only for vital signs. Simultaneous use of agonist-antagonists or partial agonists of opioid receptors (buprenorphine, nalbuphine, entanzocine) is not recommended.
The Ramleps ® drug should be used with caution in patients with opioid dependence, a history of traumatic brain injury, a convulsive syndrome susceptible to development, bile duct disease in a state of shock, a violation of the unknown etiology, respiratory insufficiency and intracranial hypertension.
Paracetamol is hepatotoxic in high doses.
In case of cancellation of tramadol, is used in therapeutic doses, symptoms of the syndrome may occur, "abolition". In rare cases, long-term uncontrolled use may develop drug dependence.
Perhaps the appearance of symptoms of "cancellation" syndrome identical to those cases of narcotic analgesics.
Discloses the use of tramadol during general anesthesia surface dinitrogen oxide is promoted awaken during surgery. It is recommended to avoid the use of tramadol during surface anesthesia (e.g., enflurane and dinitrogen monoxide) to obtain additional information.
Influence or ability to perform potentially hazardous activities that require attention and fast reactions (eg, road management, work with moving machinery)
drug Ramlepsa ® okazyvatsya pronounced effect on the ability to drive vehicles and operate moving mechanisms. Tramadol may cause drowsiness or dizziness, which may increase under the influence of alcohol and other CNS depressants, so during treatment should refrain from driving and classes of potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE

Symptoms of drug overdose Ramlepsa ® can include symptoms of an overdose of paracetamol or tramadol and both active ingredients.
Symptoms of tramadol overdose (characteristic of narcotic analgesics):
cramps, vomiting, collapse, consciousness disorders up to coma, convulsions, respiratory depression up to apnea.
Symptoms of paracetamol overdose:
Acute overdose of paracetamol (develops within 24 hours after ingestion of paracetamol): paleness of the skin, nausea, vomiting, loss of appetite anorexia, abdominal pain.
Chronic overdose of paracetamol(develops within 12-48 hours after ingestion of paracetamol): in case of severe hepatic failure poisoning can progress to encephalopathy, coma and death; cerebral edema, hypocoagulation, the development of DIC, impaired glucose metabolism (hypoglycemia) and metabolic acidosis; possible development of cardiac arrhythmias and pancreatitis, collapse. Acute renal failure (acute tubular necrosis) may occur even in the absence of severe liver disease.
Liver damage is possible in adults when receiving 4 g or more of paracetamol. Excessive amounts of a toxic metabolite (which at adequate dosage of paracetamol inaktivirustsya glutathione) binds irreversibly to the liver tissue.
Treatment

Emergency hospitalization in a specialist unit. If the patient is conscious, it is necessary to induce vomiting or gastric lavage to hold and take adsorbents (activated charcoal). Prior to the treatment must as soon as possible to determine the plasma concentrations of acetaminophen and tramadol and assess liver function (in the beginning and in dynamics (every 24 hours)). Typically revealed increased activity "liver" enzymes (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)), which is then normalized by one-two weeks. It is necessary to maintain the function of the respiratory and cardiovascular systems; ensure airway patency; when respiratory depression (overdose tramadol) administered naloxone, in convulsions - intravenous diazepam. Adults or adolescents who took over the last 4 hours,about 4g of paracetamol or more, and a child who has taken over the last 4 hours of 150 mg / kg paracetamol carried gastric lavage. After 4 hours after the overdose should determine the concentration of paracetamol in plasma for the assessment of risk of developing liver damage (by Mata-nomogram Rumakk). It may require the use of methionine or acetylcysteine ​​intravenously inside, which can have beneficial effects, at least within the first 48 hours after the overdose.It may require the use of methionine or acetylcysteine ​​intravenously inside, which can have beneficial effects, at least within the first 48 hours after the overdose.It may require the use of methionine or acetylcysteine ​​intravenously inside, which can have beneficial effects, at least within the first 48 hours after the overdose.
The most effective use acetylcysteine (intravenous administration) in the first 8 hours after ingestion of paracetamol. If more than 8 hours after ingestion of paracetamol should also apply inward or acetylcysteine intravenously throughout the treatment period. If you suspect the presence of severe overdose anetiltsisteinom treatment should be started immediately. Hemodialysis or hemofiltration not effective.
Irrespective of the dose of paracetamol antidote (acetylcysteine) must enter into or intravenously as soon as possible, if possible, during the first 8 hours after the overdose.
DRUG INTERACTION

Tramadol can cause seizures and contributes to the development of seizures in the application of selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors and norepinephrine tritsiklicheskieh antidepressants, antipsychotics and other medications that lower seizure threshold activity (such as bupropion, mirtazapine).
The simultaneous use of tramadol and serotonergic drugs (SSRIs, serotonin reuptake inhibitors and norepinephrine, MAO inhibitors, tricyclic antidepressants and mirtazapine) may cause toxicity serotonin. Serotonin syndrome should be suspected in the presence of one of the following symptoms:
- spontaneous clonus;
- induced or ocular clonus with agitation or sweating;
- tremors, and hyperreflexia;
- arterial hypertension, fever> 38 ° C, induced or ocular clonus.
Cancel serotininergicheskih preparations usually leads to a rapid improvement.
Treatment depends on the severity of symptoms.
Concomitant use with the following preparations:
- non-selective MAO inhibitors, selective MAO A inhibitors (reversible) and selective MAO inhibitors B (irreversible): risk of serotonin syndrome (diarrhea, tachycardia, sweating, tremor, confusion, even coma) or symptoms CNS excitation, reminding him.
Preparation Ramlepsa ® should be taken no earlier than two weeks after discontinuation of MAO inhibitors.
Not recommended simultaneous application with the following drugs:
- Alcohol: increased sedation of tramadol, weakening of attention. Avoid drinking alcohol or alcohol-containing drugs.
- carbamazepine and other inducers of microsomal liver enzymes (e.g., phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) may reduce the effectiveness (reduction of the analgesic effect and its duration) due to the reduction of tramadol plasma concentration.
- agonists, antagonists or partial agonists of opioid receptors (buprenorfii, nalbuphine, pentazocine) may decrease the efficiency (decrease in analgesic effect) due to competitive blocking of receptors; the risk of the syndrome of "cancellation".
Simultaneous application requires caution:
- described cases of serotonin syndrome (confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhea), which were chronologically related to the use of tramadol in conjunction with other serotonergic agents (selective serotonin reuptake inhibitor and triptans) .
- other narcotic analgesics (including antitussives and agents used as replacement therapy for opioid dependence), and barbiturates bepzodiazepiny: threat respiratory depression, which can be lethal in overdose.
- other drugs, CNS depressants: narcotic analgesics (including antitussives and agents used as replacement therapy for opioid addiction), barbiturates, benzodiazepines, anxiolytics, hypnotics, sedatives antidepressants, blockers of H 1 histamine receptors with sedative properties, neuroleptics, antihypertensive medications central action, thalidomide and baclofen - additional CNS depression caused by tramadol.
- oral anticoagulants (eg, warfarin) because there are reports of increased International Normalized Ratio (MHO), should periodically monitor the prothrombin time.
- izofermeita other inhibitors of CYP3A4, such as erythromycin and ketoconazole can inhibit the metabolism of tramadol (N-demethylation) and O-demethylated active (M1) metabolite. The clinical significance of this interaction has not been studied.
- drugs that reduce the seizure threshold, such as bupropion, serotonin reuptake inhibitors (antidepressants), tricyclic antidepressants and antipsychotics: risk of seizures.
- the rate of absorption of paracetamol is increased by metoclopramide or domperidone, and absorption is reduced by the action of cholestyramine.
- pre or postoperative application of the antiemetic drug ondansetron (a 5-blocker NTZ-serotonin receptors) requires higher doses of tramadol in patients with postoperative pain.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Store at a temperature not higher than 30 ° C in the reach of children.
Shelf life - 3 years.
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