Dolcet Mini

Tramadol hydrochloride, paracetamol.

Each tablet contains 18.75 mg tramadol hydrochloride and 162.50 mg paracetamol.
Excipients/Inactive Ingredients: The excipients are powdered cellulose, pregelatinized starch, corn starch, sodium starch glycolate, magnesium stearate, OPADRY Light Yellow, and carnauba wax.

Pharmacology: Pharmacodynamics: Pharmacodynamic Effects: Tramadol is a centrally acting analgesic compound. At least two complementary mechanisms appear applicable, binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Paracetamol is another centrally acting analgesic. The exact site and mechanism of its analgesic action is not clearly defined.
When evaluated in a standard animal model, the combination of tramadol and paracetamol exhibited a synergistic effect.
Pharmacokinetics: General: Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and paracetamol following oral administration of one tramadol/paracetamol (Dolcet Mini) tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to paracetamol.
After a single oral dose of one Tramadol/Paracetamol combination tablet (37.5 mg/325 mg) peak plasma concentrations of 64.3/55.5 ng/ml [(+)-Tramadol/(-)-Tramadol] and 4.2 μg/ml (paracetamol) are reached after 1.8 h [(+)-Tramadol/(-)-Tramadol] and 0.9 h (paracetamol), respectively. Mean elimination half lives (t_1/2) are 5.1/4.7 h [(+)-Tramadol/(-)-Tramadol] and 2.5 h (paracetamol).
Single and multiple dose pharmacokinetic studies of tramadol/paracetamol (Dolcet Mini) in volunteers showed no significant drug interactions between tramadol and paracetamol. (See Table 1.)

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Absorption: Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two tramadol/paracetamol (Dolcet Mini) tablets occurs at approximately two and three hours, respectively, post-dose in healthy adults.
Oral absorption of paracetamol following administration of tramadol/paracetamol (Dolcet Mini) is rapid and almost complete and occurs primarily in the small intestine. Peak plasma concentrations of paracetamol occur within 1 hour and are not affected by co-administration with tramadol.
Food effects: The oral administration of tramadol/paracetamol (Dolcet Mini) with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol, so that tramadol/paracetamol (Dolcet Mini) can be taken independently of meal times.
Distribution: The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20%.
Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg.
A relative small portion (~20%) of paracetamol is bound to plasma protein.
Metabolism: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of tramadol/paracetamol (Dolcet Mini) in volunteers showed no significant change compared to dosing with tramadol alone.
Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Tramadol is extensively metabolized by a number of pathways, including CYP2D6. Patients who are CYP2D6 ultra-rapid metabolizers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients (see CYP2D6 Ultra-Rapid Metabolism of Tramadol under Precautions). The prevalence of this CYP2D6 genotype varies by population and has been reported in literature to range from 1% to 10% in African Americans, Caucasian Americans, Asians and Europeans (including specific studies in Greeks, Hungarians and Northern Europeans) to as high as 29% in African/Ethiopians.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves three principle separate pathways: a) conjugation with glucuronide; b) conjugation with sulfate; and c) oxidation via cytochrome P450 enzyme pathway.
Excretion: Tramadol and its metabolites are eliminated primarily by the kidney. The plasma elimination half-lives of racemic tramadol and M1 are approximately six and seven hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing of tramadol/paracetamol (Dolcet Mini).
The half-life of paracetamol is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.
Toxicology: Non-Clinical Information: Tramadol/Paracetamol combination: There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis, or impairment of fertility.
No drug-related teratogenic effects were observed in the progeny of rats treated orally with the combination of tramadol and paracetamol. The tramadol/paracetamol combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose (50/434 mg/kg tramadol/paracetamol) 8.3 times the maximum human dose but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Lower and less severe maternally toxic dosages (10/87 and 25/217 mg/kg tramadol/paracetamol) did not produce embryo or fetal toxicity.
Tramadol hydrochloride: Carcinogenicity/Mutagenicity: A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30 mg/kg for approximately two years, although the study was not done with the Maximum Tolerated Dose). This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters.
Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
Fertility: No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.
Effect on Reproduction: Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25, or 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol in this study, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
Others: Tramadol shows tolerability in animal tests, thus continuous use and dose increasing must be used with caution.
Animal and laboratory studies in order to evaluate carcinogenicity, mutagenicity and fecundability disorders of this drug were not conducted.
Carcinogenicity: In the study of carcinogenicity in mice which received tramadol 30mg/kg (90mg/m², 0.5-fold of the maximum clinical dose per day 185mg/m²) for 2 years, there was little oncogenesis but statistically increased significantly. Risk of this oncogenesis is not considered in human and was not observed in the carcinogenesis study in rats administered with tramadol 30 mg/kg (180 mg/m², 1-fold of the maximum clinical dose per day).
Genotoxicity: Tramadol showed negative in reverse mutation test using microorganism, chromosome abnormality test using mammal culture cells, genomic mutation test using CHO cells, direct method among mice lymphoma tk+/- genomic mutation test, micronucleus test using mice and hamsters, and dominant lethal test using mice, but induced mild variation in metabolic activity method and rat micronucleus test among mouse lymphoma genomic mutation test. Given overall test results, tramadol does not have risk of genotoxicity in human body.
Fecundability: In the test that administered 50 mg/kg (350 mg/m², 1.6 times than the maximum daily clinical dosage of 185 mg/m²) of tramadol and 75 mg/kg (450 mg/m², 2.4 times than the maximum daily clinical dosage of 185 mg/m²) to female rats, no effects on fecundability was observed.

Moderate to severe acute and chronic pain.

Children aged 12 years or more and adults: Adjust the dose according to the level of pain patients feel and their treatment responses. 4 tablets are recommended as the initial dose, and the administration interval should be minimum 6 hours without exceeding 16 tablets a day. The lowest effective dose should be used for the shortest period of time.
It is recommended not to take this drug too long more than necessary, and if a long-term administration is required due to characteristics and severity of diseases, monitoring should be conducted at regular basis to confirm whether this drug is administered continuously or not.
The elderly: Administer usual dose for adults. Since oral administration of tramadol in the elderly aged 75 years or more increased elimination half-life by 17%, this drug should be administered at 6 hours interval or longer.
Patients with renal failure: Extend the administration interval to 12 hours for patients with moderate renal failure (10 - 30 mL/min of creatinine clearance).
Administration to patients with severe renal failure (less than 10 mL/min of creatinine clearance) is not recommended.
Tramadol is removed very slowly during hemodialysis and filtration, thus re-administration of this drug to maintain the antalgic effect after hemodialysis is not required.
Patients with hepatic failure: Carefully consider extending the administration interval for patients with moderate hepatic failure.
Do not administer this drug to patients with severe hepatic failure.

This drug is a combination product. In case of drug overdose, tramadol toxicity, paracetamol toxicity or symptoms and signs of toxicity of both drugs may appear.
In case of overdose of tramadol, respiratory suppression, lethargy, coma, convulsion, cardioplegia, and serious symptoms of death may appear. The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. In addition, cases of QT prolongation have been reported during overdose. Accidental ingestion of tramadol can result in respiratory depression and seizures due to an overdose of tramadol. Respiratory depression and seizures have been reported in children following ingestion of a single tablet. Fatalities due to tramadol overdose have also been reported.
In case of overdose of paracetamol, hepatic centrilobular necrosis resulting in liver failure and death may occur and renal tubular necrosis, hypoglycemia and coagulation disorder may occur. The initial symptoms seen within the first 24 hours following a paracetamol overdose may include: gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor and diaphoresis. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.
A single or multiple overdose with this drug may be a potentially lethal polydrug overdose. In case of overdose, contact institutions or hospitals where emergency care is available, and maintain a proper airway with general treatment. Symptoms resulted from overdose of tramadol due to administration of naloxone may be partially recovered, but risk of seizure will increase. As 7% of dosage was eliminated by 4-hour hemodialysis from experience of using tramadol, it is not beneficial for therapy for overdose. In case of overdose of paracetamol, administer N-acetylcysteine within 10 - 12 hours to protect the liver. In adult and pediatric patients, any individual presenting with an unknown amount of paracetamol ingested or with a questionable or unreliable history about the time of ingestion should have a plasma paracetamol level drawn and be treated with acetylcysteine. If an assay cannot be obtained and the estimated paracetamol ingestion exceeds 7.5 to 10 grams for adults and adolescents or 150 mg/kg for children, dosing with N-acetylcysteine should be initiated and continued for a full course of therapy.

Do not administer drug to the following patients: Patients who are hypersensitive to the properties of this drug.
Patients who are addicted to drugs acting on central nervous system, such as alcohol, hypnotics, centrally-acting analgesics, opiates or antipsychotics.
Patients with severe respiratory depression (mild respiratory depression may occur.)
Patients with risk of obnubilation, in case of head injuries and brain lesions.
Patients who receive MAO inhibitors or patients who experience administration within 14 days recently.
Patients with peptic ulcer and severe hematologic abnormality.
Patients with severe hepatic impairment, severe renal impairment and severe heart failure.
Breast-feeding women.
Children younger than 12 years of age.
Post-operative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
Patients with aspirin-induced asthma (asthmatic crisis induced by nonsteroidal anti-inflammatory drugs) or with its history.
Patients with acute, severe bronchial asthma in a non-monitored setting and without the availability of resuscitative equipment.
Epilepsy patients who are not controlled with drugs.

In case a person who drinks daily three glasses of alcohol or more at regular basis has to take this drug or other antipyretic analgesic, he/she should discuss with doctors or pharmacists. If these patients take this drug, liver damage can be caused.
In patients administered with paracetamol, serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) very rarely have been reported and these serious skin reactions can be fatal. Therefore, these signs of serious cutaneous reactions should be informed sufficiently to the patients, and if any signs of skin rash or other hypersensitivity reactions following administration of this drug occur, administration should be discontinued immediately.
Seizures have been reported in patients receiving tramadol within the recommended dosage range and it has shown that the seizure risk is increased with doses of tramadol above the recommended range.
Concomitant use of tramadol increases the seizure risk in patients taking with the drugs including the following: Selective serotonin reuptake inhibitor (SSRI antidepressants or anorectics); Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.); Other opioids.
Concomitant use of tramadol may increase the seizure risk in patients taking with the following drugs: MAO (Monoamine Oxidase) inhibitor; Neuroleptics; Other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol or drug withdrawal, CNS infections).
Rarely fatal anaphylactoid reactions have been reported in patients administered with tramadol.
Patients with acute, severe bronchial asthma are at increased risk of life-threatening respiratory depression when treated with opioids. This drug should only be used in this patient population in a monitored setting and with the availability of resuscitative equipment. When administering this drug in patients who may be at risk for respiratory depression, caution should be taken, and the use other non-opioid analgesics should be considered.
Concomitant use of tramadol with central nervous system (CNS) depressants including alcohol or benzodiazepines, may result in profound sedation, respiratory depression, coma, and death. Due to these risks, reserve concomitant prescribing for use of this drug and CNS depressants in patients for whom there is no alternative treatment options. If concomitant use of this drug and CNS depressants is determined, limit dosages and durations to the minimum required, and closely follow patients for signs and symptoms of respiratory depression and sedation.
If this drug is administered to patients with increased intracranial pressure or head injury, these symptoms may be exaggerated in these patients by the respiratory depressant effects of opioids and include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure.
Tramadol may lead to physical and psychological dependence in μ-opioid type.
Hepatotoxicity: This drug contains paracetamol and tramadol. Occasionally, paracetamol is associated with liver transplantation and acute hepatic failure resulting in death, and most of liver damage is involved with use of over 4,000 mg per day in combination with other paracetamol products, thus it should be used with caution. Especially, patients with hepatic impairment should consult physician before administration.
Patients who are CYP2D6 ultra-rapid metabolizers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients. This rapid conversion may result in higher than expected serum M1 levels which could lead to an increased risk of respiratory depression. Alternative medication, dose reduction and/or increased monitoring for signs of tramadol overdose, such as respiratory depression is recommended in patients known to be CYP2D6 ultra-rapid metabolizers. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (see Symptoms and signs: Tramadol under Overdosage).
Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases occurred following tonsillectomy and/or adenoidectomy, and the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. This drug is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Paracetamol + Tramadol (Dolcet mini) in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.
This drug can cause sleep-related breathing disorders such as sleep apnea syndromes (including central sleep apnea [CSA]) and hypoxia (including sleep-related hypoxia). Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an ongoing basis for the onset of a new sleep apnea, or a worsening of an existing sleep apnea. In these patients, consider reducing or stopping the opioid treatment if appropriate, using best practices for tapering of this drug.
Hyponatremia has been reported very rarely with the use of this drug, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia. In some reports, this hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of this drug and appropriate treatment (e.g. fluid restriction). During this drug treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors.

Administer drug with care to the following patients: Patients who receive morphine concomitantly or continuously (as mild morphine antagonism was recognized in the animal study, withdrawal symptoms may occur.)
Patients who receive CNS inhibitors, such as opiates, anesthetics, somnifacients, phenothiazine, tranquilizers and sedatives.
Patients with biliary tract diseases (high dosage resulted in contracting oddi sphincter was in the animal study.)
Patients with hepatic disorders (sometimes active serum GOT and GPT counts showed to increase in the animal study.)
Patients with renal impairment.
Alcohol-consuming patients.
Patients with hypersensitivity to opium.
Epilepsy patients or any patients who can have convulsion.
Patients who have altered consciousness caused by shock state and unknown cause.
General Cautions: Do not exceed a recommended dose to administer, and do not use other tramadol or paracetamol concomitantly.
This drug contains tramadol as an active ingredient, a portion of the analgesic effect of this drug is attributable to the binding of the active ingredient, tramadol, to the mu-opioid receptor. Upon repeated administration of opioids, tolerance, physical dependence, and psychological dependence may develop, even at recommended dosages. Assess each patient's risk for opioid dependence and abuse prior to prescribing this drug and monitor all patients receiving this drug for development of these behaviors. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). This should not be used in opioid-dependent patients. Tramadol has been shown to reinitiate physical dependence in some patients that have been previously dependent on other opioids. Patients who have potential drug abuse should be observed carefully and be administered for short-term. Tramadol is not appropriate for alternative drug for opioid-dependent patients, and opioid-acting drugs or withdrawal symptoms of morphine cannot be inhibited. In case of combined use with opioid agonist-antagonist (nalbuphine, buprenorphine and pentazocine), as there are risks of reduced analgesic effect and incidence of withdrawal symptom due to competitive block, a combined use is not recommended.
In case administration of this drug is discontinued unexpectedly, withdrawal symptoms (e.g. anxiety, diaphoresis, insomnia, spasticity, ache, nausea, agitans, diarrhea, upper respiratory syndrome, piloerection, excitement, nervousness, hyperkinesis, and gastrointestinal symptoms) may occur. Panic attack, severe anxiety, hallucination, sensory anomaly, tinnitus, and abnormal CNS reactions were also reported very rarely. From the clinical experience, withdrawal symptoms can be alleviated when reducing dose to discontinue.
In patients who were administered with tramadol, allergic reactions (e.g., urticaria, rash, bronchospasm, toxic skin necrosis and Stevens-Johnson syndrome, etc.) including serious and rarely fatal anaphylactic reaction are reported. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive this drug. Advise patients to seek immediate medical attention if they experience any symptoms of hypersensitivity reaction.
In case of administering tramadol to patients who have possibility of seizure or who received other drugs that decrease seizure threshold, particularly selective serotonin reabsorption inhibitors, tricyclic antidepressants, anti-psychotics, centrally-acting analgesics or local anesthetics, convulsion has been reported. Epilepsy patients who are controlled with medications or patients who have possibility of epilepsy must use this drug only when necessary.
Excessive administration of paracetamol to chronic alcoholics may increase hepatotoxicity. It is not recommended to administer this drug to patients with hepatic impairment.
Pharmacokinetic and tolerability of this drug was not tested in patients with hepatic failure. Tramadol and paracetamol are mainly metabolized in the liver. It is not recommended to use this drug to patients with severe hepatic failure.
Complex of tramadol and paracetamol was not studied in patients with renal failure. From the experience of using tramadol, excretion of tramadol and active metabolome M1 and excretory rate may decrease in patients with renal function failure. For patients with less than 30 mL/min of creatinine clearance, do not exceed 4 tablets for every 12 hours of administration interval.
In case tramadol is administered for long-term, the possibility of dependency cannot be excluded completely, so it is recommended to adjust a dosing period or to have withdrawal period temporarily.
When enflurane is used with tramadol during usual anesthesia as nitric oxide in one study, the case of weakening anesthesia during operation was reported to increase. Until additional information is available, use of tramadol should be avoided during low level of anesthesia.
Use caution when administering this drug in patients taking SSRIs. Concomitant use of tramadol with SSRI's increases the risk of adverse events, including seizures and serotonin syndrome.
Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to an active metabolite. Based upon post-marketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Risk of life-threatening respiratory depression and death is as follows: This drug is contraindicated for children younger than 12 years of age.
This drug is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
Avoid the use of this drug in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose.
Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking this drug could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression.
Impact on driving and machine control: Tramadol may cause sleepiness or vertigo, and this may be enhanced by alcohol or other CNS inhibitors. As it affects agility, caution should be used for any actions of potential risk, such as driving or machinery operating.
Use in Children: Life-threatening respiratory depression and death have occurred in children who received tramadol. In some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. The risk of life-threatening respiratory depression and death is as follows: This drug is contraindicated for all children younger than age 12 years of age.
This drug is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
Avoid the use of this drug in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
Use in the Elderly: Since decreased hepatic, renal, and cardiac functions and accompanying diseases concomitantly and various drug therapies may occur frequently, this drug should be administered with caution to elderly patients.

Tramadol has been shown to cross the placenta. No appropriate clinical study in pregnant women was conducted, and the safety for fetus is not established. It will be administered only when therapeutic benefits exceed risks in pregnant women or women capable of becoming pregnant.
The use of opioids during childbirth might result in respiratory depression in the newborn infant.
Prolonged use of this drug, or other opioids, during pregnancy may lead to neonatal opioid withdrawal syndrome. This risk is particularly increased during the last trimester (28~40 weeks) of pregnancy.
Do not administer this drug to breast-feeding women. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.
Tramadol and its metabolite (M1) are present in human milk. There is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The M1 is more potent than tramadol in mu opioid receptor binding. Published studies have reported tramadol and M1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. Women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of M1 in breast milk that can be dangerous in their breastfed infants. In women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. Patients should be informed about serious adverse reactions including excess sedation and respiratory depression in a breastfed infant during treatment with this drug.
If infants are exposed to this drug through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Clinical Trial Data: Adverse Reactions Reported by ≥ 1% of Tramadol hydrochloride + Paracetamol (Dolcet mini)-treated Patients in Placebo controlled Clinical Trials of Tramadol hydrochloride + Paracetamol (Dolcet mini). (See Table 2.)

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Adverse Reactions Reported by <1% of Ultracet-treated Patients in Placebo controlled Clinical Trials of Tramadol hydrochloride + Paracetamol (Dolcet mini). (See Table 3.)

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Adverse Reactions Identified in Clinical Trials and/or Postmarketing Experience with Tramadol. (See Table 4.)

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Post-marketing adverse events of Paracetamol Allergic reactions (mainly skin rash) or secondary hypersensitivity reaction to paracetamol were rarely reported, but generally they were recovered after administration was discontinued, and symptomatic treatment was conducted, if necessary. Hematologic disorders including thrombocytopenia and agranulocytosis have been reported, but they are not always related to paracetamol. There were several reports suggesting that a combined use of paracetamol and warfarin similar analogue may result in hypoprothrombinemia. No prothrombin time was altered in other studies.
Post-marketing adverse events: Adverse reactions identified during postmarketing experience: Hyponatremia/syndrome of inappropriate antidiuretic hormone, Fixed eruption.
As a result of post-marketing surveillance in 37,967 patients for 6 years to re-review locally, regardless of the causal relationship with drugs, the case incidence rate was reported as 4.57% (1,737 subjects/37,967 subjects, 2,501 cases). The most common adverse reactions were digestive system disorders such as nausea, constipation and vomiting, etc. with 1,391 cases (3.66%) and it was found that there were 563 cases of adverse event reports regarding nervous system disorders such as dizziness and headache (1.48%), 149 cases of generalized disorders (0.39%), 149 cases of psychiatric disorders (0.39%), 105 cases of skin and appendages disorders (0.28%), 31 cases of blood system disorders (0.08%), 28 cases of kidney and urinary system disorders (0.07%), 28 cases of circulatory system disorders (0.07%), 21 cases of respiratory system disorders (0.06%), 1 case of cardiovascular system disorders and 43 cases of other disorders (0.11%).
The incidence of adverse drug reactions for which causal relationship with this drug could not be ruled out was 4.14% (1,573 subjects/37,967 subjects, 2,244 cases). Major adverse events were nausea 1.49% (567 subjects/37,967 subjects), dizziness 0.95% (358 subjects/37,967 subjects), and others are less than 1% among reported adverse events. The classification of them based on their sites is as follows: Systemic disorders: Asthenia, Fatigue, Pyrexia, Edema, Chest pain, Spasticity, Syncope.
Cardiovascular system: Congestive heart failure.
Nervous system: Dizziness, Headache, Vertigo, Stupor, Migraine, Tremor, Sensory anomaly, Hypertonia, Exacerbated migraine, Contraction involuntary muscle, and Convulsion.
Respiratory system: Dyspnea, Asthma, Exertional dyspnea, Cough, and Bronchitis.
Kidney and urinary system: Dysuria, Urinary retention, Pollakiuria, Abnormal value of renal function and Oliguria.
Skin and appendages: Pruritus, Rash, Diaphoresis, Urticaria.
Digestive system: Nausea, Vomiting, Dyspepsia, Stomachache, Constipation, Dry mouth, Diarrhea, Dysphagia, Flatus, Tongue edema, Increased saliva, Progression of rectal cancer, Progression of esophageal cancer, Progression of gastric cancer, Paralytic ileus, Hiccup and Cholecystitis.
Psychiatric system: Drowsiness, Insomnia, Anorexia, Anxiety, Depression, Nervousness, Mood instability, Hallucination, and Depersonalization.
Blood system: Anemia, Oligochromemia, Erythrocytopenia, Leukocytopenia, Leukocytosis and Thrombocytopenia.
Circulatory system: Palpitation, Hypertension, Arrhythmia, Tachycardia, Aggravated hypertension, Aortostenosis.
Other: Melena, Increased cholesterol, Weight loss, Tinnitus, Chills, Buttock pain, Femoral pain, Allergic rhinitis, Epistaxis, Abnormal visual field, Progression of biliary tract cancer, Foreign body sensation in the eyes, Progression of liver cancer, and Hepatic dysfunction.
Serious adverse drug reactions were reported 1 case of hepatic dysfunction, cholecystitis, paralytic ileus and stupor, respectively, and unexpected adverse drug reactions were reported 1 case of cholecystitis, hiccup, paralytic ileus, abnormal renal function count (increased BUN/CR), increased saliva and melena, respectively.
The incidence rate of adverse drug reactions occurred in the study in patients with renal disorders, who are special patients, was 6.25% (11 pts/176 pts, 165 cases), a major adverse drug reaction was 4 cases of nausea and vertigo, respectively (2.27%). There were no serious adverse drug reactions and unexpected adverse events. The incidence rate of adverse drug reactions occurred in the study in patients with hepatic disorders, who are special patients, was 6.63 % (22 pts/332 pts, 36 cases), and major adverse drug reactions were 12 cases of nausea (3.61%), 6 cases of vertigo (1.81%). Serious adverse drug reactions were 1 case of paralytic ileus, cholecystitis and hepatic dysfunction, respectively (0.30%), and unexpected adverse reactions were 1 case of paralytic ileus and cholecystitis, respectively.
Serious adverse reactions which were reported voluntarily during local post-marketing surveillance were total 23 cases; 3 cases of nausea, 2 cases of dizziness and dyspnea and 1 case of stupor, migraine, language disorders, unconsciousness, recurrence of myocardial infarction, hypotension, vomiting, dyspepsia, confusion, multiple organ failure, anaphylaxis, and intentional overdose, respectively. This was reported from the uncertain size of population, and it is difficult to estimate the frequency and the causal relation of this drug.
And as a result of post-marketing clinical tests conducted on total of 5,566 people separately from post-marketing surveillance during the post-marketing survey period in Korea, total 3 cases of unexpected adverse drug reactions including 2 cases of eructation (0.04%), 1 case of chest discomfort (0.02%) were reported.
The incident of adverse events in patient group with the history of administering therapeutic drugs (anodyne) before administering this drug was shown statistically higher than those without administration history (5.92% vs 3.75%, p<0.001). In addition, in subjects whose mean dosage per day is 4 tabs or more, the incidence rate of adverse reactions was shown statistically and significantly higher than the patient group who received 2 or more and less than 4 tabs (4.36%, (1,325/30,419 pts), p<0.001).

MAO inhibitors (e.g. phenelzine, tranylcypromine, linezolid): Mechanism: Additive or synergistic pharmacodynamic effect.
Clinical Impact: The concomitant use of this drug with MAO inhibitors, or use within 14 days of their discontinuation, is contraindicated due to the increased risk of seizures and serotonin syndrome. (See Contraindications.) MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity.
Intervention: Do not use this drug in patents taking MAOIs or within 14 days of stopping such treatment.
Serotonergic Drugs (e.g. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system including mirtazapine and trazadone, and some muscle relaxants such as cyclobenzaprine, metaxalone): Mechanism: Additive or synergistic pharmacodynamic effect.
Clinical Impact: Concomitant use of tramadol with serotonergic drugs increases the risk of adverse events, including seizures and serotonin syndrome.
Intervention: Use caution when administering this drug in patients taking serotonergic drugs and monitor for signs of adverse events. Discontinue this drug if serotonin syndrome is suspected.
CYP3A4 Inducers (e.g. Rifampin, carbamazepine, phenytoin): Mechanism: Enzyme induction resulting in increased rate of metabolism of tramadol.
Clinical Impact: The concomitant use of this drug and an inducer of CYP3A4 can decrease the plasma concentration of tramadol, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.
After stopping an inducer of CYP3A4, as the effects of the inducer decline, the tramadol plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention: If concomitant use is necessary, consider increasing the drug dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If an inducer of CYP3A4 is discontinued, consider this drug dosage reduction and monitor for seizures and serotonin syndrome, and the signs of sedation and respiratory depression. In case of combined use with carbamazepine, tramadol's analgesic effect and acting time may be decreased significantly by decreased plasma concentration of tramadol. As carbamazepine increased tramadol's metabolism and may increase risk of seizures of tramadol, combined use is prohibited.
Inhibitors of CYP2D6 (e.g. Quinidine, fluoxetine, paroxetine, amitriptyline, and bupropion): Mechanism: CYP2D6 inhibition resulting in decreased rate of metabolism of tramadol.
Clinical Impact: The concomitant use of Tramadol/Paracetamol (Dolcet Mini) and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of Tramadol/Paracetamol (Dolcet Mini) is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.
After stopping an inhibitor of CYP2D6, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression.
Intervention: If concomitant use of an inhibitor of CYP2D6 is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If an inhibitor of CYP2D6 is discontinued, consider lowering this drug dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Inhibitors of CYP3A4 (e.g. Macrolide antibiotics including erythromycin, azole-antifungal agents including ketoconazole, protease inhibitors including ritonavir): Mechanism: CYP3A4 inhibition resulting in decreased rate of metabolism of tramadol.
Clinical impact: The concomitant use of this drug and an inhibitor of CYP3A4 can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. After stopping an inhibitor of CYP3A4, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease, resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of this drug until stable drug effects are achieved. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of this drug is achieved. If an inhibitor of CYP3A4 is discontinued, consider increasing the drug dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Benzodiazepines and Other Central Nervous system (CNS) Depressants including alcohol (e.g. Benzodiazepines and other sedatives/hypnotics, tranquilizers, muscle relaxants, general anesthetics, other opioids, alcohol): Mechanism: Additive or synergistic pharmacodynamic effect.
Clinical Impact: The concomitant use of tramadol with central nervous system depressants, such as benzodiazepines, alcohol, may produce additive CNS depressant effects, such as profound sedation and respiratory depression. If concomitant use of this drug with a CNS depressant is clinically necessary, prescribe the lowest effective dosages and minimum duration for both drugs and follow patients closely for signs of respiratory depression. Due to additive pharmacodynamic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.
Warfarin: Clinical Impact: In case this drug is used in combination with warfarin-like drugs, increased coagulation time (INR) was reported, so prothrombin time shall be assessed regularly if appropriate medically. Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds.
Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.
Others: An absorption rate of paracetamol may be increased with metoclopramide or domperidone, and absorption can be reduced with cholecystyramine.
Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics.

Store at temperatures not exceeding 25°C.
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store tramadol/paracetamol (Dolcet Mini) securely, in a location not accessible by others.

Analgesics (Opioid)

N02AJ13 - tramadol and paracetamol ; Belongs to the class of opioids in combination with other non-opioid analgesics. Used to relieve pain.

Rx