Tramadin PLUS

Adjunct for surgical analgesia; induction of primary anesthesia for major surgical procedures requiring favorable myocardial or cerebral oxygen balance or when extended postoperative ventilation is anticipated; epidural analgesia with bupivacaine during labor and vaginal delivery.

Unless otherwise prescribed, Tramadin PLUS should be administered as follows:

Adults and Children >16 years: Maximum Single Dose: 1-2 tabs every 4-6 hrs as needed for pain relief up to a maximum of 8 tabs/day.

Children <16 years: The safety and effectiveness of Tramadin PLUS has not been established in the pediatric population.

Elderly: No overall differences with regard to safety or pharmacokinetics were noted between subjects ≥65 years of age and younger subjects.

Tramadin PLUS can be administered without regard to food.

Paracetamol (Tramadin PLUS) + Tramadol (Tramadin PLUS) HCl (Tramadin PLUS) should not be given to patients who have previously demonstrated hypersensitivity reactions to Tramadol (Tramadin PLUS), Paracetamol (Tramadin PLUS) and any other components of the drug.

Other contraindications include: Patients who are addicted to drugs affecting the CNS such as alcohol, hypnotics, centrally-acting analgesics and anti-psychotic drugs; Patients with epilepsy not controlled by treatment; Patients at risk of mental fog caused by head injury or brain lesion; Patients with severe respiratory depression, and those with a history of aspirin-sensitive asthma; Patients with hematological abnormality and patients with peptic ulcer disease. Paracetamol (Tramadin PLUS) + Tramadol (Tramadin PLUS) HCl should be avoided if renal impairment is severe.

CYP2D6 and CYP3A4 Inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors eg, quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors) and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of Tramadol (Tramadin PLUS) increasing the risk for serious adverse events, including seizures and serotonin syndrome.

Serotonergic Drugs: There have been post-marketing reports of serotonin syndrome with use of Tramadol (Tramadin PLUS) and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when Tramadin PLUS are co-administered with other drugs that may affect the serotonergic neurotransmitter systems eg, SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible nonselective MAOI), lithium or St. John’s Wort. If concomitant treatment of Tramadin PLUS with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Triptans: Based on the mechanism of action of Tramadol (Tramadin PLUS) and the potential for serotonin syndrome, caution is advised when Tramadin PLUS are co-administered with a triptan. If concomitant treatment of Tramadol (Tramadin PLUS) HCl and Paracetamol (Tramadin PLUS) tablets with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Use With Carbamazepine: Patients taking carbamazepine may have a significantly reduced analgesic effect of Tramadol (Tramadin PLUS). Because carbamazepine increases Tramadol (Tramadin PLUS) metabolism and because of the seizure risk associated with Tramadol (Tramadin PLUS), concomitant administration of Tramadin PLUS and carbamazepine is not recommended.

Use With Quinidine: Tramadol (Tramadin PLUS) is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and Tramadol (Tramadin PLUS) results in increased concentrations of Tramadol (Tramadin PLUS) and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that Tramadol (Tramadin PLUS) has no effect on quinidine metabolism.

Potential for Other Drugs to Affect Tramadol (Tramadin PLUS): In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 eg, fluoxetine, paroxetine and amitriptyline could result in some inhibition of the metabolism of Tramadol (Tramadin PLUS). Administration of CYP3A4 inhibitors eg, ketoconazole and erythromycin or inducers eg, rifampin and St. John’s Wort, with Tramadin PLUS, may affect the metabolism of Tramadol (Tramadin PLUS) leading to altered Tramadol (Tramadin PLUS) exposure.

Potential for Tramadol (Tramadin PLUS) to Affect Other Drugs: In vitro studies indicate that Tramadol (Tramadin PLUS) is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when Tramadol (Tramadin PLUS) is administered concomitantly at therapeutic doses. Tramadol (Tramadin PLUS) does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol (Tramadin PLUS) is a mild inducer of selected drug metabolism pathways measured in animals.

Use With Cimetidine: Concomitant administration of Tramadin PLUS and cimetidine has not been studied. Concomitant administration of Tramadol (Tramadin PLUS) and cimetidine does not result in clinically significant changes in Tramadol (Tramadin PLUS) pharmacokinetics. Therefore, no alteration of the Tramadin PLUS dosage regimen is recommended.

Use With Digoxin: Tramadol (Tramadin PLUS) has revealed rare reports of digoxin toxicity.

Use With Warfarin-Like Compounds: Both Tramadol (Tramadin PLUS) and Paracetamol (Tramadin PLUS) individual products have revealed rare alterations of warfarin effect, including elevation of prothrombin times.

While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when Tramadin PLUS and warfarin-like compounds are administered concurrently.

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What are the possible side effects of Tramadin PLUS?

Common adverse reactions reported in clinical trials are constipation, nausea, diarrhea, dry mouth, psychiatric disorders, somnolence, anorexia, insomnia, dizziness, increased sweating, pruritus, prostatic disorder.

Drug Abuse and Dependence: Abuse: Tramadol (Tramadin PLUS) has mu-opioid agonist activity. Tramadin PLUS, a Tramadol (Tramadin PLUS)-containing product, can be abused and may be subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include 1 or more of the following: Impaired control over drug use, compulsive use, use for non-medical purposes, continued use despite harm or risk of harm and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics, include emergency calls or visits near the end of office hrs, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of Tramadol (Tramadin PLUS) HCl and acetaminophen tablets can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.

Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of Tramadin PLUS.

Tramadin PLUS are intended for oral use only.

Dependence: Tolerance is the need for increasing doses of drugs to maintain a defined effect eg, analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: Restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea or increased blood pressure, respiratory rate or heart rate.

Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with Tramadin PLUS.

Each film-coated tablet contains 2 analgesics, Paracetamol (Tramadin PLUS) 325 mg and Tramadol (Tramadin PLUS) HCl 37.5 mg. It also contains the following excipients: Corn starch, povidone K30, sodium starch glycolate, microcrystalline cellulose PH 101, magnesium stearate, opadry II yellow, purified water.

Tramadol (Tramadin PLUS) HCl is a white, bitter, crystalline and odorless powder. Its chemical name is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxy phenyl) cyclohexanol HCl and has a molecular weight of 299.84.

Paracetamol (Tramadin PLUS) is an analgesic and antipyretic agent which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. Its chemical name is N-acetyl-p-aminophenol and has a molecular weight of 151.17.