Tramadol + Paracetamol

Tramadol + Paracetamol is an analgesic belonging to the pharmacological class of Opioid Analgesics and NSAIDs

Tramadol + Paracetamol is approved for the treatment of diabetic neuropathy; severe pain.

Tramadol is Readily absorbed with a Bioavailability of Approx 70-75%.

Paracetamol is Readily absorbed from the gastrointestinal tract, mainly in the small intestine. Time to peak plasma concentration: Approx 10-60 minutes. Tramadol is Widely distributed in the body. Crosses the placenta; enters breast milk (small amounts). Plasma protein binding: Approx 20%.

Paracetamol is Widely distributed to body tissues, except fat. Crosses the placenta and enters breast milk. The volume of distribution: Approx 1 L/kg. Plasma protein binding: 10-25%. Tramadol is Extensively metabolized in the liver via N- and O-demethylation by CYP3A4 and CYP2D6 isoenzymes and by glucuronidation and sulfation; O-desmethyl tramadol (M1) is the active metabolite formed by CYP2D6. Paracetamol is Metabolised primarily in the liver via glucuronidation and sulfation to glucuronide and sulfate conjugates. Tramadol is excreted Via urine (approx 30% as unchanged drug, 60% as metabolites) with an Elimination half-life of Approx 6 hours (tramadol); approx 7.4 ± 1.4 hours (active metabolite). Paracetamol is excreted Via urine (<5% as unchanged drug; 60-80% as glucuronide metabolites; 20-30% as sulfate metabolites; approx 8% as cysteine and mercapturic acid metabolite) with Elimination half-life: Approx 2-3 hours.

The common side effects associated with Tramadol + Paracetamol include constipation, diarrhea, nausea, anorexia, and xerostomia (i.e., dry mouth,).etc.

Tramadol + Paracetamol is available in the form of oral solids

The molecule is available in India, USA, Canada, Australia, and Japan.

Tramadol + Paracetamol, belonging to the pharmacological class (specify) acts as an opioid analgesic and a non-opioid agent.

Tramadol is an opioid agonist and serotonin-norepinephrine reuptake inhibitor. The analgesic effect of tramadol is believed to be due to both binding to mu-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. The opioid activity of tramadol is due to both the low-affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit the reuptake of norepinephrine and serotonin in vitro. These mechanisms may contribute independently to the overall analgesic profile of tramadol. Paracetamol is a non-opioid, non-salicylate analgesic. Paracetamol acts within the CNS to increase the pain threshold by inhibiting central cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Paracetamol inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Paracetamol does not inhibit PG synthesis in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects.

The onset of action of Paracetamol: was <1 hour and Tramadol was Within 1 hour.

The duration of action of Paracetamol is 4-6 hours (analgesia).

Tmax was Approx 2 hours (tramadol); approx 3 hours (active metabolite).

Tramadol + Paracetamol is available in tablets

May administer with or without food.

Tramadol + Paracetamol can be used in the treatment of diabetic neuropathy; severe pain.

Tramadol; Paracetamol is an oral combination of an opioid analgesic and a non-opioid, non-salicylate analgesic indicated for the treatment of acute pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The safety and efficacy of tramadol; Paracetamol in pediatric patients have not been established. Tramadol; Paracetamol is contraindicated in children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy. Do not use tramadol; Paracetamol in patients who are CYP2D6 ultrarapid metabolizers. These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people, which results in higher-than-expected serum M1 concentrations.

Tramadol + Paracetamol is approved for use in the following clinical indications

• Diabetic neuropathy
• Severe pain

For the treatment of acute, severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequate

Oral dosage (tablets containing tramadol 37.5 mg and Paracetamol 325 mg)

Adults:

75 mg tramadol/650 mg Paracetamol (2 tablets) PO every 4 to 6 hours as needed. Max: 300 mg tramadol/2,600 mg Paracetamol (8 tablets)/day. Treatment is generally limited to 5 days or less.

For the treatment of diabetic neuropathy

Oral dosage (tablets containing tramadol 37.5 mg and Paracetamol 325 mg)

Adults:

1 tablet orally at bedtime as needed on days 1 to 3, followed by 1 tablet PO twice daily as needed on days 4 to 6, followed by 1 tablet orally 3 times daily as needed on days 7 to 9, then by 1 tablet PO 4 times daily as needed on day 10, and thereafter, 1 to 2 tablets PO 4 times daily as needed. Max: 8 tablets/day. Guidelines consider tramadol; Paracetamol is probably effective in lessening the pain of diabetic neuropathy.

Maximum Dosage Limits:

•Adults

300 mg/day PO tramadol and 2,600 mg/day PO Paracetamol.

•Geriatric

300 mg/day PO tramadol and 2,600 mg/day PO Paracetamol.

•Adolescents

Safety and efficacy have not been established.

•Children

12 years: Safety and efficacy have not been established.

1 to 11 years: Use is contraindicated.

•Infants

Use is contraindicated.

• (Paracetamol + Tramadol can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

37.5mg+325mg

Tablets

Tramadol + Paracetamol may be contraindicated in the following conditions:

• Paracetamol Hypersensitivity

• Adenoidectomy
• Children
• GI Obstruction
• Ileus
• Infants
• MAOI Therapy
• Neonates
• Opiate Agonist Hypersensitivity
• Respiratory Depression
• Tonsillectomy

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• Addiction, Abuse and Misuse

Paracetamol + Tramadol contains tramadol, a Schedule IV controlled substance. As an opioid, Paracetamol + Tramadol exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Paracetamol + Tramadol . Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Paracetamol + Tramadol , and monitor all patients receiving Paracetamol + Tramadol for the development of these behaviors and conditions. 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). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Paracetamol + Tramadol , but use in such patients necessitates intensive counseling about the risks and proper use of Paracetamol + Tramadol along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Paracetamol + Tramadol . Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

• Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Paracetamol + Tramadol , the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Paracetamol + Tramadol . To reduce the risk of respiratory depression, proper dosing and titration of Paracetamol + Tramadol are essential [see Dosage and Administration (2)]. Overestimating the Paracetamol + Tramadol dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Paracetamol + Tramadol , especially by children, can result in respiratory depression and death due to an overdose of tramadol.

• 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. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing 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 for post tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Paracetamol + Tramadol is contraindicated for all children younger than 12 years of age

• Paracetamol + Tramadol is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy

• Avoid the use of Paracetamol + Tramadol 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.

• Nursing Mothers

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was 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 Paracetamol + Tramadol could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with Paracetamol + Tramadol

• CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use Paracetamol + Tramadol .

• Neonatal Opioid Withdrawal Syndrome

Prolonged use of Paracetamol + Tramadol during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks of Interactions with Drugs Affecting Cytochrome P450

Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from Paracetamol + Tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Paracetamol + Tramadol requires careful consideration of the effects on the parent drug, tramadol, which is a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in µ-opioid receptor binding.

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of Paracetamol + Tramadol with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression. Follow patients receiving Paracetamol + Tramadol and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when Paracetamol + Tramadol is used in conjunction with inhibitors of CYP2D6.

Cytochrome P450 3A4

Interaction The concomitant use of Paracetamol + Tramadol with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious.

Increased sedative effect with alcohol.

There is no sufficient scientific evidence traceable regarding use and safety of Tramadol + Paracetamol in breast feeding.

May increase risk of serotonin syndrome with St. John’s wort.

The adverse reactions related to Tramadol + Paracetamol can be categorized as

• Common

Constipation , Diarrhea , Nausea , Anorexia, and Xerostomia (I.E., Dry Mouth,).

• Less Common

Anxiety, Headache, Tremor, Confusion, Nervousness

• Rare

Paresthesia, Stupor, Migraine, Amnesia, Depersonalization, Depression, Emotional Lability, Nightmares, Hallucinations, Syncope, Paranoia, Seizures, and Abnormal Thinking

The clinically relevant drug interactions of Tramadol + Paracetamol is briefly summarized here

Tramadol:

• May increase the risk of convulsions with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), TCAs and other seizure threshold lowering-drugs (e.g. bupropion, mirtazapine).
• Decreased serum concentrations with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin).
• CYP2D6 inhibitors (e.g. quinidine, fluoxetine) may increase plasma levels of tramadol and decrease plasma concentrations of M1 (active metabolite).
• CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir) may elevate tramadol plasma levels and result in increased amount of metabolism by CYP2D6 isoenzyme and higher M1 levels.
• Mixed opioid agonist/antagonists (e.g. nalbuphine, pentazocine) may reduce the analgesic effect or precipitate withdrawal symptoms of tramadol.
• May result in serotonin syndrome with serotonergic agents (e.g. triptans, SSRIs, SNRIs, TCAs). May lead to increased INR when used with warfarin.

Paracetamol:

• Increased risk of hepatotoxicity when given with other potentially hepatotoxic agents.
• Decreased absorption with colestyramine.
• May decrease the serum concentrations with rifampicin and some anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine, primidone).
• Enhances the anticoagulant effect of warfarin.
• Increased absorption with metoclopramide.
• May increase the serum concentration with probenecid.
• Potentially Fatal: Tramadol: Increased risk of serotonin syndrome when used concurrently or within 2 weeks of MAOIs. May lead to profound sedation, respiratory depression and coma with benzodiazepines and other CNS depressants.

The common side of Tramadol + Paracetamol include the following

Constipation, Diarrhea , Nausea , Anorexia, and Xerostomia (I.E., Dry Mouth,).

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.. In animal reproduction studies, the combination of tramadol and Paracetamol decreased fetal weights and increased supernumerary ribs at 1.6 times the maximum recommended human daily dosage (MRHD). In separate animal reproduction studies, tramadol administration alone during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD).

Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with Paracetamol . Treatment of pregnant rats with doses of Paracetamol approximately 1.3 times the maximum human daily dose (MRHD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately 1.9 times the MHDD.

Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with Paracetamol . Treatment of pregnant rats with doses of Paracetamol approximately 1.3 times the maximum human daily dose (MRHD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately 1.9 times the MHDD. In mice treated with Paracetamol at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation. Based on animal data, advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)]. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during postmarketing. Labor or Delivery Paracetamol + Tramadol is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. Paracetamol + Tramadol is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Paracetamol + Tramadol , can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of Paracetamol + Tramadol , if any, on the later growth, development, and functional maturation of the child is unknown.

Data Animal Data No drug-related teratogenic effects were observed in the progeny of rats treated orally with 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 (1.6 times the maximum daily human tramadol/Paracetamol dosage), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m2 basis are 1.9, 0.8, and 4.9 times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit, respectively. No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 2.3, 2.6, and 19 times the MRHD, respectively. Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human tramadol dosage). Studies in pregnant rats that received oral Paracetamol during organogenesis at doses up to 1.3 times the maximum human daily dose (MHDD = 2.6 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a doserelated increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral Paracetamol throughout gestation at doses of 1.9-times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral Paracetamol at doses 0.5-times the MHDD, based on a body surface area comparison. In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% Paracetamol via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.7, 1.3, and 2.7 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups.

Lactation Risk Summary

Paracetamol + Tramadol is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Tramadol and its metabolite, O-desmethyl tramadol (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 metabolite 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. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Paracetamol + Tramadol. Clinical Considerations If infants are exposed to Paracetamol + Tramadol 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. Data 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. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. 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.

Because of the risk of life-threatening respiratory depression and death:

• Paracetamol + Tramadol is contraindicated for all children younger than age 12 years of age.

• Paracetamol + Tramadol is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy

• Avoid the use of Paracetamol + Tramadol 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.

Geriatric Use

Elderly patients (65 years of age or older) may have increased sensitivity to tramadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Paracetamol + Tramadol slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory. Tramadol and Paracetamol are known to be substantially excreted by the kidney, and the risk of adverse reactions to these drugs may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Impairment

The pharmacokinetics and tolerability of Paracetamol + Tramadol in patients with impaired hepatic function have not been studied. Based on information using tramadol immediate-release tablets in subjects with advanced cirrhosis of the liver, tramadol exposure was higher and half-lives of tramadol and active metabolite M1 were longer than in subjects with normal hepatic function)].

As tramadol and Paracetamol are both extensively metabolized by the liver, the use of Paracetamol + Tramadol in patients with hepatic impairment is not recommended

Renal Impairment

The pharmacokinetics and tolerability of Paracetamol + Tramadol in patients with renal impairment has not been studied. Based on studies using tramadol extended-release tablets, the excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min. In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosage of Paracetamol + Tramadol not exceed 2 tablets every 12 hours.

The total amount of tramadol and M1 removed during a 4 hour dialysis period is less than 7% of the administered dose based on studies using tramadol alone. Monitor closely for signs of respiratory depression, sedation, and hypotension. 8.8 Sex Tramadol clearance was 20% higher in female subjects compared to males in four Phase 1 studies of Paracetamol + Tramadol in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.

Symptoms:

Tramadol: Miosis, CV collapse, consciousness disorders including convulsions, coma, respiratory depression leading to respiratory arrest. Paracetamol: Pallor, nausea, vomiting, abdominal pain, anorexia, abnormalities of glucose metabolism, metabolic acidosis; liver damage may be apparent after 12-48 hours of ingestion which may progress to encephalopathy in severe cases, acute renal failure with acute tubular necrosis, cardiac arrhythmia, and pancreatitis.

Management:

Supportive treatment. Perform gastric lavage to empty the stomach. Giving oral methionine or IV N-acetylcysteine may be beneficial for up to at least 48 hours after ingestion (most effective if given within 8 hours). May administer naloxone to reverse respiratory depression and diazepam for seizures. Maintain respiratory and circulatory functions.

Pharmacodynamic:

Tramadol is a centrally acting opioid analgesic that binds to μ-opiate receptors in the CNS, leading to inhibited ascending pain pathways and altered pain perception and response. It also inhibits the reuptake of norepinephrine and enhances the release of serotonin.

Paracetamol is a para-aminophenol derivative with analgesic, antipyretic and weak anti-inflammatory activity. The exact mechanism of its analgesic action is still unknown, but it is believed to be by activating the descending serotonergic inhibitory pathways in the CNS.

Pharmacokinetics:

• Paracetamol :

Absorption: Peak plasma concentrations of Paracetamol from the combination product occur in 1 hour. Absorption occurs primarily from the small intestine.

Distribution: Protein binding is minimal.

Metabolism: Paracetamol is metabolized in the liver via glucuronidation and sulfate conjugation and is excreted in the urine as glutathione and sulfate conjugates. However about 10% to 15% of the Paracetamol dose undergoes oxidative metabolism via CYP2E1 and CYP1A2 and then glucuronidation to cysteine and mercapturic acid conjugates. In cases of glucuronide depletion, such as Paracetamol overdose, a hepatotoxic metabolite is formed. The mean half-life of Paracetamol as part of the combination product is 2.5 hours. The pharmacokinetics of Paracetamol are not altered when combined with tramadol.

• Tramadol:

Absorption: Absolute bioavailability of tramadol from the combination product has not been determined, but bioavailability of tramadol as a single product is roughly 75%. Minimal protein binding occurs (roughly 20%).

Distribution: Tramadol crosses the placenta and about 0.1% is distributed into breast milk. Tramadol undergoes significant first-pass metabolism. The major metabolic pathways appear to be N- and O- demethylation, glucuronidation, and sulfation.

Metabolsim: Extensive hepatic metabolism occurs via isoenzymes CYP2D6 and CYP3A4. The formation of the active metabolite M1 (O-desmethyltramadol) is dependent upon the CYP2D6 enzyme and therefore inhibition of this enzyme can affect therapeutic response.

Elimination: The elimination mean half-life of the racemic tramadol and M1 metabolite is 5 and 7 hours, respectively. Multiple dosing lengthens the half-life of racemic tramadol to 7 to 9 hours. About 90% of a dose is excreted in the urine (30% as unchanged drug and 60% as metabolites) and 10% is excreted in the feces.

• Therapeutic Benefits of Tramadol+ Paracetamol

Tramadol/paracetamol is a rapidly-acting, longer-duration, multimodal analgesic, which is effective and generally well tolerated in patients with moderate to severe pain. It was also effective as an add-on analgesic in patients who were experiencing moderate to severe musculoskeletal pain (e.g. osteoarthritis or rheumatoid arthritis pain) despite ongoing NSAID and/or disease-modifying antirheumatic drug therapy. Two tramadol/paracetamol tablets provided greater relief of dental pain over an 8-hour period than either agent alone, with a faster onset of action than tramadol alone and a longer duration of action than either agent as monotherapy.

1. https://www.clinicalkey.com/#!/content/drug_monograph/6-s2.0-2679?scrollTo=#Indications
2. https://www.medscape.co.uk/drug/tramadol-with-paracetamol-oral-70082-70082
3. https://www.medicines.org.uk/emc/product/10547/pil
4. https://www.drugs.com/dosage/Paracetamol -tramadol.html
5. https://www.1mg.com/generics/tramadol-paracetamol-404964