Dosage & Administration
By using PrescriberAI, you agree to the AI Terms of Use.
Seglentis Prescribing Information
ADDICTION, ABUSE, AND MISUSE
Because the use of SEGLENTIS exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].
LIFE-THREATENING RESPIRATORY DEPRESSION
Serious, life-threatening, or fatal respiratory depression may occur with use of SEGLENTIS, especially during initiation. To reduce the risk of respiratory depression, proper dosing of SEGLENTIS is essential [see Warnings and Precautions (5.2)].
ACCIDENTAL INGESTION
Accidental ingestion of even one dose of SEGLENTIS, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.2)].
RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of SEGLENTIS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) and Drug Interactions (7)].
NEONATAL OPIOID WITHDRAWAL SYNDROME (NOWS)
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)].
OPIOID ANALGESIC RISK EVALUATION AND MITIGATION STRATEGY (REMS)
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)].
CARDIOVASCULAR THROMBOTIC EVENTS
- Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use [see Warnings and Precautions (5.6)].
- SEGLENTIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.6)].
GASTROINTESTINAL BLEEDING, ULCERATION, AND PERFORATION
NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events [see Warnings and Precautions (5.7)].
ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFETHREATENING RESPIRATORY DEPRESSION IN CHILDREN
Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions (5.8)]. SEGLENTIS is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of SEGLENTIS 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 [see Warnings and Precautions (5.8)].
INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SEGLENTIS requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.9), Drug Interactions (7)].
SEGLENTIS is indicated for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Limitations of Use
Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1)], reserve SEGLENTIS for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]:
- Have not been tolerated or are not expected to be tolerated,
- Have not provided adequate analgesia or are not expected to provide adequate analgesia.
SEGLENTIS should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.
Important Dosage and Administration Instructions
- Do not exceed the recommended dose of SEGLENTIS.
- Do not co-administer SEGLENTIS with other tramadol or celecoxib containing products.
- SEGLENTIS should only be prescribed by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve higher doses of opioids for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose of opioid clearly outweigh the substantial risks [see Warnings and Precautions (5.1)].
- Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
- There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
- Respiratory depression can occur at any time during opioid therapy, especially upon initiation and following a dosage increase [see Warnings and Precautions (5.2)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SEGLENTIS [see Warnings and Precautions (5.2)].
Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.3)].
Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.
Recommended Dosage
The dose of SEGLENTIS is 2 tablets every 12 hours as needed for pain and not to exceed 4 tablets over 24 hours.
Safe Reduction or Discontinuation of SEGLENTIS
Do not abruptly discontinue SEGLENTIS in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking SEGLENTIS, there are a variety of factors that should be considered, including the total daily dose of opioid (including SEGLENTIS) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on SEGLENTIS who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily opioid dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with a reduced dosing schedule of SEGLENTIS to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.29), Drug Abuse and Dependence (9.2 and 9.3)].
SEGLENTIS coated tablets contain 56 mg celecoxib and 44 mg tramadol hydrochloride (equivalent to 39 mg tramadol). The tablets are white to off-white elongated coated tablets debossed with "100" on one side and "CTC" on the other.
Pregnancy
Risk Summary
Based on animal data, advise pregnant women of the potential risk to fetus.
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions (5.4)).
Use of NSAIDs, including SEGLENTIS, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SEGLENTIS use between about 20 and 30 weeks of gestation and avoid SEGLENTIS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).
There are no available data on use of SEGLENTIS in pregnant women. In an animal reproduction study, oral administration of celecoxib and tramadol co-crystal to pregnant rabbits during the period of organogenesis, resulted in embryo-fetal deaths and an increase of incidence of vertebral defects at approximately 4.7 and 0.11 times the dose of celecoxib and tramadol, respectively, at the maximum recommended human dose (MRHD) of SEGLENTIS at 400 mg/day (224 mg celecoxib/176 mg tramadol) (see Data).
Tramadol
Available data with tramadol use in pregnant women are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 3.2, 1.4, and 8.2 times the tramadol dose of 176 mg at the MRHD of SEGLENTIS. In a pre- and post-natal development study, tramadol decreased pup body weight and increased pup mortality at 2.7 and 4.3 times the MRHD, respectively.
In a published study, tramadol caused structural abnormalities in the brains of fetuses when administered to female Sprague Dawley rats from Gestation Days 10 to 21 at 2.7 times the MRHD (see Data).
Celecoxib
Premature Closure of Fetal Ductus Arteriosus:
Use of NSAIDs, including SEGLENTIS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment:
Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 13 times the celecoxib dose of 224 mg at the MRHD of SEGLENTIS. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 4 times the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
The background risk of major birth defects and miscarriage for the indicated population is unknown. 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% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Tramadol:
Use of opioid analgesics for an extended period of time 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.
Celecoxib:
Premature Closure of Fetal Ductus Arteriosus:
Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SEGLENTIS, can cause premature closure of the fetal ductus arteriosus (see Data).
Oligohydramnios/Neonatal Renal Impairment:
If an NSAID is necessary, including SEGLENTIS, at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If SEGLENTIS treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SEGLENTIS and follow up according to clinical practice (see Data).
Labor or Delivery
Tramadol:
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. SEGLENTIS is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.
Opioid analgesics, including SEGLENTIS, 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 SEGLENTIS, if any, on the later growth, development, and functional maturation of the child is unknown.
Celecoxib:
There are no studies on the effects of SEGLENTIS during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Data
Human Data
Celecoxib:
The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib.
Premature Closure of Fetal Ductus Arteriosus
Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.
Animal Data
Treatment of pregnant rabbits during organogenesis with celecoxib and tramadol co-crystal resulted in an increase in the incidence of scoliosis and other vertebral defects (including absent thoracic hemicentrum/a and neural arch(es) and fused thoracic vertebral centra and/or neural arch(es)) at an oral dose of 100 mg/kg/day (56 mg celecoxib/44 mg tramadol/kg/day; approximately 4.7 and 0.11 times the MRHD on the basis of celecoxib and tramadol, respectively, on an AUC basis), which is a dose that also caused maternal toxicity (decreased body weight gain). In addition, there was a slight increase of post-implantation loss in rabbits at 100 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for embryofetal toxicity was 55 mg/kg/day (approximately 3.3 and 0.02 times the MRHD of celecoxib and tramadol, respectively, on an AUC basis).
Tramadol:
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 3.2, 1.4, and 8.2 times the MRHD of tramadol (176 mg) 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, decreased 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 3.9, 4.3, and 33 times the MRHD of tramadol (176 mg), respectively, on a mg/m2 basis.
Tramadol was evaluated in pre-and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (2.7 times the MRHD of tramadol on a mg/m2 basis) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (4.3 times the MRHD of tramadol on a mg/m2 basis).
In a published study, oral administration of tramadol at 50 mg/kg (2.7 times the MRHD of tramadol on a mg/m2 basis) to pregnant female rats from Gestation Days 10 to 21 caused structural abnormalities in the brains of the offspring.
Celecoxib:
Celecoxib at oral doses ≥150 mg/kg/day (approximately 4 times the level of celecoxib of 224 mg at the MRHD of SEGLENTIS based on AUC), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 13 times the MRHD based on AUC) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 13 times the MRHD based on AUC).
Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 15 times the MRHD based on AUC). The effects of SEGLENTIS on labor and delivery in pregnant women are unknown.
Lactation
Risk Summary
SEGLENTIS is not recommended for obstetrical preoperative medication or for post-delivery analgesia in lactating women because the safety of tramadol in infants and newborns has not been studied.
Tramadol
Tramadol and its metabolite, O-desmethyltramadol (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 [see Clinical Pharmacology (12.1)]. Published studies have reported tramadol and M1 in colostrum with administration of tramadol to breastfeeding 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 SEGLENTIS (see Data) [see Warnings and Precautions (5.8)].
Celecoxib
Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events.
Clinical Considerations
If infants are exposed to SEGLENTIS 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 breastfeeding is stopped.
Data
Tramadol
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.
Females and Males of Reproductive Potential
Infertility
Tramadol
Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2)].
Published studies in adult male rodents report that tramadol, at clinically relevant doses, can produce adverse effects on male reproductive hormones and tissues [see Nonclinical Toxicology (13.1)].
Celecoxib
Females:
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including celecoxib, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric Use
The safety and effectiveness of SEGLENTIS in pediatric patients have not been established.
Tramadol
Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions (5.8)]. 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:
- SEGLENTIS is contraindicated for all children younger than age 12 years of age [see Contraindications (4)].
- SEGLENTIS is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)].
Avoid the use of SEGLENTIS 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
In the randomized, double-blind, active- and placebo-controlled, parallel group study comparing SEGLENTIS to tramadol, celecoxib, and placebo in patients with acute post-operative pain following unilateral first metatarsal osteotomy with internal fixation, 9.1% of patients were ≥65 years of age. Age subgroup examination was planned by protocol and it revealed a similar trend in efficacy compared to younger patients and no untoward or unexpected adverse reactions were seen in the elderly patients who received SEGLENTIS.
No dose adjustments are required for elderly patients.
Tramadol
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. Frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.14)].
Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to regularly evaluate renal function.
Celecoxib
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, monitor patients for adverse effects [see Warnings and Precautions (5.6, 5.7, 5.20, 5.23, 5.31)]. Because SEGLENTIS is approved at a unique dosage of celecoxib, SEGLENTIS is not recommended in patients that require dosages other than 2 tablets every 12 hours, containing a total daily dose of celecoxib of 224 mg.
Of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers.
However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see Warnings and Precautions (5.7, 5.23)].
Renal Impairment
Because SEGLENTIS contains celecoxib, the use of SEGLENTIS in patients with severe renal impairment is not recommended [see Warnings and Precautions (5.23) and Clinical Pharmacology (12.3)].
The pharmacokinetics and tolerability of SEGLENTIS in patients with renal impairment has not been studied.
Tramadol
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Hepatic Impairment
As tramadol and celecoxib are both extensively metabolized by the liver, the use of SEGLENTIS in patients with moderate and severe hepatic impairment is not recommended [see Warnings and Precautions (5.20), Clinical Pharmacology (12.3)].
The pharmacokinetics and tolerability of SEGLENTIS in patients with impaired hepatic function have not been studied.
Tramadol
Metabolism of tramadol and M1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver.
Celecoxib
The daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. Because the dose of celecoxib and tramadol cannot be adjusted individually for SEGLENTIS, the use in moderate hepatic impairment is not recommended. The use of celecoxib in patients with severe hepatic impairment is not recommended [see Clinical Pharmacology (12.3)].
Poor Metabolizers of CYP2C9 Substrates
Celecoxib
In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) celecoxib is administered starting with half the lowest recommended dose [see Clinical Pharmacology (12.5)]. Because SEGLENTIS is not available in lower strengths of celecoxib, SEGLENTIS is not recommended in patients who are known or suspected to be poor CYP2C9 metabolizers [see Clinical Pharmacology (12.5)].
SEGLENTIS is contraindicated in:
- All patients younger than 12 years of age [see Warnings and Precautions (5.8)].
- Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.8)].
SEGLENTIS is also contraindicated in patients with:
- Significant respiratory depression [see Warnings and Precautions (5.2)].
- In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.6)].
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.14)].
- Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.18)].
- Previous hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to tramadol, opioids, celecoxib, sulfonamides, or any other component of the drug product [see Warnings and Precautions (5.19)].
- Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Drug Interactions (7)].
- History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [see Warnings and Precautions (5.19, 5.24)].