SEGLENTIS (tramadol hcl/celecoxib)

There are 16 contraindications. Absolute contraindication.

Contraindication List
Acute asthma attack
Adenoidectomy in pediatric patient
Alcohol intoxication
Aspirin exacerbated respiratory disease
Benzodiazepine overdose
Cerebrovascular accident
CYp2d6 poor metabolizer
CYp2d6 ultrarapid metabolizer
Gastrointestinal obstruction
History of roux-en-Y gastric bypass
Opioid overdose
Post-operative from CABG surgery
Pregnancy
Renal transplant
Serotonin syndrome
Tonsillectomy in pediatric patient

There are 31 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Alcohol use disorder
Alcohol withdrawal syndrome
Central nervous system infection
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
CYp2c9 intermediate metabolizer (activity score 1)
CYp2c9 poor metabolizer
Depression
Drug abuse
Exacerbation of chronic obstructive pulmonary disease
Familial dysautonomia
Gastrointestinal hemorrhage
Gastrointestinal perforation
Gastrointestinal ulcer
History of kidney donation
Increased risk of bleeding
Intracranial hypertension
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Lower seizure threshold
Nephrectomy
Obstructive sleep apnea syndrome
Peptic ulcer
Respiratory depression
Seizure disorder
Severe hepatic disease
Suicidal
Suicidal ideation
Systemic mastocytosis
Thrombotic disorder
Tobacco smoker

There are 11 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Adrenocortical insufficiency
Anemia
Asthma
Chronic heart failure
CYp2d6 intermediate metabolizer
Dehydration
Disease of liver
Edema
Hypertension
Hypoglycemic disorder
Hyponatremia

There are 97 severe adverse reactions.

More Frequent	Less Frequent
Abnormal hepatic function tests Accidental injury Increased alanine transaminase Increased aspartate transaminase	Respiratory depression

Rare/Very Rare

Abnormal ECG Accidental fall Accidental injury Acute eruptions of skin Acute generalized exanthematous pustulosis Acute myocardial infarction Adrenocortical insufficiency Agranulocytosis Anaphylaxis Androgen deficiency Anemia Angina Angioedema Aplastic anemia Biliary calculus Bloody stools Bronchospastic pulmonary disease Bullous dermatitis Cellulitis Cerebrovascular accident Conjunctival hemorrhage Coronary artery disease Cystitis Deep venous thrombosis Diverticulitis of gastrointestinal tract DRESS syndrome Drug dependence Dyspnea Edema Erythema multiforme Esophageal perforation Esophagitis Exfoliative dermatitis Facial edema Gastroesophageal reflux disease Gastrointestinal hemorrhage Gastrointestinal obstruction Gastrointestinal perforation Gastrointestinal ulcer Hearing loss Heart failure Hematuria Hemorrhage Hepatic failure Hepatic necrosis Hepatitis Hiatal hernia Hypercholesterolemia Hyperglycemia Hyperkalemia Hypernatremia Hypertension Hypoglycemic disorder Hypokalemia Hyponatremia Increased urinary frequency Interstitial nephritis Intracranial bleeding Jaundice Kidney stone Left ventricular hypertrophy Leukopenia Myocardial ischemia Nephrotoxicity Non-infective meningitis Pancreatitis Pancytopenia Peripheral ischemia Pneumonia Prolonged QT interval Proteinuria Pulmonary edema Pulmonary thromboembolism Renal papillary necrosis Seizure disorder Sepsis Serotonin syndrome SIADH syndrome Sinus bradycardia Sleep apnea Spasm of sphincter of oddi Stevens-johnson syndrome Suicidal Syncope Tachycardia Tendon rupture Thrombocytopenic disorder Thrombocytosis Thrombophlebitis Toxic epidermal necrolysis Vasculitis Vertigo

There are 142 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Constipation Diarrhea Dizziness Drowsy Dysgeusia Dyspepsia Flatulence Flushing Headache disorder Insomnia Nausea Peripheral edema Pharyngitis Pruritus of skin Rhinitis Skin rash Upper respiratory infection Vertigo Vomiting Xerostomia	Acute abdominal pain Acute cognitive impairment Anorexia Arthralgia Back pain Blurred vision Diarrhea Dyspepsia Epicondylitis Flatulence General weakness Headache disorder Hyperhidrosis Hypertension Insomnia Nausea Nervousness Orthostatic hypotension Sinusitis Skin rash Symptoms of anxiety Urinary retention Vasodilation of blood vessels

Rare/Very Rare

Agitation Allergic dermatitis Alopecia Anorexia Anticholinergic toxicity Arthralgia Ataxia Body fluid retention Bronchitis Bruising Cataracts Chest pain Chills Constipation Contact dermatitis Cough Cramps in legs Delirium Depersonalization Depression Dream disorder Drowsy Dry skin Dysgeusia Dysphagia Dyspnea Dysuria Ecchymosis Epistaxis Erectile dysfunction Eructation Euphoria Fatigue Fever Flu-like symptoms Flushing Gastritis Gastroenteritis General weakness Hallucinations Hearing loss Hematuria Hemorrhoids Hyperglycemia Hyperhidrosis Hyperkinesis Hypertonia Hypoesthesia Hypotension Increased appetite Increased urinary frequency Indifference Infertility Laryngitis Libido changes Loss of sense of smell Loss of taste Maculopapular rash Medication overuse headache Menstrual disorder Migraine Miosis Mood changes Muscle fasciculation Myalgia Neck stiffness Nervousness Night sweats Ocular pain Opioid induced allodynia Opioid induced hyperalgesia Ovarian cyst Pain Palpitations Paresthesia Peripheral edema Pharyngitis Pruritus of skin Sinusitis Skin irritation Skin photosensitivity Sleep disorder Stomatitis Symptoms of anxiety Syncope Synovitis Tachycardia Tenesmus Tinnitus Tremor Urinary tract infection Urticaria Visual changes Vomiting Weight gain Weight loss Xerostomia Yawning

Prolonged maternal use of opiate agonists during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.

The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported with tramadol during postmarketing experience. The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.

Use of opiates in pregnant women during labor can result in neonatal respiratory depression. Use of tramadol is not recommended immediately before or during labor, when other analgesic techniques may be more appropriate. Opiate agonists may prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is inconsistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Neonates exposed to opiates during labor should be monitored for excessive sedation and respiratory depression. An opiate antagonist must be available for reversal of opiate-induced respiratory depression.

Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared with maternal veins was 0.83 for women given tramadol during labor.

Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic maternal use of opiate agonists during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis. The manufacturers state that available data regarding use of tramadol in pregnant women are insufficient to establish the risk of major birth defects and spontaneous abortion with the drug. Based on animal data, women of childbearing potential should be advised of the potential for tramadol to cause fetal harm.

Although there are no adequate and controlled studies to date in humans, tramadol has been shown to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6, and 3.6

times, respectively, the maximum daily human dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits). Embryo and fetal toxicity consisted mainly of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters also were seen in pups from rat dams allowed to deliver.

Embryo and fetal lethality was reported in only one rabbit study, in which rabbits received tramadol hydrochloride 300 mg/kg, a dose that would cause extreme maternal toxicity in rabbits. Embryotoxicity and fetotoxicity have been demonstrated in rats when tramadol and acetaminophen were administered in fixed combination at maternally toxic doses of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.

Embryonic and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Tramadol was not teratogenic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6,

and 3.6 times, respectively, the maximum human daily dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits). No drug-related teratogenic effects were observed in progeny of mice, rats, or rabbits receiving tramadol (up to 140, 80, or 300 mg/kg or 1.7, 1.9, or 14.6 times, respectively, the maximum daily human dosage) by various routes.

Tramadol and acetaminophen in fixed combination was not teratogenic in rats at a maternally toxic dose of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs. In perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) tramadol hydrochloride doses of 50 mg/kg or higher had decreased weights, and pup survival was decreased early in lactation at tramadol hydrochloride doses of 80 mg/kg (1.2-1.6 or 1.9-2.6 times, respectively, the maximum human dose).

No toxicity was observed for progeny of dams receiving doses of 8, 10, 20, 25, or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe. Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.

Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice. Fetal renal dysfunction has been observed, on average, after days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.

Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.

Some cases of neonatal renal dysfunction have required treatment with invasive procedures, such as exchange transfusion or dialysis. Observational data regarding other embryofetal risks with NSAIAs during the first or second trimester of pregnancy are not conclusive. An increased incidence of fetuses with ventricular septal defects, sternebral fusion or abnormality, and rib fusion was observed in reproduction studies in rabbits receiving oral celecoxib dosages >=150 mg/kg daily throughout organogenesis (exposure approximately twice the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)).

A dose-dependent increase in diaphragmatic hernias was observed in rats receiving oral celecoxib dosages >=30 mg/kg daily throughout organogenesis (exposure approximately 6-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)). Reproduction studies in rats using oral dosages up to 100 mg/kg daily (exposure approximately 7-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)) did not reveal evidence of delayed labor or parturition. In rats receiving oral celecoxib dosages >=50 mg/kg daily (exposure approximately 6-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)), pre- and post-implantation losses and reduced embryonic/fetal survival were observed.

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis, such as celecoxib, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development.

In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses. The effects of celecoxib on labor and delivery are unknown. In animal studies, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased stillbirth.

Tramadol is distributed into milk. Following a single IV tramadol dose of 100 mg, the cumulative distribution into milk within 16 hours after dosing was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. Because the safety of tramadol in infants and neonates has not been established, the drug is not recommended for obstetrical preoperative medication or for use in nursing women, including use for post-delivery analgesia.

FDA review of available medical literature did not reveal evidence of an increased frequency of adverse effects in nursing infants of women receiving tramadol; however, because the drug is distributed into milk and has similar risks as codeine in ultrarapid metabolizers of CYP2D6 substrates, FDA recommends that tramadol not be used in nursing women. (See Pharmacogenomics under Cautions: Precautions and Contraindications. Also see Cautions: Precautions and Contraindications, in Codeine Phosphate and Codeine Sulfate 28:08.08.) Infants exposed to tramadol through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia). If clinical manifestations of opiate toxicity occur, caregivers should seek immediate medical treatment for the infant.

Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped. Celecoxib is distributed into milk in small amounts. Limited data obtained from nursing women receiving celecoxib indicate that the calculated average infant exposure to the drug is 10-40 mcg/kg daily, which is less than 1% of the weight-based therapeutic dosage for a 2-year-old child.

Maternal use of celecoxib was not associated with adverse effects in 2 breast-fed infants 17 and 22 months of age. It is not known whether celecoxib affects milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for celecoxib and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects. In clinical trials evaluating celecoxib for acute treatment of migraine attacks, approximately 70 patients were >=65 years of age, while in clinical trials evaluating celecoxib for other indications, more than 3300 patients were 65-74 years of age and about 1300 were >=75 years of age. No overall differences in efficacy of celecoxib were observed between geriatric and younger patients.

Although results from clinical studies indicated that renal function (measured by glomerular filtration rate, blood urea nitrogen, and creatinine) and platelet function (measured by bleeding time and platelet aggregation) in geriatric individuals receiving celecoxib did not differ from those in younger individuals, spontaneous postmarketing reports of fatal adverse GI effects and acute renal failure have occurred more often in geriatric individuals than in younger individuals. If it is determined that the anticipated benefits of celecoxib therapy outweigh the potential risks, celecoxib should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects; if used for the acute treatment of migraine attacks, celecoxib should be used for the fewest possible number of days per month. Peak plasma concentration and AUC of celecoxib (as the oral capsules) were increased 40 and 50%, respectively, in geriatric individuals (i.e., >=65 years of age), but dosage adjustment in this age group based solely on age generally is not required.

Peak plasma celecoxib concentration and AUC values were higher in geriatric women than geriatric men, predominantly because of the lower body weight of these women. In geriatric patients weighing <50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.