Source: Health Products and Food Branch (CA) Revision Year: 2020
ZYTRAM XL is contraindicated in:
Patients should be instructed not to give ZYTRAM XL to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. ZYTRAM XL should be stored securely to avoid theft or misuse.
ZYTRAM XL should only be prescribed by healthcare professionals who are knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.
ZYTRAM XL (tramadol HCl controlled release tablets) must be swallowed whole, and must not be cut, chewed, dissolved or crushed. Taking cut, broken, chewed, dissolved or crushed tablets could lead to the rapid release and absorption of a potentially fatal dose of tramadol.
Patients should be cautioned not to consume alcohol while taking ZYTRAM XL, as it may increase the chance of experiencing dangerous side effects, including death.
Hyperalgesia that will not respond to a further dose increase of tramadol can occur at particularly high doses. A tramadol dose reduction or change in opioid may be required.
Like all opioids, ZYTRAM XL is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, ZYTRAM XL should be prescribed and handled with caution. Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.
Opioids, such as ZYTRAM XL, should be used with particular care in patients with a history of alcohol and illicit/ prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
ZYTRAM XL is intended for oral use only. The tablets should be swallowed whole, and not chewed or crushed. Abuse of oral dosage forms can be expected to result in serious adverse events, including death. With parenteral abuse, the tablet excipients, especially talc, can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury, which may also be fatal.
A Risk Management Program to support the safe and effective use of ZYTRAM XL has been established. The following are considered to be the essential components of the Risk Management Program:
a) Commitment to not emphasize or highlight the scheduling status of ZYTRAM XL (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities;
b) Inclusion of a PAAB-approved fair balance statement in all ZYTRAM XL advertising and promotional materials.
Carcinogenicity: In carcinogenicity studies using tramadol, survival analysis did not show any statistically significant positive linear trend or differences in mortality among the placebo and tramadol treatment groups.
Mutagenicity: The drug had no mutagenic effect in either the micro-nucleus test, which was carried out with mice, rats and hamsters administered two single oral and parenteral doses, or in the dominant-lethal test, in which mice were administered single and repeated oral and parenteral doses.
Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of ZYTRAM XL.
The use of ZYTRAM XL in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure.
The effect of tramadol on the QT/QTc interval were evaluated in a dedicated randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple dose ECG study in healthy subjects (n=62). The study involved administration of tramadol at a supra-therapeutic dose of 100 mg every 6 h on days 1-3 (400 mg/day), with a single 100 mg dose on day 4, or 150 mg every 6 h (600 mg/day) on days 1-3, with a single 150 mg dose on day 4. The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms (90% CI 3.2, 7.8) in the 400 mg/day treatment arm and 6.5 ms (90% CI 4.1, 8.8) in the 600 mg/day mg treatment arm, both occurring at the 8h time point (see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology). Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose (see ADVERSE REACTIONS, PostMarketing Reports with Tramadol; DRUG INTERACTIONS, QTc Interval-Prolonging Drugs; OVERDOSAGE).
Many drugs that cause QTc prolongation are suspected to increase the risk of torsade de pointes. Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
Particular care should be exercised when administering ZYTRAM XL to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug.
Risk factors for torsade de pointes in the general population include, but are not limited to, the following:
When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.
As with other opioids, tolerance and physical dependence may develop upon repeated administration of ZYTRAM XL and there is a potential for development of psychological dependence.
Physical dependence and tolerance reflect the neuroadapatation of the opiate receptors to chronic exposure to an opiate and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes.
Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage).
ZYTRAM XL is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia. Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to ZYTRAM XL; extreme caution and awareness is warranted to mitigate the risk.
Increasing concentrations of alcohol in the dissolution medium, resulted in a slight decrease in the rate of release of tramadol from ZYTRAM XL tablets. The clinical significance of the slight decrease in dissolution rate is unknown.
ZYTRAM XL may impair the mental and/or physical abilities needed for certain potentially hazardous tasks such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of tramadol with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol. Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery.
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
Tramadol and other tramadol-like opioids have been shown to decrease bowel motility. Tramadol may obscure the diagnosis or clinical course of patients with acute abdominal conditions (see CONTRAINDICATIONS) and is also contraindicated in patients with paralytic ileus, appendicitis and pancreatitis. Opioids may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease for worsening symptoms (see CONTRAINDICATIONS and ADVERSE REACTIONS, Nausea and Vomiting and Constipation).
ZYTRAM XL is contraindicated in patients with severe hepatic impairment. The elimination halflife of tramadol and its active metabolite may be prolonged in patients with hepatic impairment.
Not applicable.
Prolonged maternal use of opioid during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening.
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.
Use of ZYTRAM XL is contraindicated in pregnant women (see CONTRAINDICATIONS).
ZYTRAM XL should be used with caution and in reduced dosages during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see DRUG INTERACTIONS). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when ZYTRAM XL is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see DRUG INTERACTIONS).
ZYTRAM XL should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see CONTRAINDICATIONS, ADVERSE REACTIONS, Sedation, and DRUG INTERACTIONS).
Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest.
Serotonin toxicity also known as serotonin syndrome is a potentially life-threatening condition and has been reported with Tramadol Hydrochloride, including ZYTRAM XL, particularly during combined use with other serotonergic drugs (See DRUG INTERACTIONS).
Serotonin toxicity is characterised by neuromuscular excitation, autonomic stimulation (e.g. tachycardia, flushing) and altered mental state (e.g. anxiety, agitation, hypomania). In accordance with the Hunter Criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent, one of the following is observed:
If concomitant treatment with ZYTRAM XL and other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see DRUG INTERACTIONS). If serotonin toxicity is suspected, discontinuation of the serotonergic agents should be considered.
The respiratory depressant effects of tramadol, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Opioid analgesics, including tramadol may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, tramadol should not be used (see CONTRAINDICATIONS).
ZYTRAM XL is contraindicated for peri-operative pain relief. ZYTRAM XL is not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain).
In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with ZYTRAM XL for at least 48 hours before the operation and ZYTRAM XL should not be used in the immediate post-operative period and until the patient is ambulatory and gastrointestinal function is normal. If ZYTRAM XL is to be continued after the patient recovers from the post-operative period, a new dosage should be administered in accordance with the changed need for pain relief. The risk of withdrawal in opioid-tolerant patients should be addressed as clinically indicated (see Withdrawal Symptoms).
The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate training and experience (e.g., by an anesthesiologist).
Tramadol and other tramadol-like opioids has been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving tramadol. Standard supportive therapy should be implemented.
ZYTRAM XL should not be used in the early post-operative period (12 to 24 hours post-surgery) unless the patient is ambulatory and gastrointestinal function is normal.
ZYTRAM XL is contraindicated in patients with severe renal impairment. The elimination half-life of tramadol and its active metabolite may be prolonged in patients with renal impairment.
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, 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. Tramadol should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see CONTRAINDICATIONS).
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ZYTRAM XL, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with ZYTRAM XL and following dose increases. Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
To reduce the risk of respiratory depression, proper dosing and titration of ZYTRAM XL are essential. Overestimating the ZYTRAM XL dose when converting patients from another opioid product can result in fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see WARNINGS AND PRECAUTIONS, Special Populations, Special Risk Groups and DOSAGE AND ADMINISTRATION).
Some individuals may be CYP2D6 ultra-rapid metabolizers. These individuals convert tramadol more rapidly than other people into its more potent opioid metabolite O-desmethyltramadol (M1). This rapid conversion could result in higher than expected opioid-like side effects including life-threatening respiratory depression (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women; DRUG INTERACTIONS, Overview). The prevalence of this CYP2D6 phenotype varies widely in the population (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Race).
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with ZYTRAM XL, as in these patients, even usual therapeutic doses of ZYTRAM XL may decrease respiratory drive to the point of apnea. In these patients, use of alternative non-opioid analgesics should be considered, if possible. The use of ZYTRAM XL is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS).
Opioids can cause sleep-related breathing disorders such as sleep apnea syndromes (including central sleep apnea [CSA]) and hypoxia (including sleep-related hypoxia). Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an ongoing basis for the onset of a new sleep apnea, or a worsening of an existing sleep apnea. In these patients, consider reducing or stopping the opioid treatment if appropriate, using best practices for tapering of opioids (see WARNINGS AND PRECAUTIONS, Dependence/Tolerance; DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage).
There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnea, led to rare, but life-threatening adverse events and should not be used (see CONTRAINDICATIONS).
Serious potential consequences of overdosage with ZYTRAM XL are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
Do not prescribe ZYTRAM XL for patients who are suicidal or addiction prone.
ZYTRAM XL should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur it is often following the first dose. Other reported reactions include pruritus, hives, bronchospasm and angioedema. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol (see CONTRAINDICATIONS).
Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:
*Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics) or serotoninnorepinephrine reuptake inhibitors (SNRIs),
*Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, mirtazapine), or
*Opioids
Administration of tramadol may also enhance the seizure risk in patients taking:
Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons and used with extreme caution. In tramadol overdose, naloxone administration may increase the risk of seizure.
Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see ADVERSE REACTIONS, PostMarketing Experience).
A patient information sheet should be provided to patients when ZYTRAM XL tablets are dispensed to them.
Patients receiving ZYTRAM XL should be given the following instructions by the physician:
Tramadol should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to elderly or debilitated patients, patients with reduced hepatic function or severe renal dysfunction, and in patients with severely impaired pulmonary function, Addison’s disease, biliary tract disorders, hypotension with hypovolaemia, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture.
The administration of opioid analgesics, including tramadol, may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
Studies in humans have not been conducted. ZYTRAM XL crosses the placental barrier and is contraindicated in pregnant women (see CONTRAINDICATIONS).
Pregnant women using opioids should not discontinue their medication abruptly as this can cause pregnancy complication such as miscarriage or still-birth. Tapering should be slow and under medical supervision to avoid serious adverse events to the fetus.
Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, can be life-threatening (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS), and ADVERSE REACTIONS, Post-Market Adverse Reactions).
Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing reports with tramadol hydrochloride immediate-release products.
Use of ZYTRAM XL is contraindicated in pregnant women (see CONTRAINDICATIONS). The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown.
Since opioids can cross the placental barrier and are excreted in breast milk, ZYTRAM XL is contraindicated in nursing women and during labour and delivery. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if ZYTRAM XL is used in this population.
Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Some women are CYP2D6 ultra-rapid metabolizers of tramadol, which may lead to dangerously higher-than-expected serum levels of M1 that could pass to their breast-fed infants. Therefore, maternal use of tramadol can lead to serious adverse reactions, including death in nursing infants (see WARNINGS AND PRECAUTIONS, Respiratory).
Since its safety in infants and newborns has not been studied, tramadol should not be administered for obstetrical preoperative medication, post-delivery analgesia or at any time during breastfeeding.
The safety and efficacy of ZYTRAM XL has not been studied in the pediatric population. Therefore, use of ZYTRAM XL tablets is not recommended in patients under 18 years of age. Further, adolescent patients (12 to 18 years old) who are obese or have conditions such as obstructive sleep apnea or severe lung disease may be at increased risk of serious breathing problems; the use of ZYTRAM XL is not recommended in these pediatrics patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrated slowly, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The elimination half-life of tramadol may be prolonged in patients over 75 years, thereby increasing the potential for adverse events (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).
ZYTRAM XL is contraindicated in patients with several hepatic impairment (Child-Pugh Class C) (see CONTRAINDICATIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).
ZYTRAM XL is contraindicated in patients with creatine clearances of less than 30 mL/min (see CONTRAINDICATIONS and and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).
Adverse effects of ZYTRAM XL are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards associated with opioids include respiratory and central nervous system depression and, to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
The pre-marketing development program for ZYTRAM XL included exposure to a total of 1,213 participants in seven randomized, double-blind controlled clinical trials (n=1,028) and one six- month open-label trial (n=185). A summary of adverse events occurring at an incidence of 1% or more is given in Table 2, which includes all events, whether considered by the clinical investigator to be related to the study drug or not.
The most common adverse effects with ZYTRAM XL are constipation, dizziness, headache, nausea, somnolence and vomiting. These are common effects associated with other drugs with opioid-agonist activity. Slower titration, a 7 day as compared to a 2-day schedule, may be an effective strategy to reduce adverse effects.
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Table 2. Adverse Events Reports in ZYTRAM XL Clinical Trials (≥1%):
| Number of Patients | % of Patients n=1,213 | |
|---|---|---|
| Body as a Whole | ||
| Headache | 132 | 10.9 |
| Asthenia | 93 | 7.7 |
| Hyperhidrosis | 69 | 5.7 |
| Pain | 26 | 2.1 |
| Central Nervous System | ||
| Dizziness | 214 | 17.6 |
| Somnolence | 191 | 15.7 |
| Depression | 12 | 1.0 |
| Insomnia | 24 | 2.0 |
| Tremor | 13 | 1.1 |
| Vasodilation | 24 | 2.0 |
| Digestive System | ||
| Constipation | 274 | 22.6 |
| Nausea | 357 | 29.4 |
| Vomiting | 135 | 11.1 |
| Diarrhea | 54 | 4.5 |
| Abdominal pain | 30 | 2.5 |
| Anorexia | 42 | 3.5 |
| Dry mouth | 61 | 5.0 |
| Dyspepsia | 49 | 4.0 |
| Flatulence | 15 | 1.2 |
| Respiratory System | ||
| Cough increased | 11 | 1.0 |
| Pharyngitis | 17 | 1.4 |
| Skin and Appendages | ||
| Pruritus | 27 | 2.2 |
Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.
Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.
The following adverse effects occur less frequently with opioid analgesics and include those reported in ZYTRAM XL clinical trials, whether related or not to tramadol.
Body as a Whole: abnormal gait, accidental injury, back pain, chest pain, chills and fever, flu syndrome, infection, malaise, photosensitivity, syncope.
Cardiovascular: angina pectoris, arrhythmia, atrial flutter, hypertension, migraine, palpitation, peripheral vascular disorder, phlebitis, tachycardia.
Digestive: abnormal stools, bloating, diverticulitis, eructation, gastric motility reduced, gastritis, gastroenteritis, gastrointestinal hemorrhage, hiccup, irritable bowel syndrome, laryngitis, melena, pancreatitis, rectal disorder, rectal hemorrhage, thirst, tongue disorder, weight decrease.
Endocrine: abnormal ejaculation, impotence, libido decreased.
Hemolytic & Lymphatic: hemolytic anemia, liver function test abnormal.
Metabolic & Nutritional: alkaline phosphatase increased, hypercholesteremia, hyperglycemia, hyperlipemia, peripheral edema, hepatic enzymes increased. Musculoskeletal: arthritis, arthrosis, bursitis, cramps, fatigue, gout, joint disorder, knee effusion, muscle pain, muscle weakness, myalgia, myopathy, pathological fracture, tendon disorder.
Nervous: abnormal coordination, abnormal dreams, abnormal thinking, amnesia, anxiety, apathy, ataxia, carpal tunnel syndrome, confusional state, depersonalization, affect lability, euphoric mood, hallucinations, hyperesthesia, hypertonia, anosmia or hyposmia, malaise, myoclonus, nervousness, paresthesia, vertigo, obstructive sleep apnea syndrome
Respiratory: asthma, bronchospasm, dyspnea, epistaxis, hemoptysis, hyperventilation, pneumonia, respiratory disorder, rhinitis, sinusitis.
Skin: acne, dermatitis, dry skin, eczema, flushing, gooseflesh, herpes simplex, herpes zoster, purpura, rash, sebaceous cyst.
Special Senses: amblyopia, blepharitis, cellulitis, conjunctivitis, dry eyes, eustachian tube dysfunction, eye pain, halitosis, lacrimation disorder, otitis media, sore mouth, taste perversion, tinnitus, tooth disorder, visual impairment.
Urogenital: albuminuria, calcium crystalluria, cystitis, dysuria, enlarged prostate, gynecomastia, hematuria, nocturia, polyuria, renal pain, urinary retention, urinary tract infection, urine abnormality, vaginal hemorrhage.
In clinical trials where clinical abnormalities were recorded (n= 245), the following laboratory abnormalities were reported: ALT (3%), AST (2%), alkaline phosphatase (4%), creatinine (2%), BUN (4%), potassium (2%), sodium (1%), bilirubin (0.4%), basophils (0.4%), eosinophils (0.4%), lymphocytes (3%), monocytes (3%), neutrophils (1%), LDH (4%), RBC (3%), platelets (2%), WBC (2%), glucose (0.4%), triglycerides (1%) and TSH (0.4%).
Neonatal opioid withdrawal syndrome has resulted from prolonged use of tramadol.
The following adverse reactions have been identified during post approval use of tramadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use (see WARNINGS AND PRECAUTIONS, Endocrine).
Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRI’s and MAOIs.
Adverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioedema and urticaria), bradycardia, cognitive disorders, seizures, decreased activity, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremor), hypotension, micturition disorder, psychomotor hyperactivity, respiratory depression and sensory disturbance.
Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate.
Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson Syndrome and suicidal tendency.
Electrocardiogram QT prolonged, ventricular fibrillation, and ventricular tachycardia have been reported during post-market use.
In vitro studies indicated that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol 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 is a mild inducer of selected drug metabolism pathways measured in animals.
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS AND PRECAUTIONS, Neurologic, Interactions with CNS Depressants (including benzodiazepines and alcohol) and Driving and Operating Machinery). ZYTRAM XL should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.
MAO Inhibitors: Monoamine oxidase inhibitors (MAO) intensify the effects of opioid drugs which can cause anxiety, confusion and decreased respiration. ZYTRAM XL is contraindicated in patients receiving MAO Inhibitors or who have used them within the previous 14 days (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS).
Drugs That Lower Seizure Threshold: Tramadol can increase the potential for selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants (TCAs), anti-psychotics and other seizure threshold lowering drugs (i.e., bupropion, mirtazapine, tetrahydrocannabinol) to cause seizures (see WARNINGS AND PRECAUTIONS).
Serotonergic Agents: The development of a potentially life-threatening Serotonin Syndrome may occur with use of tramadol products, including ZYTRAM XL, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium or St. John’s Wort, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which may impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). If concomitant treatment of ZYTRAM XL 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.
CNS Depressants: Concurrent administration of tramadol with other centrally acting drugs, including alcohol, centrally acting analgesics, opioids and psychotropic drugs may potentiate CNS depressant effects or exacerbate adverse drug reactions of tramadol.
Carbamazepine: Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Since carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ZYTRAM XL and carbamazepine is not recommended.
Quinidine: Tramadol is metabolized to M1 by the CYP2D6 isoenzyme. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol 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 has no effect on quinidine metabolism.
Inhibitors of CYP2D6: Inhibitors of CYP2D6 (e.g., quinidine, fluoxetine, paroxetine, amitriptyline) may inhibit the metabolism of tramadol, resulting in increased serum concentrations of tramadol and decreased concentrations of its O-demethylated metabolite (M1). Co-administration of quinidine did not diminish the analgesic effect of tramadol in human experimental pain models.
Inhibitors or Inducers of CYP3A4: Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort may affect the metabolism of tramadol, leading to altered tramadol exposure.
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors such as quinidine, fluoxetine, paroxetine, amitriptyline (CYP2D6 inhibitors), ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures, serotonin syndrome, and QTc interval prolongation, potentially resulting in cardiac arrhythmias.
QTc Interval-Prolonging Drugs: The concomitant use of ZYTRAM XL with QTc intervalprolonging drugs should be avoided. Drugs that have been associated with QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc interval prolongation and/or torsade de pointes:
Drugs that Affect Electrolytes: The use of ZYTRAM XL with drugs that can decrease electrolyte levels should be avoided to the extent possible. Drugs that can decrease electrolyte levels include, but are not limited to, the following:
The above list of potentially interacting drugs is not comprehensive. Current information sources should be consulted for newly approved drugs that prolong the QTc interval or decrease electrolytes, as well as for older drugs for which these effects have recently been established. (See WARNINGS AND PRECAUTIONS, Cardiovascular; ADVERSE REACTIONS, PostMarketing Reports with Tramadol; ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).
Cimetidine: Concomitant administration of tramadol and cimetidine is associated with a small prolongation of the half-life of tramadol, but no alteration of the ZYTRAM XL dosage regimen is recommended.
Digoxin: Digoxin toxicity has occurred rarely during co-administration of digoxin and tramadol.
Protease Inhibitors, e.g., ritonavir: Co-administered ritonavir may increase the serum concentration of tramadol, resulting in tramadol toxicity.
Warfarin and other coumarin anticoagulants: Alteration of the effect of warfarin, including elevation of prothrombin times (international normalized ratio/INR), has been reported rarely during co-administration of warfarin and tramadol. While such changes have been generally of limited clinical significance for the individual products, care should be taken when commencing treatment with tramadol in patients on anticoagulants. Periodic evaluation of prothrombin time should be performed when ZYTRAM XL tablets and warfarin-like compounds are administered concurrently.
In the presence of food, the availability and controlled-release properties of ZYTRAM XL tablets were maintained with no evidence of dose dumping.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
The concomitant use of alcohol should be avoided (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
