Ultram

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• digoxin (Lanoxin)
• warfarin (Coumadin, Jantoven)
• central nervous system depressants such as alcohol, tranquilizers, or sedative hypnotics
• other opioid medications such as hydrocodone (Vicodin) or oxycodone (Oxycontin)
• medications that block the enzyme CYP3A4 such as some macrolide antibiotics (clarithromycin, telithromycin), some HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (boceprevir, telaprevir), some azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan (Vaprisol), delavirdine (Rescriptor), and nefazodone (Serzone)
• medications that increase the activity of the enzyme CYP3A4 such as carbamazepine (Tegretol, Equetro, Carbatrol), phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), St John's wort, and nimodipine (Nimotop)
• medications that block the enzyme CYP2D6 such as quinidine (Qualaquin), fluoxetine (Prozac,Sarafem), amitriptyline (Elavil, Amitril, Amitid), and paroxetine (Paxil)
• triptans such as sumatriptan (Imitrex, Treximet), eletriptan (Relpax), almotriptan (Axert), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig)
• monoamine oxidase inhibitors such as tranylcypromine (Parnate), phenelzine (Nardil), selegiline (Eldepryl, Zelapar), isocarboxazid (Marplan), and rasagiline (Azilect)
• selective serotonin reuptake inhibitors (SSRIs) such as escitalopram (Lexapro), sertraline (Zoloft), citalopram (Celexa), vilazodone (Viibryd), paroxetine (Paxil), fluoxetine (Prozac, Sarafem, Symbyax), and fluvoxamine (Luvox)
• tricyclic antidepressants such as trimipramine (Surmontil), amitriptyline (Elavil), nortriptyline (Pamelor, Aventyl), protriptyline (Vivactil), and clomipramine (Anafranil)
• other tricyclic compounds such as cyclobenzaprine (Flexeril) and promethazine (Phenergan)

This is not a complete list of Ultram drug interactions.  Ask your doctor or pharmacist for more information.

Take Ultram exactly as prescribed.

This medication comes in immediate release tablet and can be taken up to 6 times a day, with or without food.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Ultram at the same time.

Synthetic, centrally active analgesic;1 2 3 4 5 15 53 not an opium derivative or a semisynthetic derivative of morphine or thebaine.1 21 22 53

Administration

Oral Administration

Administer orally alone or in fixed combination with acetaminophen.1 51 53

Administer without regard to meals.1

Administer once daily in a consistent manner relative to food intake.53

Swallow tablets whole; do not crush, chew, or split.53

Manufacturer makes no specific recommendation regarding administration with food.51

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as tramadol hydrochloride; dosage expressed in terms of the salt.1 51 53

Adults

Initially, 25 mg daily in the morning; titrate dosage slowly to reduce risk of adverse effects.1 Increase dosage in 25-mg increments as separate doses every 3 days to a dosage of 100 mg daily (25 mg 4 times daily);1 then may increase total daily dosage by 50 mg every 3 days as tolerated, up to 200 mg daily (50 mg 4 times daily.)1 After titration, 50–100 mg can be given every 4–6 hours, up to 400 mg daily.1

If more rapid onset of analgesia is required, may initiate therapy at 50–100 mg every 4–6 hours (up to 400 mg daily), but risk of adverse events may be increased.1

Initially, 100 mg once daily; increase dosage in 100-mg increments every 5 days, as needed and tolerated, up to 300 mg daily.53

75 mg of tramadol hydrochloride every 4–6 hours as needed (up to 300 mg daily).51

Prescribing Limits

Adults

Maximum 400 mg daily.1

Maximum 300 mg daily.53

Maximum 300 mg daily.21 51

Special Populations

Hepatic Impairment

In patients with cirrhosis, 50 mg (as conventional tablets) every 12 hours.1 (See Special Populations under Pharmacokinetics.)

Extended-release tablets not recommended for use in patients with severe (Child-Pugh class C) hepatic impairment.53 Available tablet strengths do not provide sufficient dosing flexibility for safe use in these patients.53

Tramadol in fixed combination with acetaminophen not recommended in patients with hepatic impairment.51

Renal Impairment

Reduced dosage recommended in patients with severe renal impairment (Clcr <30 mL/minute).1 51 (See Special Populations under Pharmacokinetics.)

Conventional tablets: 50–100 mg of tramadol every 12 hours (maximum 200 mg daily).1 In hemodialysis patients, administer the patient’s regular dose on dialysis days (not substantially removed by dialysis).1

Fixed combination with acetaminophen: Maximum of 75 mg of tramadol hydrochloride (in combination with acetaminophen) every 12 hours.51

Extended-release tablets not recommended.53 Available tablet strengths do not provide sufficient dosing flexibility for safe use.53

Geriatric Patients

Cautious dosage selection; initiate therapy at the lower end of the dosage range.1 53

In patients >75 years of age, maximum 300 mg daily.1

Storage

Oral

Tight containers at 25°C (may be exposed to 15–30°C).1

25°C (may be exposed to 15–30°C).53

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule IV (C-IV) drug, effective August 18, 2014.56

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Ultram has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg Ultram tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Ultram has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving Ultram. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of Ultram in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX) daily.

Titration Trials

In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily Ultram dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate Ultram therapy using slower titration rates.

A 16-day titration schedule, starting with 25 mg qAM and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg four times per day), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg four times per day), resulted in fewer discontinuations due to nausea or vomiting and fewer discontinuations due to any cause than did a 10-day titration schedule.

Figure 2:

Addiction, Abuse, and Misuse

Ultram contains tramadol, a Schedule IV controlled substance. As an opioid, Ultram exposes users to the risks of addiction, abuse, and misuse (see DRUG ABUSE AND DEPENDENCE).

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Ultram. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Ultram, and monitor all patients receiving Ultram for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Ultram, but use in such patients necessitates intensive counseling about the risks and proper use of Ultram along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Ultram. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug (see PRECAUTIONS; Information for Patients). Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status (see OVERDOSAGE). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Ultram, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of Ultram.

To reduce the risk of respiratory depression, proper dosing and titration of Ultram are essential (see DOSAGE AND ADMINISTRATION). Overestimating the Ultram dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Ultram, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Ultram is contraindicated for all children younger than 12 years of age (see CONTRAINDICATIONS).
• Ultram is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS).
• Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose (see PRECAUTIONS/Pediatric Use, OVERDOSAGE).

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of the active metabolite O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking Ultram could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with Ultram (see PRECAUTIONS/Nursing Mothers).

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

Neonatal Opioid Withdrawal Syndrome

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

Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

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

The concomitant use of Ultram with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression.

Follow patients receiving Ultram and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when Ultram is used in conjunction with inhibitors of CYP2D6 (see PRECAUTIONS; Drug Interactions).

The concomitant use of Ultram with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.

The concomitant use of Ultram with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.

Follow patients receiving Ultram and any CYP3A4 inhibitor or inducer for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Ultram is used in conjunction with inhibitors and inducers of CYP3A4 (see PRECAUTIONS; Drug Interactions).

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Ultram with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

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 PRECAUTIONS; 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 Ultram 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 PRECAUTIONS; Drug Interactions, Information for Patients/Caregivers).

Serotonin Syndrome Risk

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see PRECAUTIONS; Drug Interactions). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Ultram if serotonin syndrome is suspected.

Increased Risk of Seizure

Seizures have been reported in patients receiving Ultram within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of Ultram above the recommended range. Concomitant use of Ultram increases the seizure risk in patients taking:

• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
• Other opioids,
• MAO inhibitors (see also WARNINGS, Serotonin Syndrome Risk),
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizure 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). In Ultram overdose, naloxone administration may increase the risk of seizure.

Suicide Risk

• Do not prescribe Ultram for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed. (see DRUG ABUSE AND DEPENDENCE).
• Prescribe Ultram Tablets with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression (see PRECAUTIONS; Drug Interactions).
• Inform patients not to exceed the recommended dose and to limit their intake of alcohol (see DOSAGE AND ADMINISTRATION).

Adrenal Insufficiency

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.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Ultram in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Ultram -treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Ultram (see WARNINGS).

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see WARNINGS).

Monitor such patients closely, particularly when initiating and titrating Ultram and when Ultram is given concomitantly with other drugs that depress respiration (see WARNINGS). Alternatively, consider the use of non-opioid analgesics in these patients.

Severe Hypotension

Ultram may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) (see PRECAUTIONS; Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Ultram. In patients with circulatory shock, Ultram may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Ultram in patients with circulatory shock.

Risks of use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Ultram may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Ultram.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Ultram in patients with impaired consciousness or coma.

Risks of use in Patients with Gastrointestinal Conditions

Ultram is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus (see CONTRAINDICATIONS).

The tramadol in Ultram may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

Anaphylaxis and Other Hypersensitivity Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with Ultram. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to tramadol and other opioids may be at increased risk and therefore should not receive Ultram (see CONTRAINDICATIONS). If anaphylaxis or other hypersensitivity occurs, stop administration of Ultram immediately, discontinue Ultram permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. (see CONTRAINDICATIONS, PRECAUTIONS; Information for Patients)

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Ultram. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing Ultram in a physically-dependent patient, gradually taper the dosage (see DOSAGE AND ADMINISTRATION). Do not abruptly discontinue Ultram in these patients (see DRUG ABUSE AND DEPENDENCE).

Risks of Driving and Operating Machinery

Ultram may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Ultram and know how they will react to the medication.

Controlled Substance

Ultram (tramadol hydrochloride) Tablets contain tramadol, a Schedule IV controlled substance.

Abuse

Ultram contains tramadol, a substance with a high potential for abuse similar to other opioids. Ultram can be abused and is subject to misuse, addiction, and criminal diversion (see WARNINGS).

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Ultram, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Ultram is intended for oral use only. Abuse of Ultram poses a risk of overdose and death. The risk is increased with concurrent abuse of Ultram with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Ultram should not be abruptly discontinued in a physically dependent patient (see DOSAGE AND ADMINISTRATION). If Ultram is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs (see PRECAUTIONS; Pregnancy).

Take Ultram exactly as prescribed. Follow all directions on your prescription label. Tramadol can slow or stop your breathing, especially when you start using this medicine or whenever your dose is changed. Never take Ultram in larger amounts, or for longer than prescribed. Tell your doctor if the medicine seems to stop working as well in relieving your pain.

Tramadol may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. MISUSE OF PAIN MEDICATION CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription. Selling or giving away Ultram is against the law.

Stop taking all other around-the-clock narcotic pain medications when you start taking Ultram.

Ultram can be taken with or without food, but take it the same way each time.

Do not crush, break, or open an extended-release tablet. Swallow the tablet whole to avoid exposure to a potentially fatal dose.

Never crush or break a Ultram tablet to inhale the powder or mix it into a liquid to inject the drug into your vein. This practice has resulted in death.

If you use the extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine.

Do not stop using this medicine suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using this medicine.

Store at room temperature away from moisture and heat.

Keep track of the amount of medicine used from each new bottle. Ultram is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.