"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
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: [see DRUG INTERACTIONS]
- Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
- Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
- Other opioids,
- MAO inhibitors [see DRUG INTERACTIONS],
- Neuroleptics, or
- Other drugs that reduce the seizure threshold.
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).
In tramadol overdose, naloxone administration may increase the risk of seizure.
- Do not prescribe ConZip™ 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 ConZip™ with caution for patients with a history of misuse and/or are taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression [see DRUG INTERACTIONS].
- Tell your patients not to exceed the recommended dose and to limit their intake of alcohol [see DOSAGE AND ADMINISTRATION].
Serotonin Syndrome Risk
The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including ConZip™, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose. [see CLINICAL PHARMACOLOGY].
Serotonin syndrome 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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. 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 codeine and other opioids may be at increased risk and therefore should not receive ConZip™ [see CONTRAINDICATIONS].
Administer ConZip™ cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. If large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures [see OVERDOSAGE].
Interaction With Central Nervous System (CNS) Depressants, Including Alcohol and Drugs of Abuse
Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Use ConZip™ with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ConZip™ increases the risk of CNS and respiratory depression in these patients. Alcohol-containing beverages should not be consumed by patients using ConZip™ [see DRUG INTERACTIONS, and OVERDOSAGE].
Patients with Increased Intracranial Pressure or Head Trauma
Use ConZip™ with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ConZip™.
Use in Ambulatory Patients
ConZip™ may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Caution patients initiating therapy with ConZip™ or those whose dose has been increased to refrain from potentially hazardous activities until it is established that their mental and physical abilities are not significantly impaired.
Use With MAO Inhibitors and SSRIs
Use ConZip™ with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of ConZip™ with MAO inhibitors or SSRI's increases the risk of adverse reactions, including seizure and serotonin syndrome.
Withdrawal symptoms may occur if ConZip™ is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience with other formulations of tramadol suggests that withdrawal symptoms may be reduced by tapering ConZip™ when discontinuing tramadol therapy.
Misuse, Abuse and Diversion of Opioids
ConZip™ contains tramadol, an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing ConZip™ in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
ConZip™ could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death [see Drug Abuse And Dependence, and OVERDOSAGE].
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Risk of Overdosage
Serious potential consequences of overdosage with ConZip™ 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].
Acute Abdominal Conditions
The administration of ConZip™ may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Use ConZip™ during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products. ConZip™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (1.6-fold the maximum daily human dose (MDHD)) in rats and 100 mg/kg (approximately 6.5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2.3-fold MDHD), 80 mg/kg in rats (2.6-fold MDHD) or 300 mg/kg in rabbits (approximately 19-fold MDHD).
Tramadol caused a reduction in neonatal body weight at a dose of 50 mg/kg (1.6-fold the MDHD) and reduced pup survival at an oral dose of 80 mg/kg (approximately 2.6-fold MDHD) when rats were treated during late gestation throughout lactation period.
Labor and Delivery
ConZip™ should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn [see Drug Abuse And Dependence]. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
The effect of ConZip™, if any, on the later growth, development, and functional maturation of the child is unknown.
ConZip™ is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg 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. It is not known whether this drug is excreted in human milk following an oral dose.
The safety and efficacy of ConZip™ in patients under 18 years of age have not been established. The use of ConZip™ in the pediatric population is not recommended.
In general, caution should be used when selecting the dose for an elderly patient. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to ConZip™ in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia. For this reason, ConZip™ should be used with great caution in patients older than 75 years of age [see DOSAGE AND ADMINISTRATION].
Patients with Renal Impairment
ConZip™ has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ConZip™ should not be used in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Patients with Hepatic Impairment
ConZip™ has not been studied in patients with hepatic impairment. The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ConZip™ should not be used in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/25/2013
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