"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.
The following serious or otherwise important adverse reactions are described in greater detail, in other sections:
- Seizure risk [see WARNINGS AND PRECAUTIONS]
- Suicide risk [see WARNINGS AND PRECAUTIONS]
- Serotonin syndrome [see WARNINGS AND PRECAUTIONS]
- Anaphylactoid and allergic reactions [see WARNINGS AND PRECAUTIONS]
- Respiratory depression [see WARNINGS AND PRECAUTIONS]
- Withdrawal symptoms [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ConZip™ capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, doubleblind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table 1).
Table 1: Incidence (%) of patients with adverse
reaction rates ≥ 5% from four doubleblind, placebo controlled studies in
patients with moderate to moderately severe chronic pain by dose (N=1917).
|Headache||99 (23.1)||96 (22.1)||200 (19.0)||128 (19.8)|
|Nausea||69 (16.1)||93 (21.4)||265 (25.1)||37 (5.7)|
|Somnolence||50 (11.7)||60 (13.8)||170 (16.1)||26 (4.0)|
|Dizziness||41 (9.6)||54 (12.4)||143 (13.6)||31 (4.8)|
|Constipation||40 (9.3)||59 (13.6)||225 (21.3)||27 (4.2)|
|Vomiting||28 (6.5)||45 (10.4)||98 (9.3)||12 (1.9)|
|Arthralgia||23 (5.4)||20 (4.6)||53 (5.0)||33 (5.1)|
|Dry Mouth||20 (4.7)||36 (8.3)||138 (13.1)||22 (3.4)|
|Sweating||18 (4.2)||23 (5.3)||71 (6.7)||4 (0.6)|
|Asthenia||15 (3.5)||26 (6.0)||91 (8.6)||17 (2.6)|
|Pruritus||13 (3.0)||25 (5.8)||77 (7.3)||12 (1.9)|
|Anorexia||9 (2.1)||23 (5.3)||60 (5.7)||1 (0.2)|
|Insomnia||9 (2.1)||9 (2.1)||53 (5.0)||11 (1.7)|
The following adverse reactions were reported from all chronic pain studies (N=1917). The lists below include adverse reactions not otherwise noted in Table 1.
Adverse reactions with incidence rates of 1.0% to < 5.0%
Cardiac disorders: hypertension
General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain
Investigations: hyperglycemia, urine abnormality
Metabolism and nutrition disorders: peripheral edema, weight loss
Musculoskeletal, connective tissue and bone disorders: myalgia
Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness
Skin and subcutaneous tissue disorders: rash
Urogenital disorders: prostatic disorder, urinary tract infection
Vascular disorders: vasodilatation
Adverse reactions with incidence rates of 0.5% to < 1.0% at any dose and serious adverse reactions reported in at least two patients.
Gastrointestinal disorders: gastroenteritis
General disorders: neck rigidity, viral infection
Hematologic/Lymphatic disorders: anemia, ecchymoses
Respiratory disorders: pneumonia
Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria
Special Senses: eye disorder, lacrimation disorder
Read the ConZip (tramadol hydrochloride extended-release capsules) Side Effects Center for a complete guide to possible side effects
Drugs Affecting Seizure Threshold
Concomitant use of tramadol increases the seizure risk in patients taking SSRI/SNRI antidepressants or anorectics, TCA antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics or other drugs that lower the seizure threshold [see WARNINGS AND PRECAUTIONS].
CYP2D6 and/or CYP3A4 inhibitors
Tramadol is metabolized by CYP2D6 to form the active metabolite, O-desmethyl tramadol (M1). In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
Tramadol is also metabolized by CYP3A4 [see CLINICAL PHARMACOLOGY]. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin with ConZip™ may affect the metabolism of tramadol leading to altered tramadol exposure.
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome [see CLINICAL PHARMACOLOGY].
There have been post-marketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when ConZip™ is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of ConZip™ 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 [see WARNINGS AND PRECAUTIONS].
Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ConZip™ is co-administered with a triptan. If concomitant treatment of ConZip™ with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS].
Interaction With Central Nervous System (CNS) Depressants
ConZip™ should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ConZip™ increases the risk of CNS and respiratory depression in these patients [see WARNINGS AND PRECAUTIONS].
Quinidine is a strong inhibitor of CYP2D6. Coadministration of quinidine with an extended-release tramadol product resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown. [see CLINICAL PHARMACOLOGY]. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Digoxin and Warfarins
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Administration of CYP3A4 inducers, such as carbamazepine, rifampin and St. John's Wort, with ConZip™ may affect the metabolism of tramadol leading to reduced tramadol exposure [see CLINICAL PHARMACOLOGY].
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ConZip™ and carbamazepine is not recommended.
Drug Abuse And Dependence
ConZip™ is not a Controlled Substance.
ConZip™ contains tramadol, a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. 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” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians 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 and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. ConZip™, like other opioids, may be diverted for non-medical use. Careful record keeping of prescribing information, including quantity, frequency, and renewal requests 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.
ConZip™ is intended for oral use only. The crushed capsule poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the capsule excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Use in Drug and Alcohol Addiction
ConZip™ is an opioid with no approved use for 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. Concerns about abuse and addiction should not prevent the proper management of pain. However 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.
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other 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.
Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous opioid therapy.
Withdrawal symptoms may occur if ConZip™ is discontinued abruptly. Onset of adverse events are likely to occur after treatment is stopped. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experiences with tramadol suggests that withdrawal symptoms may be reduced by tapering ConZip™ when discontinuing tramadol therapy [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 4/25/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional ConZip Information
Report Problems to the Food and Drug Administration
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Chronic Pain/Back Pain
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