Medical Editor: John P. Cunha, DO, FACOEP
What Is ConZip?
ConZip (tramadol hydrochloride) is an analgesic (pain reliever) used to treat moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.
What Are Side Effects of ConZip?
Common side effects of ConZip include:
- trouble sleeping,
- dry mouth,
- loss of appetite,
- spinning sensation,
- itching or skin rash,
- vision problems,
- joint pain, and
Seek medical care or call 911 at once if you have the following serious side effects:
- Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
- Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.
Dosage for ConZip
ConZip is an extended-release formulation intended for once a day dosing, starting at an initial dose of 100 mg once daily and adjusted as necessary by 100 mg increments every five days to achieve a balance between relief of pain and tolerability.
What Drugs, Substances, or Supplements Interact with ConZip?
ConZip may interact with antidepressants, MAOIs, neuroleptics, quinidine, ketoconazole, antibiotics, lithium, St. John's Wort, triptans, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers, sedative hypnotics, digoxin, warfarin, carbamazepine, or rifampin. Tell your doctor all medications and supplements you use.
ConZip During Pregnancy and Breastfeeding
During pregnancy, ConZip should be used only if prescribed. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.
Our ConZip (tramadol hydrochloride) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
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Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning in your eyes, skin pain, red or purple skin rash that spreads and causes blistering and peeling).
Tramadol can slow or stop your breathing, and death may occur. A person caring for you should give naloxone and/or seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.
Call your doctor at once if you have:
- noisy breathing, sighing, shallow breathing, breathing that stops during sleep;
- a slow heart rate or weak pulse;
- a light-headed feeling, like you might pass out;
- seizure (convulsions); or
- low cortisol levels--nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness.
Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.
Serious breathing problems may be more likely in older adults and people who are debilitated or have wasting syndrome or chronic breathing disorders.
Common side effects may include:
- constipation, nausea, vomiting, stomach pain;
- dizziness, drowsiness, tiredness;
- headache; or
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
The following serious or otherwise important adverse reactions are described in greater detail, in other sections:
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Interactions with Benzodiazepines and Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Suicide [see WARNINGS AND PRECAUTIONS]
- Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
- Severe Hypotension [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Withdrawal [see WARNINGS AND PRECAUTIONS]
Clinical Trials 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, double-blind, 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 Double-Blind, 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
Gastrointestinal disorders: dyspepsia, flatulence
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
Nervous system disorders: paresthesia, tremor, withdrawal syndrome
Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness
Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis
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
Cardiac disorders: EKG abnormal, hypotension, tachycardia
Gastrointestinal disorders: gastroenteritis
General disorders: neck rigidity, viral infection
Hematologic/Lymphatic disorders: anemia, ecchymoses
Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased
Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps
Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo
Respiratory disorders: pneumonia
Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria
Special Senses: eye disorder, lacrimation disorder
Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention
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.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in CONZIP.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].
QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting.
Metabolism And Nutrition Disorders
Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see WARNINGS AND PRECAUTIONS].
Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see WARNINGS AND PRECAUTIONS].
Table 2 includes clinically significant drug interactions with CONZIP.
Table 2: Clinically Significant Drug Interactions with CONZIP
|Inhibitors of CYP2D6|
|Clinical Impact:||The concomitant use of CONZIP and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of CONZIP is achieved. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.|
|After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see CLINICAL PHARMACOLOGY].|
|Intervention:||If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.
If a CYP2D6 inhibitor is discontinued, consider lowering CONZIP dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
|Examples:||Quinidine, fluoxetine, paroxetine and bupropion|
|Inhibitors of CYP3A4|
|Clinical Impact :||The concomitant use of CONZIP and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of CONZIP is achieved.|
|After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.|
|Intervention:||If concomitant use is necessary, consider dosage reduction of CONZIP until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the CONZIP dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
|Examples:||Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)|
|Clinical Impact:||The concomitant use of CONZIP and CYP3A4 inducers can decrease the plasma concentration of tramadol, [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see WARNINGS AND PRECAUTIONS].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratorydepression.
|Intervention:||If concomitant use is necessary, consider increasing the CONZIP dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider CONZIP dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression.
|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.|
|Examples:||Rifampin, carbamazepine, phenytoin|
|Benzodiazepines and Other Central Nervous System (CNS) Depressants|
|Clinical Impact:||Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.|
|Intervention:||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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol|
|Clinical Impact:||The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.|
|Intervention:||If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue CONZIP if serotoninsyndrome is suspected.|
|Examples:||Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)|
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact:||MAOI interactions with opioids may manifest as serotonin syndrome [see WARNINGS AND PRECAUTIONS] or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS AND PRECAUTIONS].|
|Intervention:||Do not use CONZIP in patients taking MAOIs or within 14 days of stopping such treatment.|
|Examples:||Phenelzine, tranylcypromine, linezolid|
|Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics|
|Clinical Impact:||May reduce the analgesic effect of CONZIP and/or precipitate withdrawal symptoms.|
|Intervention:||Avoid concomitant use.|
|Examples:||Butorphanol, nalbuphine, pentazocine, buprenorphine|
|Clinical Impact:||Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of CONZIP and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention:||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.|
|Clinical Impact:||The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.|
|Intervention:||Monitor patients for signs of urinary retention or reduced gastric motility when CONZIP is used concomitantly with anticholinergic drugs.|
|Clinical Impact:||Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.|
|Intervention:||Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.|
|Clinical Impact:||Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.|
|Intervention:||Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.|
Drug Abuse And Dependence
CONZIP contains tramadol, a Schedule IV controlled substance.
CONZIP contains tramadol, a substance with a high potential for abuse similar to other opioids, and can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].
The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.
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 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 healthcare providers. "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.
CONZIP, 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.
Risks Specific to Abuse of CONZIP
CONZIP is for oral use only. The abuse of CONZIP poses a risk of overdose and death. The risk is increased with concurrent use of CONZIP with alcohol and other central nervous system depressants. With intravenous abuse, the inactive ingredients in CONZIP can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, 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.
Both tolerance and physical dependence can develop during chronic opioid therapy. 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). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting 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 (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioidusage.
Do not abruptly discontinue CONZIP in a patient physically dependent on opioids. Rapid tapering of CONZIP in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.
When discontinuing CONZIP, gradually taper the dosage using a patient-specific plan that considers the following: the dose of CONZIP the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use In Specific Populations].
Read the entire FDA prescribing information for ConZip (Tramadol Hydrochloride Extended-release Capsules)
© ConZip Patient Information is supplied by Cerner Multum, Inc. and ConZip Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.
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