These Highlights Do Not Include All The Information Needed To Use Conzip®

Addiction, Abuse, and Misuse

Because the use of CONZIP exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Dispense in a tight container. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.

Store CONZIP securely and dispose of properly.

CONZIP contains tramadol, a substance with potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of CONZIP increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of CONZIP with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of CONZIP abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use CONZIP in combination with other abused drugs.

"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 provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

CONZIP, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

CONZIP (tramadol hydrochloride) is an opioid agonist in an extended-release oral formulation. The chemical name for tramadol hydrochloride USP is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

Figure 1

The molecular weight of tramadol hydrochloride USP is 299.8. It is a white, bitter, crystalline and odorless powder that is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7.

CONZIP capsules contain a total dose of tramadol hydrochloride 100, 200, and 300 mg in a combination of immediate-release and extended-release components.

CONZIP capsules are white in color. Inactive ingredients include gelatin, titanium dioxide, shellac, FD & C Blue #2 aluminum lake (E132) (100 and 200 mg capsules), D & C Red #7 calcium lake (E180) (200 and 300 mg capsules), D & C Yellow #10 aluminum lake (300 mg capsule), lactose monohydrate 200 mesh, microcrystalline cellulose, povidone K30, corn starch, sodium starch glycolate, magnesium stearate, sucrose stearate, hypromellose, talc, polysorbate 80, Eudragit NE 30D, and simethicone emulsion.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal 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 use.

Do not rapidly reduce or 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 an extended period of time 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 (2.5) , Warnings and Precautions (5.18)].

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 (8.1)].

Do not rapidly reduce or abruptly discontinue CONZIP in a patient physically dependent on opioids. When discontinuing CONZIP in a physically-dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) , Drug Abuse and Dependence (9.3)].

Additionally, 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 CONZIP. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing CONZIP, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue CONZIP [see Drug Abuse and Dependence (9.3)].

• 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 (9.2)].
• Prescribe CONZIP with caution for patients with a history of misuse and/or who are currently 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 (7)].
• Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration (2.1) , Warnings and Precautions (5.3)].

Hyponatremia (serum sodium <135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level <120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Assess patients for signs and symptoms of hyponatremia (e.g., confusion, disorientation) during treatment with CONZIP, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue CONZIP [see Dosage and Administration (2.5)].

Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g., diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration (2.5)].

The safety and effectiveness of CONZIP in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions (5.6)]. In some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. Because of the risk of life-threatening respiratory depression and death:

• CONZIP is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• CONZIP is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)].
• Avoid the use of CONZIP 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 [see Warnings and Precautions (5.6)].

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 (2.3)].

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of CONZIP slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.12)].

Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

It is safer to underestimate a patient's 24-hour tramadol requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour tramadol dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to CONZIP.

CONZIP is bioequivalent under fasting conditions to another extended-release tramadol product [see Clinical Pharmacology (12.3)] which demonstrated efficacy in two of four clinical trials of patients with chronic pain. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 - 100 mm visual analog scale (VAS).

In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment with the extended-release tramadol product was initiated at 100 mg once daily for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in active treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 2).

Figure 2

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day. Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (VAS) score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving the extended-release tramadol product and placebo (see Figure 3).

Figure 3

Four randomized, placebo-controlled clinical trials of CONZIP were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described. Two trials were 12-week randomized placebo-controlled trials of CONZIP 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied CONZIP 300 mg/day. In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose.

CONZIP is contraindicated for:

• All children younger than 12 years of age [see Warnings and Precautions (5.6)]
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6)]

CONZIP is also contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.12)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.12)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.16)]
• Hypersensitivity to tramadol (e.g., anaphylaxis) [see Warnings and Precautions (5.17) , Adverse Reactions (6)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [see Drug Interactions (7)]

The following serious or otherwise important adverse reactions are described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]
• Serotonin Syndrome [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Suicide [see Warnings and Precautions (5.11)]
• Adrenal Insufficiency [see Warnings and Precautions (5.13)]
• Severe Hypotension [see Warnings and Precautions (5.14)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.16)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.17)]
• Withdrawal [see Warnings and Precautions (5.18)]

Table 2 includes clinically significant drug interactions with CONZIP.

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 (Child-Pugh Class C). Therefore, CONZIP should not be used in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. CONZIP is administered as a racemate and both tramadol and M1 are detected in the circulation. The C_max and AUC of CONZIP capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. 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 (Child-Pugh Class C). Therefore, CONZIP should not be used in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

CONZIP is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

CONZIP 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 Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of CONZIP. In patients with circulatory shock, CONZIP may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of CONZIP in patients with circulatory shock.

CONZIP contains tramadol, an opioid agonist, and an inhibitor of reuptake of norepinephrine and serotonin. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to mu-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed.

CONZIP contains tramadol, a Schedule IV controlled substance.

• Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.8)
• Serotonin Syndrome Risk: Potentially life-threatening condition could result from use of CONZIP, particularly during concomitant use of serotonergic drugs. (5.9)
• Increased Risk of Seizures: Present within recommended dosage range. Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. (5.10, 7)
• Suicide Risk: Do not use CONZIP in suicidal or addiction-prone patients. Use with caution in those taking tranquilizers, antidepressants or abuse alcohol. (5.11)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.12)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.13)
• Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of CONZIP in patients with circulatory shock. (5.14)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of CONZIP in patients with impaired consciousness or coma. (5.15)

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.

• CONZIP should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (2.1)
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of CONZIP for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2, 5)
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with CONZIP. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2)
• CONZIP is administered orally once daily. (2.1)
• Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with CONZIP, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3)
• For patients currently on tramadol IR: Calculate total 24-hr IR dose, and initiate CONZIP at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. (2.3, 2.4)
• For patients converting from other opioid analgesics: Discontinue all other opioid analgesics other than as needed for breakthrough pain and initiate CONZIP at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance. (2.3, 2.4)
• Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. (2.4)
• Periodically reassess patients receiving CONZIP to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.4)
• Do not rapidly reduce or abruptly discontinue CONZIP in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5, 5.18)

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol products, including CONZIP, 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. 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 CONZIP if serotonin syndrome is suspected.

Extended-release capsules are available as:

100 mg Capsules: White capsule imprinted with blue ink "G 252" on cap and "100" between lines on the body

200 mg Capsules: White capsule imprinted with violet ink "G 253" on cap and "200" between lines on the body

300 mg Capsules: White capsule imprinted with red ink "G 254" on cap and "300" between lines on the body

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.

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)
• Severe Hepatic or Renal Impairment: Use not recommended. (8.6, 8.7)

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).

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.

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 (7)]

• Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
• Other opioids,
• Monoamine oxidase inhibitors (MAOIs) [see Warnings and Precautions (5.9) , Drug Interactions (7)],
• 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, administration of an opioid overdose reversal agent (e.g., naloxone or nalmefene) may increase the risk of seizure.

CONZIP contains tramadol, a Schedule IV controlled substance. As an opioid, CONZIP exposes users to the risks of addiction, abuse and misuse.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed CONZIP. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing CONZIP, and reassess all patients receiving CONZIP 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 CONZIP but use in such patients necessitates intensive counseling about the risks and proper use of CONZIP along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2)].

Abuse or misuse of CONZIP by splitting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see Overdosage (10)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing CONZIP. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

CONZIP (tramadol hydrochloride) capsules are supplied as opaque white hard gelatin capsules, imprinted as follows.

Individually titrate CONZIP by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. The maximum daily dose of CONZIP is 300 mg per day.

Continually reevaluate patients receiving CONZIP to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.18)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of CONZIP or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the CONZIP dosage.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the CONZIP dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Use of CONZIP for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

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 overdose reversal agents, depending on the patient's clinical status [see Overdosage (10)]. 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 CONZIP, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of CONZIP are essential [see Dosage and Administration (2)]. Overestimating the CONZIP 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 CONZIP, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

CONZIP is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

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

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate. [see Clinical Pharmacology (12.2)].

CONZIP 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 CONZIP and know how they will react to the medication.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5) , Warnings and Precautions (5.18)].

Do not rapidly reduce or abruptly discontinue CONZIP in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking CONZIP, there are a variety of factors that should be considered, including the total daily dose of opioid (including CONZIP) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on CONZIP who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.18) , Drug Abuse and Dependence (9.3)].

• CONZIP should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
• Do not use CONZIP concomitantly with other tramadol products [see Warnings and Precautions (5.7), (5.15)].
• Do not administer CONZIP at a dose exceeding 300 mg per day.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of CONZIP for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with CONZIP. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2)].
• CONZIP is administered orally once daily.
• Instruct patients to swallow CONZIP capsules whole, and to take it with liquid. Breaking, chewing, splitting, or dissolving CONZIP capsules will result in uncontrolled delivery of tramadol and can lead to overdose or death [see Warnings and Precautions (5.1)].
• CONZIP may be taken without regard to food. It is recommended that CONZIP be taken in a consistent manner [see Clinical Pharmacology (12.3)].

Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur, it is often following the first dose. Other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive CONZIP. If anaphylaxis or other hypersensitivity occurs, stop administration of CONZIP immediately, discontinue CONZIP 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 (4)].

NDC 68025-071-30

ConZip^®

(tramadol hydrochloride)

extended-release capsules

CIV

100 mg per capsule

Once daily

Rx Only

VERTICAL

PHARMACEUTICALS, LLC

30 Capsules

NDC 68025-072-30

ConZip^®

(tramadol hydrochloride)

extended-release capsules

CIV

200 mg per capsule

Once daily

Rx Only

VERTICAL

PHARMACEUTICALS, LLC

30 Capsules

NDC 68025-073-30

ConZip^®

(tramadol hydrochloride)

extended-release capsules

CIV

300 mg per capsule

Once daily

Rx Only

VERTICAL

PHARMACEUTICALS, LLC

30 Capsules

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF CONZIP

See full prescribing information for complete boxed warning.

• CONZIP exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration are essential. Instruct patients to swallow CONZIP capsules intact, and not to split, chew, crush, or dissolve content of the capsules to avoid exposure to a potentially fatal dose of tramadol. (2.1, 5.2)
• Accidental ingestion of CONZIP, especially by children, can result in a fatal overdose of tramadol. (5.2)
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.3, 7)
• Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4)
• Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (5.5)
• CONZIP is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) Avoid the use of CONZIP 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. (5.6)
• The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with CONZIP requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. (5.7, 7)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from CONZIP are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with CONZIP requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and mu-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in mu-opioid receptor binding [see Drug Interactions (7)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of CONZIP with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin and pregabalin], and other opioids). 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 Drug Interactions (7)].

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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when CONZIP 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 depressants 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 (7)].

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.2, 5.3) ].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2)].

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

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:

• CONZIP is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• CONZIP is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)].
• Avoid the use of CONZIP 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 Use in Specific Populations (8.4) , Overdosage (10)].

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), CONZIP 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 CONZIP.

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

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

Addiction, Abuse, and Misuse

Because the use of CONZIP exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Dispense in a tight container. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.

Store CONZIP securely and dispose of properly.

CONZIP contains tramadol, a substance with potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of CONZIP increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of CONZIP with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of CONZIP abuse include those with a history of prolonged use of any opioid, including products containing tramadol, those with a history of drug or alcohol abuse, or those who use CONZIP in combination with other abused drugs.

"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 provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

CONZIP, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

CONZIP (tramadol hydrochloride) is an opioid agonist in an extended-release oral formulation. The chemical name for tramadol hydrochloride USP is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

Figure 1

The molecular weight of tramadol hydrochloride USP is 299.8. It is a white, bitter, crystalline and odorless powder that is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7.

CONZIP capsules contain a total dose of tramadol hydrochloride 100, 200, and 300 mg in a combination of immediate-release and extended-release components.

CONZIP capsules are white in color. Inactive ingredients include gelatin, titanium dioxide, shellac, FD & C Blue #2 aluminum lake (E132) (100 and 200 mg capsules), D & C Red #7 calcium lake (E180) (200 and 300 mg capsules), D & C Yellow #10 aluminum lake (300 mg capsule), lactose monohydrate 200 mesh, microcrystalline cellulose, povidone K30, corn starch, sodium starch glycolate, magnesium stearate, sucrose stearate, hypromellose, talc, polysorbate 80, Eudragit NE 30D, and simethicone emulsion.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal 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 use.

Do not rapidly reduce or 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 an extended period of time 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 (2.5) , Warnings and Precautions (5.18)].

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 (8.1)].

Do not rapidly reduce or abruptly discontinue CONZIP in a patient physically dependent on opioids. When discontinuing CONZIP in a physically-dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) , Drug Abuse and Dependence (9.3)].

Additionally, 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 CONZIP. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing CONZIP, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue CONZIP [see Drug Abuse and Dependence (9.3)].

• 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 (9.2)].
• Prescribe CONZIP with caution for patients with a history of misuse and/or who are currently 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 (7)].
• Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration (2.1) , Warnings and Precautions (5.3)].

Hyponatremia (serum sodium <135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level <120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Assess patients for signs and symptoms of hyponatremia (e.g., confusion, disorientation) during treatment with CONZIP, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue CONZIP [see Dosage and Administration (2.5)].

Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g., diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration (2.5)].

The safety and effectiveness of CONZIP in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions (5.6)]. In some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol. Because of the risk of life-threatening respiratory depression and death:

• CONZIP is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• CONZIP is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)].
• Avoid the use of CONZIP 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 [see Warnings and Precautions (5.6)].

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 (2.3)].

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of CONZIP slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.12)].

Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

It is safer to underestimate a patient's 24-hour tramadol requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour tramadol dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to CONZIP.

CONZIP is bioequivalent under fasting conditions to another extended-release tramadol product [see Clinical Pharmacology (12.3)] which demonstrated efficacy in two of four clinical trials of patients with chronic pain. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 - 100 mm visual analog scale (VAS).

In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment with the extended-release tramadol product was initiated at 100 mg once daily for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in active treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 2).

Figure 2

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day. Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (VAS) score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving the extended-release tramadol product and placebo (see Figure 3).

Figure 3

Four randomized, placebo-controlled clinical trials of CONZIP were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described. Two trials were 12-week randomized placebo-controlled trials of CONZIP 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied CONZIP 300 mg/day. In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose.

CONZIP is contraindicated for:

• All children younger than 12 years of age [see Warnings and Precautions (5.6)]
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6)]

CONZIP is also contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.12)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.12)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.16)]
• Hypersensitivity to tramadol (e.g., anaphylaxis) [see Warnings and Precautions (5.17) , Adverse Reactions (6)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [see Drug Interactions (7)]

The following serious or otherwise important adverse reactions are described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]
• Serotonin Syndrome [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Suicide [see Warnings and Precautions (5.11)]
• Adrenal Insufficiency [see Warnings and Precautions (5.13)]
• Severe Hypotension [see Warnings and Precautions (5.14)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.16)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.17)]
• Withdrawal [see Warnings and Precautions (5.18)]

Table 2 includes clinically significant drug interactions with CONZIP.

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 (Child-Pugh Class C). Therefore, CONZIP should not be used in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. CONZIP is administered as a racemate and both tramadol and M1 are detected in the circulation. The C_max and AUC of CONZIP capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. 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 (Child-Pugh Class C). Therefore, CONZIP should not be used in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

CONZIP is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

CONZIP 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 Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of CONZIP. In patients with circulatory shock, CONZIP may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of CONZIP in patients with circulatory shock.

CONZIP contains tramadol, an opioid agonist, and an inhibitor of reuptake of norepinephrine and serotonin. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to mu-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed.

CONZIP contains tramadol, a Schedule IV controlled substance.

• Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.8)
• Serotonin Syndrome Risk: Potentially life-threatening condition could result from use of CONZIP, particularly during concomitant use of serotonergic drugs. (5.9)
• Increased Risk of Seizures: Present within recommended dosage range. Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures. (5.10, 7)
• Suicide Risk: Do not use CONZIP in suicidal or addiction-prone patients. Use with caution in those taking tranquilizers, antidepressants or abuse alcohol. (5.11)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.12)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.13)
• Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of CONZIP in patients with circulatory shock. (5.14)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of CONZIP in patients with impaired consciousness or coma. (5.15)

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.

• CONZIP should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (2.1)
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of CONZIP for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2, 5)
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with CONZIP. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2)
• CONZIP is administered orally once daily. (2.1)
• Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with CONZIP, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3)
• For patients currently on tramadol IR: Calculate total 24-hr IR dose, and initiate CONZIP at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. (2.3, 2.4)
• For patients converting from other opioid analgesics: Discontinue all other opioid analgesics other than as needed for breakthrough pain and initiate CONZIP at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance. (2.3, 2.4)
• Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. (2.4)
• Periodically reassess patients receiving CONZIP to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.4)
• Do not rapidly reduce or abruptly discontinue CONZIP in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5, 5.18)

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol products, including CONZIP, 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. 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 CONZIP if serotonin syndrome is suspected.

Extended-release capsules are available as:

100 mg Capsules: White capsule imprinted with blue ink "G 252" on cap and "100" between lines on the body

200 mg Capsules: White capsule imprinted with violet ink "G 253" on cap and "200" between lines on the body

300 mg Capsules: White capsule imprinted with red ink "G 254" on cap and "300" between lines on the body

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.

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)
• Severe Hepatic or Renal Impairment: Use not recommended. (8.6, 8.7)

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).

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.

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 (7)]

• Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
• Other opioids,
• Monoamine oxidase inhibitors (MAOIs) [see Warnings and Precautions (5.9) , Drug Interactions (7)],
• 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, administration of an opioid overdose reversal agent (e.g., naloxone or nalmefene) may increase the risk of seizure.

CONZIP contains tramadol, a Schedule IV controlled substance. As an opioid, CONZIP exposes users to the risks of addiction, abuse and misuse.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed CONZIP. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing CONZIP, and reassess all patients receiving CONZIP 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 CONZIP but use in such patients necessitates intensive counseling about the risks and proper use of CONZIP along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2)].

Abuse or misuse of CONZIP by splitting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see Overdosage (10)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing CONZIP. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

CONZIP (tramadol hydrochloride) capsules are supplied as opaque white hard gelatin capsules, imprinted as follows.

Individually titrate CONZIP by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. The maximum daily dose of CONZIP is 300 mg per day.

Continually reevaluate patients receiving CONZIP to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.18)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of CONZIP or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the CONZIP dosage.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the CONZIP dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Use of CONZIP for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

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 overdose reversal agents, depending on the patient's clinical status [see Overdosage (10)]. 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 CONZIP, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of CONZIP are essential [see Dosage and Administration (2)]. Overestimating the CONZIP 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 CONZIP, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

CONZIP is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

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

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate. [see Clinical Pharmacology (12.2)].

CONZIP 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 CONZIP and know how they will react to the medication.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5) , Warnings and Precautions (5.18)].

Do not rapidly reduce or abruptly discontinue CONZIP in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking CONZIP, there are a variety of factors that should be considered, including the total daily dose of opioid (including CONZIP) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on CONZIP who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.18) , Drug Abuse and Dependence (9.3)].

• CONZIP should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
• Do not use CONZIP concomitantly with other tramadol products [see Warnings and Precautions (5.7), (5.15)].
• Do not administer CONZIP at a dose exceeding 300 mg per day.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of CONZIP for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with CONZIP. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2)].
• CONZIP is administered orally once daily.
• Instruct patients to swallow CONZIP capsules whole, and to take it with liquid. Breaking, chewing, splitting, or dissolving CONZIP capsules will result in uncontrolled delivery of tramadol and can lead to overdose or death [see Warnings and Precautions (5.1)].
• CONZIP may be taken without regard to food. It is recommended that CONZIP be taken in a consistent manner [see Clinical Pharmacology (12.3)].

Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur, it is often following the first dose. Other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive CONZIP. If anaphylaxis or other hypersensitivity occurs, stop administration of CONZIP immediately, discontinue CONZIP 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 (4)].

NDC 68025-071-30

ConZip^®

(tramadol hydrochloride)

extended-release capsules

CIV

100 mg per capsule

Once daily

Rx Only

VERTICAL

PHARMACEUTICALS, LLC

30 Capsules

NDC 68025-072-30

ConZip^®

(tramadol hydrochloride)

extended-release capsules

CIV

200 mg per capsule

Once daily

Rx Only

VERTICAL

PHARMACEUTICALS, LLC

30 Capsules

NDC 68025-073-30

ConZip^®

(tramadol hydrochloride)

extended-release capsules

CIV

300 mg per capsule

Once daily

Rx Only

VERTICAL

PHARMACEUTICALS, LLC

30 Capsules

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF CONZIP

See full prescribing information for complete boxed warning.

• CONZIP exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration are essential. Instruct patients to swallow CONZIP capsules intact, and not to split, chew, crush, or dissolve content of the capsules to avoid exposure to a potentially fatal dose of tramadol. (2.1, 5.2)
• Accidental ingestion of CONZIP, especially by children, can result in a fatal overdose of tramadol. (5.2)
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.3, 7)
• Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4)
• Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (5.5)
• CONZIP is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) Avoid the use of CONZIP 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. (5.6)
• The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with CONZIP requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. (5.7, 7)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from CONZIP are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with CONZIP requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and mu-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in mu-opioid receptor binding [see Drug Interactions (7)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of CONZIP with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin and pregabalin], and other opioids). 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 Drug Interactions (7)].

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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when CONZIP 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 depressants 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 (7)].

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.2, 5.3) ].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2)].

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

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:

• CONZIP is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• CONZIP is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)].
• Avoid the use of CONZIP 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 Use in Specific Populations (8.4) , Overdosage (10)].

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), CONZIP 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 CONZIP.

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

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