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The following serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Interactions with Benzodiazepines and Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
- Severe Hypotension [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Withdrawal [see WARNINGS AND PRECAUTIONS]
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of ZOHYDRO ER was evaluated in a total of 1,148 subjects in Phase 3 clinical trials.
Table 3 lists the most frequently occurring adverse reactions occurring at a greater frequency than placebo from the placebo-controlled trial in subjects with moderate-to-severe chronic lower back pain.
Table 3. Treatment-Emergent Adverse Events in ≥2% of Subjects During the Open-Label Titration Period and/or the Double-Blind Treatment Period, by Preferred Term — Number (%) of Treated Subjects (Placebo-Controlled Study in Opioid-Experienced Subjects with Moderate-to-Severe Chronic Lower Back Pain)
|Open-Label Titration Period||Double-Blind Treatment Period|
|ZOHYDRO ER||ZOHYDRO ER||Placebo|
|Preferred Term||(N = 510)||(n = 151)||(n = 151)|
|Constipation||56 (11%)||12 (8%)||0 (0%)|
|Nausea||50 (10%)||11 (7%)||5 (3%)|
|Somnolence||24 (5%)||1 (1%)||0 (0%)|
|Fatigue||21 (4%)||1 (1%)||2 (1%)|
|Headache||19 (4%)||0 (0%)||2 (1%)|
|Dizziness||17 (3%)||3 (2%)||1 (1%)|
|Dry mouth||16 (3%)||0 (0%)||0 (0%)|
|Vomiting||14 (3%)||7 (5%)||1 (1%)|
|Pruritus||13 (3%)||0 (0%)||0 (0%)|
|Abdominal pain||8 (2%)||4 (3%)||0 (0%)|
|Edema peripheral||7 (1%)||4 (3%)||0 (0%)|
|Upper respiratory tract infection||7 (1%)||5 (3%)||1 (1%)|
|Muscle spasms||6 (1%)||4 (3%)||2 (1%)|
|Urinary tract infection||4 (1%)||8 (5%)||3 (2%)|
|Back pain||4 (1%)||6 (4%)||5 (3%)|
|Tremor||1 (0%)||4 (3%)||1 (1%)|
The common (≥1% to <10%) adverse drug reactions reported at least once by subjects treated with ZOHYDRO ER in the Phase 3 clinical trials and not represented in Table 3 were:
Gastrointestinal Disorders: abdominal discomfort, abdominal pain, gastroesophageal reflux disease
General Disorders and Administration Site Conditions: non-cardiac chest pain, pain, peripheral edema, pyrexia
Investigations: increased blood cholesterol, increased gamma-glutamyltransferase
Metabolism and Nutrition Disorders: dehydration, hypokalemia
Psychiatric Disorders: anxiety, depression, insomnia
Respiratory, Thoracic, and Mediastinal Disorders: cough, dyspnea
Vascular Disorders: hot flush
The following adverse reactions have been identified during post approval use of hydrocodone. 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.
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis has been reported with ingredients contained in ZOHYDRO ER.
Read the Zohydro ER (hydrocodone bitartrate extended release capsules) Side Effects Center for a complete guide to possible side effects
|Clinical Impact:||Concomitant use of alcohol with ZOHYDRO ER can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone.|
|Intervention:||Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on ZOHYDRO ER therapy [see CLINICAL PHARMACOLOGY|
|Inhibitors of CYP3A4 and CYP2D6|
The concomitant use of ZOHYDRO ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of ZOHYDRO ER and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of ZOHYDRO ER is achieved [see WARNINGS AND PRECAUTIONS].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
If concomitant use is necessary, consider dosage reduction of ZOHYDRO ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the ZOHYDRO ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
|Examples:||Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)|
The concomitant use of ZOHYDRO ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see WARNINGS AND PRECAUTIONS].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
|Intervention:||If concomitant use is necessary, consider increasing the ZOHYDRO ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ZOHYDRO ER dosage reduction and monitor for signs of respiratory depression.|
|Examples:||Rifampin, carbamazepine, phenytoin|
|Benzodiazepines and other Central Nervous System (CNS) Depressants|
|Clinical Impact:||Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.|
|Intervention:||Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS AND PRECAUTIONS]|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.|
|Clinical Impact:||The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.|
|Intervention:||If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ZOHYDRO ER if serotonin syndrome is suspected.|
|Examples:||Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).|
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact:||MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see DRUG INTERACTIONS].|
|Intervention:||The use of ZOHYDRO ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.|
|Examples:||Phenelzine, tranylcypromine, linezolid|
|Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics|
|Clinical Impact:||May reduce the analgesic effect of ZOHYDRO ER and/or precipitate withdrawal symptoms.|
|Intervention:||Avoid concomitant use.|
|Examples:||butorphanol, nalbuphine, pentazocine, buprenorphine|
|Clinical Impact:||Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ZOHYDRO ER and/or the muscle relaxant as necessary.|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention:||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.|
|Clinical Impact:||The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.|
|Intervention:||Monitor patients for signs of urinary retention or reduced gastric motility when ZOHYDRO ER is used concomitantly with anticholinergic drugs.|
ZOHYDRO ER contains hydrocodone bitartrate, a Schedule II controlled substance.
ZOHYDRO ER contains hydrocodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. ZOHYDRO ER can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].
The high drug content in extended release formulations adds to the risk of adverse outcomes from abuse and misuse.
All patients treated with opioids require careful monitoring for signs of abuse and addiction as use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use then to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
"Drug-seeking" behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people with untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
ZOHYDRO ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing, storage, and disposal are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific To Abuse Of ZOHYDRO ER
ZOHYDRO ER is for oral use only. Abuse of ZOHYDRO ER poses a risk of overdose and death. The risk is increased with concurrent use of ZOHYDRO ER with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved ZOHYDRO ER enhances drug release and increases the risk of overdose and death.
With intravenous abuse, the inactive ingredients in ZOHYDRO ER can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (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 opioid usage.
ZOHYDRO ER should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If ZOHYDRO ER is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use In Specific Populations].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/6/2017
Additional Zohydro ER Information
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