"July 10, 2015 -- Popular painkillers like ibuprofen and naproxen have carried warnings for years about potential risks of heart attacks and strokes. This week, the FDA decided to strengthen those warnings on the medications, known as nonsteroidal"...
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 Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Hypotensive Effect [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Conditions [see WARNINGS AND PRECAUTIONS]
- Seizures [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)
|Preferred Term||Open-Label Titration Period||Double-Blind Treatment Period|
(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
Read the Zohydro ER (hydrocodone bitartrate extended release capsules) Side Effects Center for a complete guide to possible side effects
Concomitant use of alcohol with ZOHYDRO ER can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on ZOHYDRO ER therapy [see CLINICAL PHARMACOLOGY].
The concomitant use of ZOHYDRO ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, can increase the risk of respiratory depression, profound sedation, coma, or death. Monitor patients receiving CNS depressants and ZOHYDRO ER for signs of respiratory depression, sedation, and hypotension.
Drugs Affecting Cytochrome P450 Isoenzymes
Inhibitors of CYP3A4 and 2D6
Because the CYP3A4 isoenzyme plays a major role in the metabolism of hydrocodone, drugs that inhibit CYP3A4 activity may cause decreased clearance of hydrocodone which could lead to an increase in hydrocodone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with ZOHYDRO ER is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see CLINICAL PHARMACOLOGY].
Inducers of CYP3A4
Cytochrome P450 3A4 inducers may induce the metabolism of hydrocodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration with ZOHYDRO ER is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see CLINICAL PHARMACOLOGY].
After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression [see CLINICAL PHARMACOLOGY].
Interactions With Mixed Agonist/Antagonist Opioid Analgesics
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of hydrocodone or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving ZOHYDRO ER.
Monoamine Oxidase Inhibitors
The effects of opioid analgesics may be potentiated by monoamine oxidase (MAO) inhibitors. ZOHYDRO ER is not recommended for use in patients who have received MAO inhibitors within 14 days as severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. No specific interaction between hydrocodone and MAO inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.
Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may increase the risk of urinary retention or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention and constipation in addition to respiratory and central nervous system depression when ZOHYDRO ER is used concurrently with anticholinergic drugs.
Drug Abuse And Dependence
ZOHYDRO ER contains hydrocodone bitartrate, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. The high drug content in the extended-release formulation 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.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common to addicts and drug abusers. Drug seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people with untreated addiction, and criminals seeking drugs to sell. 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. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
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 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, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose 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 (pentazocine, butorphanol, nalbuphine), or partial agonists (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, an abstinence 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 symptoms [see Use In Specific Populations].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/28/2015
Additional Zohydro ER Information
Report Problems to the Food and Drug Administration
Chronic Pain/Back Pain
Find tips and advances in treatment.