Each hydrocodone bitartrate and ibuprofen tablet contains:

Hydrocodone Bitartrate, USP  7.5 mg

Ibuprofen, USP    200 mg



Hydrocodone Bitartrate and Ibuprofen Tablets are supplied in a fixed combination tablet form for oral administration. Hydrocodone Bitartrate and Ibuprofen Tablets combines the opioid agonist agent, hydrocodone bitartrate, with the nonsteroidal anti-inflammatory (NSAID) agent, ibuprofen.



Hydrocodone bitartrate is a semisynthetic opioid agonist. Its chemical name is: 4,5 α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). Its chemical formula is: C18H21NO3•C4H6O6•2½H2O, and the molecular weight is 494.50. Its structural formula is:

Ibuprofen is a non-steroidal anti-inflammatory agent [non-selective COX inhibitor] with analgesic and antipyretic properties. Its chemical name is: (±)-2-(p-isobutylphenyl) propionic acid. Its chemical formula is: C13H18O2, and the molecular weight is: 206.29. Its structural formula is:

Inactive ingredients in Hydrocodone Bitartrate and Ibuprofen tablets include: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, sodium starch glycolate, sodium lauryl sulfate, polysorbate 80, hypromellose, titanium dioxide and polyethylene glycol.

Mechanism of Action

Hydrocodone Component

Hydrocodone  is  a  full  opioid  agonist  with  relative  selectivity  for  the  mu-opioid  receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with hydrocodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.



Ibuprofen Component

Ibuprofen has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action, like that of other NSAIDs, is not completely understood, but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Ibuprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.



Pharmacodynamics

Effects on the Central Nervous System

Hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.



Effects on the Gastrointestinal Tract and Other Smooth Muscle

Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid- induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.



Effects on the Cardiovascular System

Hydrocodone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.



Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans (see ADVERSE REACTIONS: Post marketing Experience). They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date (see ADVERSE REACTIONS: Post marketing Experience).



Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in both in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.



Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance (seeDOSAGE AND ADMINISTRATION).



Concentration-Adverse Reaction Relationships

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions (see DOSAGE AND ADMINISTRATION).



In a healthy volunteer study, ibuprofen 400 mg given once daily, administered 2 hours prior to immediate-release aspirin (81 mg) for 6 days, showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane 82 (TxB2) inhibition at 24 hours following the day-6 aspirin dose [53%]. An interaction was still observed, but minimized, when ibuprofen 400 mg given once-daily was administered as early as 8 hours prior to the immediate-release aspirin dose [90.7%]. However, there was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg, given once daily, was administered 2 hours after (but not concomitantly, 15 min, or 30 min after) the immediate-release aspirin dose [99.2%].

In another study, where immediate-release aspirin 81 mg was administered once daily with ibuprofen 400 mg given three times daily (1 , 7, and 13 hours post-aspirin dose) for 10 consecutive days, the mean % serum thromboxane 82 (TxB2) inhibition suggested no interaction with the antiplatelet activity of aspirin [98.3%]. However, there were individual subjects with serum TxB2 inhibition below 95%, with the lowest being 90.2%.

When a similarly designed study was conducted with enteric-coated aspirin, where healthy subjects were administered enteric-coated aspirin 81 mg once daily for 6 days and ibuprofen 400 mg three times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours following the day-6 aspirin dose [67%]. [See Precautions/Drug Interactions].



Pharmacokinetics

Absorption

After oral dosing with the Hydrocodone Bitartrate and Ibuprofen Tablets, a peak hydrocodone plasma level of 27 ng/mL is achieved at 1.7 hours, and a peak ibuprofen plasma level of 30 mcg/mL is achieved at 1.8 hours. The effect of food on the absorption of either component from the Hydrocodone Bitartrate and Ibuprofen Tablets tablet has not been established.



Distribution

Ibuprofen is highly protein-bound (99%) like most other non-steroidal anti-inflammatory agents. Although the extent of protein binding of hydrocodone in human plasma has not been definitely determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range.



Elimination

Metabolism

Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N­ demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. Hydromorphone, a potent opioid, is formed from the O-demethylation of hydrocodone and contributes to the total analgesic effect of hydrocodone. The O- and N- demethylation processes are mediated by separate P-450 isoenzymes: CYP2D6 and CYP3A4, respectively.

Ibuprofen is present in this product as a racemate, and following absorption it undergoes interconversion in the plasma from the R-isomer to the S-isomer. Both the R- and S- isomers are metabolized to two primary metabolites: (+)-2-4'-(2hydroxy-2-methyl-propyl) phenyl propionic acid and (+)-2-4'-(2carboxypropyl) phenyl propionic acid, both of which circulate in the plasma at low levels relative to the parent.



Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours. Ibuprofen is excreted in the urine, 50% to 60% as metabolites and approximately 15% as unchanged drug and conjugate. The plasma half-life is 2.2 hours.



Specific Populations

No significant pharmacokinetic differences based on age or gender have been demonstrated. The pharmacokinetics of hydrocodone and ibuprofen from Hydrocodone Bitartrate and Ibuprofen Tablets have not been evaluated in children.



Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of the Hydrocodone Bitartrate and Ibuprofen Tablets dosage form has not been determined.



Drug Interaction Studies

Aspirin

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known (see PRECAUTIONS: Drug Interactions).

In single-dose studies of post-surgical pain (abdominal, gynecological, orthopedic), 940 patients were studied at doses of one or two tablets. Hydrocodone Bitartrate and Ibuprofen Tablets produced greater efficacy than placebo and each of its individual components given at the same dose. No advantage was demonstrated for the two-tablet dose.

Hydrocodone Bitartrate and Ibuprofen Tablets are indicated for the short-term management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.



Limitations of Use

Carefully consider the potential benefits and risks of Hydrocodone Bitartrate and Ibuprofen Tablets and other treatment options before deciding to use Hydrocodone Bitartrate and Ibuprofen Tablets Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation). Do not use Hydrocodone Bitartrate and Ibuprofen Tablets for the treatment of conditions such as osteoarthritis or rheumatoid arthritis.

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses (seeWARNINGS: Addiction, Abuse, and Misuse), reserve Hydrocodone Bitartrate and Ibuprofen Tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics):

•   Have not been tolerated, or are not expected to be tolerated,

•   Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Hydrocodone Bitartrate and Ibuprofen Tablets are contraindicated in patients with:

• Significant respiratory depression (see WARNINGS: Life-Threatening Respiratory Depression).
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see WARNINGS: Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients).
• Known or suspected gastrointestinal obstruction, including paralytic ileus (see WARNINGS: Risks of Use in Patients with Gastrointestinal Conditions).
• Known hypersensitivity (e.g., anaphylactic reactions, serious skin reactions) to hydrocodone, ibuprofen, or any components of the drug product (see WARNINGS: Anaphylactic Reactions, Serious Skin Reactions). Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone.
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactic Reactions, Exacerbation of Asthma Related to Aspirin Sensitivity).
•  In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS: Cardiovascular Thrombotic Events).
  
  

Hydrocodone Component

Addiction, Abuse, and Misuse:

Hydrocodone Bitartrate and Ibuprofen Tablets contains hydrocodone, a Schedule II controlled substance. As an opioid- containing product, Hydrocodone Bitartrate and Ibuprofen Tablets exposes users to the risks of addiction, abuse, and misuse (see DRUG ABUSE AND DEPENDENCE).



Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydrocodone Bitartrate and Ibuprofen Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.



Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Hydrocodone Bitartrate and Ibuprofen Tablets, and monitor all patients receiving Hydrocodone Bitartrate and Ibuprofen Tablets 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 Hydrocodone Bitartrate and Ibuprofen Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Hydrocodone Bitartrate and Ibuprofen Tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose (see WARNINGS, Life-Threatening Respiratory Depression; Dosage and Administration, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose).



Opioids are sought by drug abusers and people with addiction disorders, and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydrocodone Bitartrate and Ibuprofen Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug (see PRECAUTIONS: Information for Patients). 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.

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):

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 Health Care 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 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

 

Life-Threatening Respiratory Depression

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 antagonists, depending on the patient’s clinical status (seeOVERDOSAGE). 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 Hydrocodone Bitartrate and Ibuprofen Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Hydrocodone Bitartrate and Ibuprofen Tablets.



To reduce the risk of respiratory depression, proper dosing and titration of Hydrocodone Bitartrate and Ibuprofen Tablets are essential (see DOSAGE AND ADMINISTRATION). Overestimating the Hydrocodone Bitartrate and Ibuprofen Tablets 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 Hydrocodone Bitartrate and Ibuprofen Tablets, especially by children, can result in respiratory depression and death due to an overdose of Hydrocodone Bitartrate and Ibuprofen Tablets.

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 (see PRECAUTIONS, Information for Patients).

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).

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Hydrocodone Bitartrate and Ibuprofen Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered (see PRECAUTIONS, Information for Patients).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone (see WARNINGS, Addiction, Abuse, and Misuse, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants; PRECAUTIONS, Information for Patients).

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Hydrocodone Bitartrate and Ibuprofen Tablets 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see

PRECAUTIONS: Pregnancy, Information for Patients).



Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Hydrocodone Bitartrate and Ibuprofen Tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression (see WARNINGS: Life- Threatening Respiratory Depression), particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Ibuprofen Tablets are achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Hydrocodone Bitartrate and Ibuprofen Tablets -treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using Hydrocodone Bitartrate and Ibuprofen Tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Hydrocodone Bitartrate and Ibuprofen Tablets- treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Hydrocodone Bitartrate and Ibuprofen Tablets until stable drug effects are achieved (see DOSAGE AND ADMINISTRATION, PRECAUTIONS: Drug Interactions).



Concomitant use of Hydrocodone Bitartrate and Ibuprofen Tablets with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using Hydrocodone Bitartrate and Ibuprofen Tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur (see DOSAGE AND ADMINISTRATION, PRECAUTIONS: Drug Interactions).



Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydrocodone Bitartrate and Ibuprofen Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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 PRECAUTIONS: Drug Interactions).



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. Follow patients closely for signs and symptoms of respiratory depression and sedation.



If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose (see WARNINGS, Life-Threatening Respiratory Depression; Dosage and Administration, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose).



Advise both patients and caregivers about the risks of respiratory depression and sedation when Hydrocodone Bitartrate and Ibuprofen Tablets are 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 depressant 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 PRECAUTIONS: Drug Interactions, Information for Patients).



Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Hydrocodone Bitartrate and Ibuprofen Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Hydrocodone Bitartrate and Ibuprofen Tablets -treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hydrocodone Bitartrate and Ibuprofen Tablets (see WARNINGS: Life-Threatening Respiratory Depression).



Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see WARNINGS: Life-Threatening Respiratory Depression).



Monitor such patients closely, particularly when initiating and titrating Hydrocodone Bitartrate and Ibuprofen Tablets and when Hydrocodone Bitartrate and Ibuprofen Tablets are given concomitantly with other drugs that depress respiration (see WARNINGS: Life-Threatening Respiratory Depression). Alternatively, consider the use of non- opioid analgesics in these patients.



Adrenal Insufficiency

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.



Severe Hypotension

Hydrocodone Bitartrate and Ibuprofen Tablets 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 PRECAUTIONS: Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydrocodone Bitartrate and Ibuprofen Tablets. In patients with circulatory shock, Hydrocodone Bitartrate and Ibuprofen Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate and Ibuprofen Tablets in patients with circulatory shock.



Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

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), Hydrocodone Bitartrate and Ibuprofen Tablets 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 Hydrocodone Bitartrate and Ibuprofen Tablets.



Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydrocodone Bitartrate and Ibuprofen Tablets in patients with impaired consciousness or coma.



Risks of Use in Patients with Gastrointestinal Conditions

Hydrocodone Bitartrate and Ibuprofen Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.



The hydrocodone in Hydrocodone Bitartrate and Ibuprofen Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.



Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in Hydrocodone Bitartrate and Ibuprofen Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hydrocodone Bitartrate and Ibuprofen Tablets therapy.



Withdrawal



Do not abruptly discontinue Hydrocodone Bitartrate and Ibuprofen Tablets in a patient physically dependent on opioids. When discontinuing Hydrocodone Bitartrate and Ibuprofen Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of Hydrocodone Bitartrate and Ibuprofen Tablets  in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration, Drug Abuse and Dependence].





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 Hydrocodone Bitartrate and Ibuprofen Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see PRECAUTIONS/Drug Interactions].



Risks of Driving and Operating Machinery

Hydrocodone Bitartrate and Ibuprofen Tablets 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 Hydrocodone Bitartrate and Ibuprofen Tablets and know how they will react to the medication (see PRECAUTIONS: Information for Patients).



Ibuprofen Component

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.



To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.



There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation).



Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS).



Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.



Avoid the use of hydrocodone bitartrate and ibuprofen tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If hydrocodone bitartrate and ibuprofen tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.



Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with Hydrocodone Bitartrate and Ibuprofen Tablets. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.



Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most post marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.



Strategies to Minimize the GI Risks in NSAID-treated patients:

• Use the lowest effective dosage for the shortest possible duration.

• Avoid administration of more than one NSAID at a time.

• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.

• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue hydrocodone bitartrate and ibuprofen tablets until a serious GI adverse event is ruled out.

• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS: Drug Interactions).



Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials with NSAIDS. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.



Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients taking NSAIDs including ibuprofen.



Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flulike” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue hydrocodone bitartrate and ibuprofen tablets immediately, and perform a clinical evaluation of the patient.



Hypertension

NSAID-containing products, including, can lead to new onset or worsening of pre-existing hypertension, both Hydrocodone Bitartrate and Ibuprofen Tablets of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS: Drug Interactions).



Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.



Heart Failure and Edema

The Coxib and Traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.



Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of hydrocodone bitartrate and ibuprofen tablets may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (see PRECAUTIONS: Drug Interactions).



Avoid the use of hydrocodone bitartrate and ibuprofen tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If hydrocodone bitartrate and ibuprofen tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.



Renal Toxicity and Hyperkalemia



Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.



Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or angiotensin receptor blockers (ARBs), and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.



No information is available from controlled clinical studies regarding the use of hydrocodone bitartrate and ibuprofen tablets in patients with advanced renal disease. The renal effects of hydrocodone bitartrate and ibuprofen tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.



Correct volume status in dehydrated or hypovolemic patients prior to initiating Hydrocodone Bitartrate and Ibuprofen Tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of hydrocodone bitartrate and ibuprofen tablets (see PRECAUTIONS: Drug Interactions). Avoid the use of hydrocodone bitartrate and ibuprofen tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If hydrocodone bitartrate and ibuprofen tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.



Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, those effects have been attributed to a hyporeninemic-hypoaldosteronism state.



Anaphylactic Reactions

Ibuprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS: Exacerbation of Asthma Related to Aspirin Sensitivity).



Seek emergency help if an anaphylactic reaction occurs. Exacerbation of Asthma Related to Aspirin Sensitivity



A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, hydrocodone bitartrate and ibuprofen tablets are contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS). When hydrocodone bitartrate and ibuprofen tablets are used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.



Serious Skin Reactions

NSAIDs, including ibuprofen, can cause serious skin adverse events such as exfoliative dermatitis, Stevens - Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of hydrocodone bitartrate and ibuprofen tablets at the first appearance of skin rash or any other sign of hypersensitivity hydrocodone bitartrate and ibuprofen tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS).

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Hydrocodone Bitartrate and Ibuprofen Tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue Hydrocodone Bitartrate and Ibuprofen Tablets and evaluate the patient immediately.

Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs, including Hydrocodone Bitartrate And Ibuprofen Tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs including Hydrocodone Bitartrate And Ibuprofen Tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment:

Use of NSAIDs, including Hydrocodone Bitartrate And Ibuprofen Tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Hydrocodone Bitartrate And Ibuprofen Tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Hydrocodone Bitartrate And Ibuprofen Tablets treatment extends beyond 48 hours. Discontinue Hydrocodone Bitartrate And Ibuprofen Tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).

Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with hydrocodone bitartrate and ibuprofen tablets have any signs or symptoms of anemia, monitor hemoglobin or hematocrit.



NSAID-containing products, including Hydrocodone Bitartrate and Ibuprofen Tablets, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS: Drug Interactions).



Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy as found in Hydrocodone Bitartrate and Ibuprofen Tablets. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on Hydrocodone Bitartrate and Ibuprofen Tablets, the possibility of its being related to ibuprofen should be considered.

Masking of Inflammation and Fever

The pharmacological activity of hydrocodone bitartrate and ibuprofen tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.



Ophthalmological Effects

Blurred or diminished vision, scotomata, and changes in color vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and color vision testing.

The following adverse reactions are described below and elsewhere in the labeling including the

WARNINGS section.

• Addiction, Abuse, and Misuse
• Life-Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Cytochrome P450 3A4 Inhibitors and Inducers
• Interactions with Benzodiazepines or Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Seizures
• Withdrawal
• Cardiovascular Thrombotic Events
• Gastrointestinal Bleeding, Ulceration, and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Exacerbation of Asthma Related to Aspirin Sensitivity
• Serious Skin Reactions
• Premature Closure of Fetal Ductus Arteriosus
• Hematologic Toxicity
• Aseptic Meningitis

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 

Hydrocodone bitartrate and ibuprofen tablets were administered to approximately 300 pain patients in a safety study that employed dosages and a duration of treatment sufficient to encompass the recommended usage (see DOSAGE AND ADMINISTRATION). Adverse event rates generally increased with increasing daily dose. The event rates reported below are from approximately 150 patients who were in a group that received one tablet of hydrocodone bitartrate and ibuprofen tablets an average of three to four times daily. The overall incidence rates of adverse experiences in the trials were fairly similar for this patient group and those who received the comparison treatment, acetaminophen 600 mg with codeine 60 mg. 

The following lists adverse events that occurred with an incidence of 1% or greater in clinical trials of Hydrocodone Bitartrate and Ibuprofen Tablets, without regard to the causal relationship of the events to the drug. To distinguish different rates of occurrence in clinical studies, the adverse events are listed as follows:

name of adverse event = less than 3%

adverse events marked with an asterisk * = 3% to 9%

adverse event rates over 9% are in parentheses.

Body as a Whole

Abdominal pain*; Asthenia*; Fever; Flu syndrome; Headache (27%); Infection*; Pain.

Cardiovascular

Palpitations; Vasodilation.

Central Nervous System

Anxiety*; Confusion; Dizziness (14%); Hypertonia; Insomnia*; Nervousness*; Paresthesia;

Somnolence (22%); Thinking abnormalities.  

Digestive

Anorexia; Constipation (22%); Diarrhea*; Dry mouth*; Dyspepsia (12%); Flatulence*; Gastritis; 

Melena; Mouth ulcers; Nausea (21%); Thirst; Vomiting*.

Metabolic and Nutritional Disorders

Edema*.

Respiratory

Dyspnea; Hiccups; Pharyngitis; Rhinitis.

Skin and Appendages

Pruritus*; Sweating*.

Special Senses

Tinnitus.

Urogenital

Urinary frequency.

Incidence less than 1%

Body as a Whole

Allergic reaction.

Cardiovascular

Arrhythmia; Hypotension; Tachycardia.

Central Nervous System

Agitation; Abnormal dreams; Decreased libido; Depression; Euphoria; Mood changes; Neuralgia; Slurred speech; Tremor, Vertigo.

Digestive

Chalky stool; "Clenching teeth"; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liver enzyme elevation.

Metabolic and Nutritional

Weight decrease.

Musculoskeletal

Arthralgia; Myalgia.

Respiratory

Asthma; Bronchitis; Hoarseness; Increased cough; Pulmonary congestion; Pneumonia; Shallow breathing; Sinusitis.

Skin and Appendages

Rash; Urticaria.

Special Senses

Altered vision; Bad taste; Dry eyes.

Urogenital

Cystitis; Glycosuria; Impotence; Urinary incontinence; Urinary retention. 

Post marketing Experience

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. 

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Ibuprofen Tablets.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see CLINICAL PHARMACOLOGY: Pharmacodynamics). 

Following an acute over dosage, toxicity may result from hydrocodone and/or ibuprofen.

Clinical Presentation

Hydrocodone Component

Acute overdose with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Ibuprofen Component

Symptoms following acute NSAID over dosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation). Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare (see WARNINGS: Hypertension, Renal Toxicity and Hyperkalemia).

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone, carefully monitor the patient until spontaneous respiration is reliably re­-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Manage patients with symptomatic and supportive care following an NSAID over dosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about over dosage treatment contact a poison control center (1-800-222-1222). 

Carefully consider the potential benefits and risks of hydrocodone bitartrate and ibuprofen tablets and other treatment options before deciding to use Hydrocodone Bitartrate And Ibuprofen Tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation).

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse (seeWARNINGS: Addiction, Abuse, and Misuse).

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with hydrocodone bitartrate and ibuprofen tablets and adjust the dosage accordingly (seeWARNINGS: Life-Threatening Respiratory Depression).

After observing the response to initial therapy with Hydrocodone Bitartrate and Ibuprofen Tablets, the dose and frequency should be adjusted to suit an individual patient's needs.

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Hydrocodone Bitartrate and Ibuprofen Tablets (see WARNINGS, Life-Threatening Respiratory Depression; PRECAUTIONS, Information for Patients).



Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).



Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient (see WARNINGS, Addiction, Abuse, and Misuse, Life-Threatening Respiratory Depression, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants).



Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.



Initial Dosage

For the short-term (generally less than 10 days) management of acute pain, the recommended dose of hydrocodone bitartrate and ibuprofen tablets are one tablet every 4 to 6 hours, as necessary. Dosage should not exceed 5 tablets in a 24-hour period. It should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The lowest effective dose or the longest dosing interval should be sought for each patient (see WARNINGS), especially in the elderly. After observing the initial response to therapy with Hydrocodone Bitartrate and Ibuprofen Tablets, the dose and frequency of dosing should be adjusted to suit the individual patient's need, without exceeding the total daily dose recommended.

Titration and Maintenance of Therapy

Individually titrate Hydrocodone Bitartrate and Ibuprofen Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydrocodone Bitartrate and Ibuprofen Tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse (see WARNINGS: Addiction, Abuse, and Misuse). 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.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Hydrocodone Bitartrate and Ibuprofen Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Safe Reduction or Discontinuation of Hydrocodone Bitartrate and Ibuprofen Tablets

Do not abruptly discontinue Hydrocodone Bitartrate and Ibuprofen tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in 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. 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 Hydrocodone Bitartrate and Ibuprofen tablets there are a variety of factors that should be considered, including the dose of Hydrocodone Bitartrate and Ibuprofen tablets 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 co-morbid 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 Hydrocodone Bitartrate and Ibuprofen tablets 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, monitor 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 a long duration 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/ Withdrawal, DRUG ABUSE AND DEPENDENCE].

Hydrocodone Bitartrate and Ibuprofen Tablets, 7.5 mg/200 mg are white to off-white, round, film coated tablets, debossed with “U13” on one side and plain on the other side.



Bottles of 10                  NDC 13107-004-11

Bottles of 100                NDC 13107-004-01

Bottles of 500                NDC 13107-004-05

Bottles of 1,000             NDC 13107-004-99



Storage



Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].





Dispense in a tight, light-resistant container. Keep this and all medication out of the reach of children.



A Schedule II Controlled Drug Substance.





Store Hydrocodone Bitartrate and Ibuprofen Tablets securely and dispose of properly [see PRECAUTIONS/ Information for Patients].

 

Dispense with Medication Guide available at https://www.aurobindousa.com/medication-guides/

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Revised: 03/2021

This Medication Guide has been approved by the U.S. Food and Drug Administration.



Dispense with Medication Guide available at https://www.aurobindousa.com/medication-guides/



Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Revised: 03/2021

NDC 13107-004-01

Hydrocodone Bitartrate and Ibuprofen Tablets CII

7.5 mg/200 mg

Pharmacist: Please dispense with medication

guide provided separately

Rx only                             100 Tablets