Hydrocodone Bitartrate and Ibuprofen (hydrocodone bitartrate 5 mg ibuprofen 200 mg) Dailymed

Precautions

Maskingof 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.

OphthalmologicalEffects

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.

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with hydrocodone bitartrate and ibuprofen tablets and periodically during the course of ongoing therapy.

Storage and Disposal:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store hydrocodone bitartrate and ibuprofen tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see WARNINGS , DRUG ABUSE AND DEPENDENCE]. Inform patients that leaving hydrocodone bitartrate and ibuprofen tablets  unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused hydrocodone bitartrate and ibuprofen tablets  should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete ul of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

• Addiction, Abuse, and Misuse Inform patients that the use of hydrocodone bitartrate and ibuprofen tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS: Addiction, Abuse, and Misuse). Instruct patients not to share hydrocodone bitartrate and ibuprofen tablets with others and to take steps to protect hydrocodone bitartrate and ibuprofen tablets from theft or misuse.
• Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hydrocodone bitartrate and ibuprofen tablets or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS: Life-Threatening Respiratory Depression). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
• Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see WARNINGS: Life-Threatening Respiratory Depression).
• Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate and ibuprofen tablets is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider (see WARNINGS: Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants, PRECAUTIONS: Drug Interactions).
• Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications (see PRECAUTIONS: Drug Interactions).
• MAOI Interaction Inform patients to avoid taking hydrocodone bitartrate and ibuprofen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and ibuprofen tablets (see PRECAUTIONS: Drug Interactions).
• Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS: Adrenal Insufficiency).
• Important Administration Instructions Instruct patients how to properly take hydrocodone bitartrate and ibuprofen tablets. For the short-term (generally less than 10 days) management of acute pain, the recommended dose of hydrocodone bitartrate and ibuprofen tablets is one tablet every 4 to 6 hours, as necessary. Inform patients that the dosage should not exceed 5 tablets in a 24-hour period (see DOSAGE AND ADMINISTRATION).                                                                                                                                              Important Discontinuation Instructions  In order to avoid developing withdrawal symptoms, instruct patients not to discontinue hydrocodone bitartrate and ibuprofen tablets without first discussing a tapering plan with the prescriber [see DOSAGE AND ADMINISTRATION]
• Hypotension Inform patients that hydrocodone bitartrate and ibuprofen tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (see WARNINGS: Severe Hypotension).                                                                                                            
• Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and ibuprofen tablets. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS, WARNINGS: Anaphylactic Reactions).
• Pregnancy N e onatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of hydrocodone bitartrate and ibuprofen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see Boxed Warning, WARNINGS: Neonatal Opioid Withdrawal Syndrome, PRECAUTIONS: Pregnancy).
• Embryo-Fetal Toxicity Inform female patients of reproductive potential that hydrocodone bitartrate and ibuprofen tablets can cause fetal harm and to inform the prescriber of a known or suspected pregnancy. Inform pregnant women to avoid use of hydrocodone bitartrate and ibuprofen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of premature closing of the fetal ductus arteriosus (see WARNINGS: Premature Closure of Fetal Ductus Arteriosis, PRECAUTIONS: Pregnancy).
• Lactation Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs (see PRECAUTIONS: Nursing Mothers).
• Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible. Advise female patients of reproductive potential who desire pregnancy that NSAIDs, including hydrocodone bitartrate and ibuprofen tablets, may be associated with a reversible delay in ovulation (see PRECAUTIONS: Carcinogenicity, Mutagenicity, Impairment of Fertility).
• Driving or Operating Heavy Machinery Inform patients that hydrocodone bitartrate and ibuprofen tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication (see WARNINGS: Risks of Driving and Operating Machinery).
• Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS: Clinical Trials Experience).
• Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS: Cardiovascular Thrombotic Events).
• Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation).
• Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop hydrocodone bitartrate and ibuprofen tablets and seek immediate medical therapy (see WARNINGS: Hepatotoxicity).
• Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS: Heart Failure and Edema).
• Serious Skin Reactions Advise patients to stop hydrocodone bitartrate and ibuprofen tablets immediately if they develop any type of rash and to contact their healthcare provider as soon as possible (see WARNINGS: Serious Skin Reactions).
• Avoid Concomitant use of NSAIDs Inform patients that the concomitant use of hydrocodone bitartrate and ibuprofen tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation, PRECAUTIONS: Drug Interactions). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
• Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with hydrocodone bitartrate and ibuprofen tablets until they talk to their healthcare provider (see PRECAUTIONS: Drug Interactions).
• Ophthalmological Effects Instruct patients to report any signs of blurred vision or other eye symptoms (see PRECAUTIONS: Ophthalmological Effects).

LaboratoryMonitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients with a CBC and a chemistry profile periodically (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation, Renal Toxicity and Hyperkalemia, Hepatotoxicity).

Drug Interactions

I nhibitors of CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and ibuprofen tablets is achieved (see WARNINGS: Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers).

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease (see CLINICAL PHARMACOLOGY: Pharmacokinetics), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone bitartrate and ibuprofen tablets.

If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

C YP3A4 Inducers The concomitant use of hydrocodone bitartrate and ibuprofen tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone (see WARNINGS: Withdrawal).

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase (see CLINICAL PHARMACOLOGY: Pharmacokinetics), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use is necessary, consider a dosage increase of hydrocodone bitartrate and ibuprofen tablets until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and ibuprofen tablets dosage reduction and monitor for signs of respiratory depression.

B e nzodiazepines and Other Central Nervous System (CNS) Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants such as benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

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: Life- Threatening Respiratory Depression).

S er otonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol),certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome (see PRECAUTIONS: Information for Patients).

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and ibuprofen tablets if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs) MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

If urgent use of an opioid is necessary with MAOIs such as phenelzine, tranylcypromine, linezolid, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

The use of hydrocodone bitartrate and ibuprofen tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Agonist/antagonist analgesics such as pentazocine, nalbuphine, butorphanol and buprenorphine may reduce the analgesic effect of hydrocodone bitartrate and ibuprofen tablets and/or precipitate withdrawal symptoms in these patients.

Avoid concomitant use of these drugs.

Muscle Relaxants Hydrocodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of hydrocodone bitartrate and ibuprofen tablets and/or the muscle relaxant as necessary.

Anticholinergics The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate and ibuprofen tablets are used concomitantly with anticholinergic drugs.

Drugs That Interfere With Hemostasis Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone.

Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Monitor patients with concomitant use of hydrocodone bitartrate and ibuprofen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding (see WARNINGS: Hematologic Toxicity).

Aspirin

Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with entericcoated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology/Pharmacodynamics].

Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate.

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation).

Concomitant use of hydrocodone bitartrate and ibuprofen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity).

ACE-Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia). These effects are usually reversible.

When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia).

Digoxin The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and digoxin, monitor serum digoxin levels.

L ithium NSAIDs have produced elevations in plasma lithium concentration and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and lithium, monitor patients for signs of lithium toxicity.

Methotrexate Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and methotrexate, monitor patients for methotrexate toxicity.

C y c losporine Concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and cyclosporine, monitor patients for signs of worsening renal function.

NSAIDs and Salicylates Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation).

The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.

Pemetrexed Concomitant use of hydrocodone bitartrate and ibuprofen tablets and pemetrexed may increase the risk of pemetrexed­-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

During concomitant use of hydrocodone bitartrate and ibuprofen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

Carcinogenicity, Mutagenicity, Impairment of Fertility

C arc inogenesis Long-term animal studies to evaluate the carcinogenic potential of the combination of hydrocodone and ibuprofen, ibuprofen alone, or hydrocodone alone have not been conducted.

Mutagenesis The mutagenic potential of the combination of hydrocodone and ibuprofen or hydrocodone alone has not been investigated.

In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay).

Impairment of Fertility Animal studies evaluating the impact of the combination of hydrocodone and ibuprofen or hydrocodone alone on fertility have not been conducted.

In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.2-times the MRHD of 1000 mg ibuprofen based on body surface area comparison) did not impact male or female fertility or litter size.

In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.03-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males but decreased ovulation was reported in females.

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including ibuprofen, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAID-containing products, including hydrocodone bitartrate and ibuprofen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible (see ADVERSE REACTIONS: Postmarketing Experience).

Pregnancy

R isk Summary Use of drug products containing NSAIDs, including hydrocodone bitartrate and ibuprofen tablets, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including hydrocodone bitartrate and ibuprofen tablets, in pregnant women starting at 30 weeks gestation (third trimester). Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome (see WARNINGS: Neonatal Opioid Withdrawal Syndrome). There are no available data with hydrocodone bitartrate and ibuprofen tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.

In animal reproduction studies, an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals was observed when the combination of hydrocodone and ibuprofen was administered orally to pregnant rabbits during organogenesis at 1.8 times the maximum daily dose. There are no animal reproductive and developmental toxicology studies with hydrocodone alone.

In published animal reproduction studies testing ibuprofen alone, there were no clear developmental effects at doses up to 1.2 times the maximum recommended human dose (MRHD) in the rabbit and 1.8 times in the MRHD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 3 times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

C linical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see WARNINGS: Neonatal Opioid Withdrawal Syndrome).

L abor and Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

There are no studies on the effects of hydrocodone bitartrate and ibuprofen tablets during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Hydrocodone bitartrate and ibuprofen tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including hydrocodone bitartrate and ibuprofen tablets, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data Animal Data Pregnant rabbits were treated with 10, 33, or 95 mg/kg of 1:27 ratio of hydrocodone:ibuprofen (the high dose is 1.8 times the maximum daily dose of both compounds based on surface area) from Gestation Day 5 to 18. The dose of 95 mg/kg of the combination, which also produced maternal toxicity (44% decrease in body weight gain compared to control), resulted in an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals (a minor abnormality).

Pregnant rats were treated with 50, 100, or 166 mg/kg of a 1:27 ratio of hydrocodone:ibuprofen (the high dose is 1.6 times the maximum daily dose of both compounds based on body surface area) from Gestation Day 5 to 15. No reproductive toxicity was noted despite the presence of maternal toxicity in the 100 and 166 mg/kg groups (21% and 60% decrease in body weight gain compared to control).

In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.15, 0.39, or 1.2 times the maximum recommended human daily dose of 1000 mg of ibuprofen based on body surface area) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. This dose was associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.07, 0.2, 0.6, 1.8 times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above.

In a published study, rats were orally dosed with 300 mg/kg ibuprofen (3 times the maximum human daily dose of 1000 mg based on body surface area) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity (1 out of 20 animals). In the same study/publication rabbits were dosed on Gestation Day 9, 10 and 11 with 500 mg/kg (9.7 times the maximum human daily dose), and only one incidence each of a membranous ventricular septal defect and gastroschisis was noted in the rabbit fetuses. This dose was also associated with maternal toxicity.

Nursing Mothers

R isk Summary Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions.

Limited published literature reports that, following oral administration, ibuprofen is present in human milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose.

Lactation studies have not been conducted with hydrocodone bitartrate and ibuprofen tablets, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for hydrocodone bitartrate and ibuprofen tablets and any potential adverse effects on the breastfed infant from hydrocodone bitartrate and ibuprofen tablets or from the underlying maternal condition.

C linical Considerations Monitor infants exposed to hydrocodone bitartrate and ibuprofen tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydrocodone is stopped, or when breastfeeding is stopped.

Pediatric Use

The safety and effectiveness of hydrocodone bitartrate and ibuprofen tablets in pediatric patients below the age of 16 have not been established.

Geriatric Use

In controlled clinical trials there was no difference in tolerability between patients < 65 years of age and those ≥ 65, apart from an increased tendency of the elderly to develop constipation. However, elderly patients are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and renal adverse reactions as well as possible increased risk of respiratory depression with opioids. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy (see WARNINGS: Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Renal Toxicity and Hyperkalemia).

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of hydrocodone bitartrate and ibuprofen tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see WARNINGS: Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients).

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

Hepatic Impairment

Patients with hepatic impairment may have higher hydrocodone plasma concentrations than those with normal function. In patients with severe hepatic impairment, use a low initial dose. Monitor these patients closely for adverse events such as respiratory depression, sedation, and hypotension.

Renal Impairment

Patients with renal impairment may have higher hydrocodone plasma concentrations than those with normal function. Use a low initial dose in patients with renal impairment and monitor closely for adverse events such as respiratory depression, sedation, and hypotension.