"Nov. 1, 2012 -- Two more drugs made by the New England Compounding Center (NECC) are crawling with various kinds of bacteria, FDA tests reveal.
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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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS; Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
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 (see CONTRAINDICATIONS).
NSAIDs, including Combunox (oxycodone hcl and ibuprofen) , can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Combunox (oxycodone hcl and ibuprofen) , should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Combunox (oxycodone hcl and ibuprofen) should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including Combunox (oxycodone hcl and ibuprofen) , can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the 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 NSAIDs. 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 occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Misuse Abuse and Diversion of Opioids
Combunox (oxycodone hcl and ibuprofen) contains oxycodone, which is an opioid agonist, and a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by abusers and people with addiction disorders, and are subject to diversion.
Combunox (oxycodone hcl and ibuprofen) can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Combunox (oxycodone hcl and ibuprofen) in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion (see Drug Abuse And Dependence).
Oxycodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory centers. Oxycodone HCl also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Combunox (oxycodone hcl and ibuprofen) should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Combunox (oxycodone hcl and ibuprofen) may decrease respiratory drive to the point of apnea.
Combunox (oxycodone hcl and ibuprofen) , like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Combunox (oxycodone hcl and ibuprofen) may produce orthostatic hypotension in ambulatory patients. Combunox (oxycodone hcl and ibuprofen) , like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.
Acute Abdominal Conditions
The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Anaphylactoid reactions may occur in patients without known prior exposure to Combunox (oxycodone hcl and ibuprofen) . Combunox (oxycodone hcl and ibuprofen) should not be given to patients with the aspirin triad or a history of angioedema. The triad typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Fatal reactions to NSAIDs have been reported in such patients (see CONTRAINDICATIONS and PRECAUTIONS; Pre-existing Asthma). Emergency help should be sought when anaphylactoid reaction occurs.
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 a nonsteroidal anti-inflammatory drug 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, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
In patients with advanced kidney disease, treatment with Combunox (oxycodone hcl and ibuprofen) is not recommended. No information is available from controlled clinical studies regarding the use of Combunox (oxycodone hcl and ibuprofen) in patients with advanced renal disease However, if Combunox (oxycodone hcl and ibuprofen) therapy must be initiated, due to the NSAID component, close monitoring of the patient's kidney function is advisable (see WARNINGS; Renal Effects).
NSAIDs, including Combunox (oxycodone hcl and 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. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Starting at 30 weeks gestation, Combunox (oxycodone hcl and ibuprofen) , and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus may occur.
Interactions with Alcohol and Drugs of Abuse
Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Combunox (oxycodone hcl and ibuprofen) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Combunox (oxycodone hcl and ibuprofen) in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Special Risk Patients
As with any opioid analgesic agent, Combunox (oxycodone hcl and ibuprofen) tablets should be used with caution in elderly or debilitated patients, and those with severe impairment of hepatic, pulmonary or renal function, hypothyroidism, Addison's disease, acute alcoholism, convulsive disorders, CNS depression or coma, delirium tremens, kyphoscoliosis associated with respiratory depression, toxic psychosis, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression, postural hypotension, and altered mental states should be kept in mind.
Use in Pancreatic/Biliary Tract Disease
Combunox (oxycodone hcl and ibuprofen) may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like Combunox (oxycodone hcl and ibuprofen) may cause increases in the serum amylase level.
Oxycodone suppresses the cough reflex; as with other opioid containing products, caution should be exercised when Combunox (oxycodone hcl and ibuprofen) is used postoperatively and in patients with pulmonary disease.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including ibuprofen as found in Combunox (oxycodone hcl and ibuprofen) . These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Combunox (oxycodone hcl and ibuprofen) . If clinical signs and symptoms consistent with liver disease develop, or if systematic manifestations occur (e.g., eosinophilia, rash, etc.), Combunox (oxycodone hcl and ibuprofen) should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen as found in Combunox (oxycodone hcl and ibuprofen) . This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ibuprofen, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Combunox (oxycodone hcl and ibuprofen) who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Patients previously treated with NSAIDs and currently using Combunox (oxycodone hcl and ibuprofen) should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Combunox (oxycodone hcl and ibuprofen) should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen as found in COMBUNOX (oxycodone hcl and ibuprofen) . 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 Combunox (oxycodone hcl and ibuprofen) , the possibility of its being related to ibuprofen should be considered.
Information for Patients
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Combunox (oxycodone hcl and ibuprofen) , similar to other opioid-containing analgesics, may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly.
- The combination of this product with alcohol and other CNS depressants may produce an additive CNS depression and should be avoided.
- Combunox (oxycodone hcl and ibuprofen) can be abused in a manner similar to other opioid agonists, legal or illicit. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.
- Combunox (oxycodone hcl and ibuprofen) , like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS; Cardiovascular Effects).
- Combunox (oxycodone hcl and ibuprofen) , like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS; Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Combunox (oxycodone hcl and ibuprofen) , like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever or other signs of hypersensitivity, and should ask medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physician as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritius, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to seek immediate medical therapy.
- Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, Combunox (oxycodone hcl and ibuprofen) should be avoided because it may cause premature closure of the ductus arteriosus.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Combunox (oxycodone hcl and ibuprofen) should be discontinued.
Carcinogenicity, Mutagenicity and Impairment of Fertility
Studies to evaluate the potential effects of the combination of oxycodone and ibuprofen on carcinogenicity and mutagenicity have not been conducted.
Oxycodone HCl was not genotoxic in the following assays: Ames bacterial mutuation assay, chromosomal aberrations in cultured human lymphocytes, and in vivo mouse micronucleus assay in mice.
There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered oxycodone HCl; ibuprofen up to (1:80 mg/kg/day) which is equivalent to 0.5-times the maximum recommended human daily dose (MRHD) (20:1600 mg/day) on a body surface area (mg/m² ) basis.
Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation
Starting at 30 weeks gestation, Combunox (oxycodone hcl and ibuprofen) , and other NSAIDS, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Combunox (oxycodone hcl and ibuprofen) can cause fetal harm when administered to a pregnant woman starting at 30 weeks gestation. If Combunox (oxycodone hcl and ibuprofen) , and other NSAIDS, are used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus. There are no adequate and well-controlled studies in pregnant women. Prior to 30 weeks gestation, Combunox (oxycodone hcl and ibuprofen) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
Animal studies to assess the potential effects of the combination of oxycodone and ibuprofen on embryo-fetal development were conducted in the rat and rabbit model.
Pregnant rats were treated by oral gavage with combination doses of oxycodone:ibuprofen mg/kg/day (0.25:20, 0.5:40, 1:80, or 2:160) on days 7-16 of gestation. There was no evidence for developmental toxicity or teratogenicity at any dose, although maternal toxicity was noted at doses of 0.5:40 and above. The highest dose tested in the rat (2:160 mg/kg/day) is equivalent to the maximum recommended human daily dose (20:1600 mg/day) on a body surface area (mg/m²) basis. This dose was associated with maternal toxicity (death, clinical signs, decreased BW).
Pregnant rabbits were treated by oral gavage with combination doses of oxycodone/ibuprofen (0.38:30, 0.75:60, 1.5:120 or 3:240 mg/kg/day) on gestation days 7-19. Oxycodone/ibuprofen treatment was not teratogenic under the conditions of the assay. Maternal toxicity was noted at doses of 1.5:120 (reduced body weight and food consumption) and 3:240 mg/kg/day (mortality). The NOAEL for maternal toxicity, 0.75:60 mg/kg/day, is 0.75 fold the proposed maximum daily human dose based upon the body surface area. Developmental toxicity, as evidenced by delayed ossification and reduced fetal body weights, was noted at the highest dose, which is approximately 3 times the MRHD on a mg/m² basis, and is likely due to maternal toxicity. The fetal no adverse effect level (NOAEL) of 1.5:120 mg/kg/day is approximately 1.5 times the MRHD on a mg/m² basis.
In a pre- and postnatal development study conducted in rats, there was increased mortality of pups born to dams dose with 0.5:40 mg/kg/day oxydocone:ibuprofen and above which is equivalent to 0.25-times of the MRHD (20:1600 mg/day) on a body surface area (mg/m²) basis. There was an increase in stillborn F1 pups and decrease in mean pup weight in dams dosed with 1:80 mg/kg/day oxycodone:ibuprofen, which is 0.5-times the MRHD (20:1600 mg/day) on a body surface area (mg/m²) basis.
Babies born to mothers who have been taking opioids regularly prior to delivery will be physical dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.
Labor and Delivery
Combunox (oxycodone hcl and ibuprofen) should not be used during the third trimester of pregnancy due to the potential for ibuprofen to inhibit prostaglandin synthetase which may prolong pregnancy and inhibit labor. Oxycodone is not recommended for use in women during and immediately prior to labor and delivery because oral opioids may cause respiratory depression in the newborn.
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Combunox (oxycodone hcl and ibuprofen) on labor and delivery in pregnant women are unknown.
It is not known whether Combunox (oxycodone hcl and ibuprofen) is excreted in human milk. Oxycodone is excreted in human milk. Withdrawal symptoms and/or respiratory depression have been observed in neonates whose mothers were taking narcotic analgesics during pregnancy. Although adverse effects in the nursing infant have not been documented, withdrawal can occur in breast-feeding infants when maternal administration of an opioid analgesic is discontinued. Because many drugs are excreted in human-milk and because of the potential for serious adverse reactions in nursing infants from Combunox (oxycodone hcl and ibuprofen) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
In the placebo-controlled, clinical studies of pain following dental surgery, 109 patients between the ages of 14 and 17 years were administered a single dose of Combunox (oxycodone hcl and ibuprofen) . No apparent differences were noted in the safety of Combunox (oxycodone hcl and ibuprofen) in patients below and above 17 years of age. Combunox (oxycodone hcl and ibuprofen) has not been studied in patients under 14 years of age. Safety and effectiveness in pediatric patients below the age of 14 have not been established.
Of the total number of subjects in clinical studies of Combunox (oxycodone hcl and ibuprofen) , 89 patients were 65 and over, while 37 patients were 75 and over. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
However, because the elderly may be more sensitive to the renal and gastrointestinal effects of nonsteroidal anti-inflammatory agents as well as possible increased risk of respiratory depression with opioids, extra caution should be used when treating the elderly with Combunox (oxycodone hcl and ibuprofen) .This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/23/2010
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