Flunidol may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Flunixin meglumine (a derivative of Flunixin) is reported as an ingredient of Flunidol in the following countries:
International Drug Name Search
Cardiovascular Risk
Gastrointestinal Risk
Caldolor is indicated in adults for the management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics.
Caldolor is indicated for the reduction of fever in adults.
Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with Caldolor, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed 3200 mg total daily dose.
To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of Caldolor.
Administer 400 mg to 800 mg intravenously every 6 hours as necessary. Infusion time must be no less than 30 minutes.
Administer 400 mg intravenously, followed by 400 mg every 4 to 6 hours or 100-200 mg every 4 hours as necessary. Infusion time must be no less than 30 minutes.
Caldolor must be diluted prior to intravenous infusion. Dilute to a final concentration of 4 mg/mL or less. Appropriate diluents include 0.9% Sodium Chloride Injection USP (normal saline), 5% Dextrose Injection USP (D5W), or Lactated Ringers Solution.
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
Diluted solutions are stable for up to 24 hours at ambient temperature (approximately 20 to 25° C) and room lighting.
Infusion time must be no less than 30 minutes.
Caldolor is available as a 400 mg/4 mL single-dose vial (100 mg/mL) and 800 mg/8 mL single-dose vial (100 mg/mL).
Caldolor is contraindicated in patients with known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to ibuprofen [see Warnings and Precautions (5.7, 5.8)].
Caldolor is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.12)].
Caldolor is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].
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, use the lowest effective dose 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.
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 (4.3)].
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 gastrointestinal (GI) events [see Warnings and Precautions (5.2)].
NSAIDs, including ibuprofen, can cause serious 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.
Prescribe NSAIDs, including Caldolor, with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to treated patients with neither of these risk factors. Other factors that increase the risk of 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 reports of spontaneous 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, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI 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.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including 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 have been reported, including jaundice, fulminant hepatitis, liver necrosis and hepatic failure, some with fatal outcomes. A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen should be discontinued.
NSAIDs, including ibuprofen, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including ibuprofen, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy.
Patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Fluid retention and edema have been observed in some patients taking NSAIDs. Use Caldolor with caution in patients with fluid retention or heart failure.
Use caution when initiating treatment with Caldolor in patients with considerable dehydration.
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, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Caldolor in patients with advanced renal disease. If Caldolor therapy must be initiated in patients with advanced renal disease, closely monitor the patient's renal function.
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen. Caldolor is contraindicated in patients with the aspirin triad. This symptom complex 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 [see Contraindications (4.2)].
NSAIDs, including ibuprofen, can cause serious skin adverse reactions 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 manifestations, and to discontinue Caldolor at the first appearance of skin rash or any other sign of hypersensitivity.
Starting at 30 weeks gestation, Caldolor, and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur [see Use in Specific Populations (8.1)].
The pharmacological activity of ibuprofen in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Caldolor must be diluted prior to use. Infusion of the drug product without dilution can cause hemolysis [see Dosage and Administration (2.3)].
Anemia may occur in patients receiving NSAIDs, including ibuprofen. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis. In patients on long-term treatment with NSAIDs, including ibuprofen, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effects on platelet function are less severe quantitatively, of shorter duration, and reversible. Carefully monitor patients who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
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 NSAIDs has been reported in such aspirin-sensitive patients, including bronchospasm, Caldolor is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.
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.
Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen therapy. 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 underlying chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen, give consideration to whether or not the signs or symptoms are related to ibuprofen therapy.
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 CBC and chemistry profiles checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash), or abnormal liver tests persist or worsen, discontinue Caldolor.
The following serious adverse reactions are discussed elsewhere in the labeling:
The most common adverse reactions reported in clinical studies are nausea, flatulence, vomiting, and headache.
The most common reason for discontinuation due to adverse events in controlled trials of Caldolor is pruritus (<1%).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During clinical development, 560 patients were exposed to Caldolor, 438 in pain and 122 with fever. In the pain studies, Caldolor was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, Caldolor was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days.
The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal.
Pain Studies
The incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post-operative patients comparing Caldolor to placebo in patients also receiving morphine as needed for post-operative pain.
| Event | Caldolor | Placebo (N=287) | |
|---|---|---|---|
| 400 mg (N=134) | 800 mg (N=304) | ||
| |||
| Any Reaction | 118 (88%) | 260 (86%) | 258 (90%) |
| Nausea | 77 (57%) | 161 (53%) | 179 (62%) |
| Vomiting | 30 (22%) | 46 (15%) | 50 (17%) |
| Flatulence | 10 (7%) | 49 (16%) | 44 (15%) |
| Headache | 12 (9%) | 35 (12%) | 31 (11%) |
| Hemorrhage | 13 (10%) | 13 (4%) | 16 (6%) |
| Dizziness | 8 (6%) | 13 (4%) | 5 (2%) |
| Edema peripheral | 1 (<1%) | 9 (3%) | 4 (1%) |
| Urinary retention | 7 (5%) | 10 (3%) | 10 (3%) |
| Anemia | 5 (4%) | 7 (2%) | 6 (2%) |
| Decreased hemoglobin | 4 (3%) | 6 (2%) | 3 (1%) |
| Dyspepsia | 6 (4%) | 4 (1%) | 2 (<1%) |
| Wound hemorrhage | 4 (3%) | 4 (1%) | 4 (1%) |
| Abdominal discomfort | 4 (3%) | 2 (<1%) | 0 |
| Cough | 4 (3%) | 2 (<1%) | 1 (<1%) |
| Hypokalemia | 5 (4%) | 3 (<1%) | 8 (3%) |
Fever Studies
Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two Caldolor-treated patients included abdominal pain and nasal congestion.
In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below.
| Event | Caldolor | Placebo N=28 | ||
|---|---|---|---|---|
| 100 mg N=30 | 200 mg N=30 | 400 mg N=31 | ||
| Any Reaction | 27 (87%) | 25 (83%) | 23 (74%) | 25 (89%) |
| Anemia | 5 (17%) | 6 (20%) | 11 (36%) | 4 (14%) |
| Eosinophilia | 7 (23%) | 7 (23%) | 8 (26%) | 7 (25%) |
| Hypokalemia | 4 (13%) | 4 (13%) | 6 (19%) | 5 (18%) |
| Hypoproteinemia | 3 (10%) | 0 | 4 (13%) | 2 (7%) |
| Neutropenia | 2 (7%) | 2 (7%) | 4 (13%) | 2 (7%) |
| Blood urea increased | 0 | 0 | 3 (10%) | 0 |
| Hypernatremia | 2 (7%) | 0 | 3 (10%) | 0 |
| Hypertension | 0 | 0 | 3 (10%) | 0 |
| Hypoalbuminemia | 3 (10%) | 1 (3%) | 3 (10%) | 1 (4%) |
| Hypotension | 0 | 2 (7%) | 3 (10%) | 1 (4%) |
| Diarrhea | 3 (10%) | 3 (10%) | 2 (7%) | 2 (7%) |
| Pneumonia bacterial | 3 (10%) | 1 (3%) | 2 (7%) | 0 |
| Blood LDH increased | 3 (10%) | 2 (7%) | 1 (3%) | 1 (4%) |
| Thrombocythemia | 3 (10%) | 2 (7%) | 1 (3%) | 0 |
| Bacteremia | 4 (13%) | 0 | 0 | 0 |
When ibuprofen is administered with aspirin, ibuprofen's protein binding is reduced, although the clearance of free ibuprofen is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Caldolor and aspirin is not generally recommended because of the potential for increased adverse effects.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a higher risk of serious GI bleeding than users of either drug alone [see Warnings and Precautions (5.2)].
NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
Clinical studies and postmarketing observations have shown that ibuprofen can reduce the natriuretic effects of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe patients closely for signs of renal failure, as well as to assure diuretic efficacy [see Warnings and Precautions (5.6)].
NSAIDs have produced elevations of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance of lithium decreased by 20%. This effect has been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This indicates that NSAIDs may enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate.
In studies of human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.
Teratogenic effects - Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.
Starting at 30 weeks gestation, Caldolor, and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Caldolor can cause fetal harm when administered to a pregnant woman starting at 30 weeks gestation.
There are no adequate, well-controlled studies in pregnant women. Prior to 30 weeks gestation, Caldolor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities.
The effects of Caldolor on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia and delayed parturition, and decreased pup survival.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caldolor, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of Caldolor for management of pain and reduction of fever has not been established in pediatric patients below the age of 17 years.
Clinical studies of Caldolor did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be cautious, 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. Elderly patients are at increased risk for serious GI adverse events.
The following signs and symptoms have occurred in individuals following an overdose of oral ibuprofen: abdominal pain, nausea, vomiting, drowsiness, and dizziness. There are no specific measures to treat acute overdosage with Caldolor. There is no known antidote to ibuprofen. In case of an overdosage, discontinue Caldolor therapy and consider contacting a regional poison control center at 1-800-222-1222.
Caldolor contains the active ingredient ibuprofen, which is (±)-2-(p-isobutylphenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74-77°C. It has a molecular weight of 206.28. It is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. The structural formula of ibuprofen is represented below:
Each 1 mL of solution contains 100 mg of ibuprofen in Water for Injection, USP. The product also contains 78 mg/mL arginine at a molar ratio of 0.92:1 arginine:ibuprofen. The solution pH is about 7.4.
Caldolor is sterile and is intended for intravenous administration only.
Ibuprofen's mechanism of action, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Caldolor possesses anti-inflammatory, analgesic, and antipyretic activity.
Ibuprofen is a racemic mixture of [-]R- and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~60%) interconverted into the active [+]S species in adults. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. The pharmacokinetic parameters of Caldolor determined in a study with volunteers are presented below.
| 400 mg* Caldolor Mean (CV%) | 800 mg* Caldolor Mean (CV%) | |
|---|---|---|
| AUC = Area-under-the-curve Cmax = Peak plasma concentration CV = Coefficient of Variation KEL = First-order elimination rate constant T1/2 = Elimination half-life | ||
| ||
| Number of Patients | 12 | 12 |
| AUC (mcg.h/mL) | 109.3 (26.4) | 192.8 (18.5) |
| Cmax (mcg/mL) | 39.2 (15.5) | 72.6 (13.2) |
| KEL (1/h) | 0.32 (17.9) | 0.29 (12.8) |
| T1/2 (h) | 2.22 (20.1) | 2.44 (12.9) |
Ibuprofen, like most NSAIDs, is highly protein bound (>99% bound at 20 mcg/mL). Protein binding is saturable, and at concentrations >20 mcg/mL binding is nonlinear. Based on oral dosing data, there is an age- or fever-related change in volume of distribution for ibuprofen.
The effect of Caldolor on acute pain was evaluated in two multi-center, randomized, double-blind, placebo-controlled studies.
In a study of women who had undergone an elective abdominal hysterectomy, 319 patients were randomized and treated with Caldolor 800 mg or placebo administered every 6 hours (started intra-operatively) and morphine administered on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the mean morphine consumption through 24 hours in patients who received Caldolor as compared to those receiving placebo (47 mg and 56 mg, respectively). The clinical relevance of this finding is supported by a greater reduction in pain intensity over 24 hours for patients treated with Caldolor, even though morphine was available on an as needed basis.
In a study of patients who had undergone an elective abdominal or orthopedic surgery, 406 patients (87 men, 319 women) were randomized to receive Caldolor 400 mg, Caldolor 800 mg, or placebo administered every 6 hours (started intra-operatively), and morphine on an as needed basis. This study failed to demonstrate a statistically significant difference in outcome between patients receiving Caldolor 800 mg or 400 mg and placebo, although there were trends favoring the active treatments.
The effect of Caldolor on fever was evaluated in two randomized, double-blind studies.
In a multi-center study, 120 hospitalized patients (88 men, 32 women) with temperatures of 101°F or greater were randomized to Caldolor 400 mg, 200 mg, 100 mg or placebo, administered every 4 hours for 24 hours. Each of the three Caldolor doses, 100 mg, 200 mg, and 400 mg, resulted in a statistically greater percentage of patients with a reduced temperature (<101°F) after 4 hours, compared to placebo (65%, 73%, 77% and 32%, respectively). The dose response is shown in the figure below.
Figure 1: Temperature Reduction by Treatment Group, Hospitalized Febrile Patients
In a single-center study, 60 hospitalized patients (48 men, 12 women) with uncomplicated P. falciparum malaria having temperatures ≥100.4°F were randomized to Caldolor 400 mg or placebo, administered every 6 hours for 72 hours of treatment. There was a significant reduction in fever within the first 24 hours of treatment, measured as the area above the temperature 98.6°F vs. time curve for patients treated with Caldolor.
Caldolor is available in the following strengths:
400 mg/4 mL (100 mg/mL)
Carton of 25 vials, NDC 66220-247-04
800 mg/8 mL (100 mg/mL)
Carton of 25 vials, NDC 66220-287-08
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
The stopper in the Caldolor vial does not contain natural rubber latex, dry natural rubber, or blends of natural rubber.
Patients should be informed of the following information before initiating therapy with an NSAID.
Ibuprofen, like other NSAIDs, may cause serious CV events such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, advise patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, and slurring of speech, and to ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.1)].
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, advise patients to be alert for the signs and symptoms of ulcerations and bleeding, and to ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.2)].
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). Instruct patients to stop therapy with Caldolor and seek immediate medical therapy if any of these occur [see Warnings and Precautions (5.3)].
Ibuprofen, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, advise patients to be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and to ask for medical advice when observing any indicative sign or symptoms. Advise patients to stop Caldolor immediately if they develop any type of rash, and to contact a physician as soon as possible [see Warnings and Precautions (5.8)].
Advise patients to promptly report to their physicians signs or symptoms of unexplained weight gain or edema during treatment with Caldolor [see Warnings and Precautions (5.5)].
Inform patients of the signs of an anaphylactoid reaction (e.g. difficulty in breathing, swelling of the face or throat). If these occur, therapy should be discontinued and medical therapy initiated [see Warnings and Precautions (5.7)].
Starting at 30 weeks gestation, Caldolor and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur [see Use in Specific Populations (8.1)].
Manufactured for:
Cumberland Pharmaceuticals Inc.
Nashville, TN 37203
US Patent Number 6,727,286
PRINCIPAL DISPLAY PANEL - 4 mL vial
NDC 66220-247-04
Caldolor™
(ibuprofen) Injection
400 mg/4 mL
(100 mg/mL) Rx Only
PRINCIPAL DISPLAY PANEL - 4 mL Carton
25 × 4 mL Vials
Caldolor™
(ibuprofen) Injection
400 mg/4 mL
(100 mg/mL)
NDC 66220-247-04
400 mg/4 mL
For
Intravenous
Use
CUMBERLAND®
PHARMACEUTICALS
PRINCIPAL DISPLAY PANEL - 8 mL Vial
NDC 66220-287-08
Rx Only
Caldolor™
(ibuprofen) Injection
800 mg/8 mL
(100 mg/mL)
FOR INTRAVENOUS USE.
Store at controlled room temperature,
20°C-25°C (68°F-77°F).
Single dose vial, discard unused portion.
DOSAGE: See package insert for
dosage information.
PRINCIPAL DISPLAY PANEL - 8 mL Carton
25 × 8 mL Vials
800 mg/8 mL
NDC 66220-287-08
For
Intravenous
Use
Caldolor™
(ibuprofen) Injection
800 mg/8 mL
(100 mg/mL)
CUMBERLAND®
PHARMACEUTICALS
PRINCIPAL DISPLAY PANEL - 4 mL Vial
NDC 66220-247-04
Caldolor™
(ibuprofen) Injection
400 mg/4 mL
(100 mg/mL)
PRINCIPAL DISPLAY PANEL - 4 mL Carton
25 × 4 mL Vials
400 mg/4 mL
NDC 66220-247-04
For
Intravenous
Use
Caldolor™
(ibuprofen) Injection
400 mg/4 mL
(100 mg/mL)
CUMBERLAND®
PHARMACEUTICALS
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA022348 | 08/27/2009 | |
Generic Name: brompheniramine/dextromethorphan/phenylpropanolamine (brome fen IR a meen/dex troe meth OR fan/fen ill proe pa NOLE a meen)
Brand Names: Delhistine DM, Dimetapp Cold and Cough Liquigel, Dimetapp DM, DM Cold and Cough, Histinex DM, Iohist DM, Liquihistine DM, Poly DM, Poly Histine DM, Prohistine DM, Trihist DM
Brompheniramine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in your body. Brompheniramine prevents sneezing; itchy, watery eyes and nose; and other symptoms of allergies and hay fever.
Dextromethorphan is a cough suppressant. It suppresses an area in the brain that causes coughing
Phenylpropanolamine is a decongestant. It constricts (shrinks) blood vessels (veins and arteries). This reduces the blood flow, allowing nasal passages to open up.
Brompheniramine/dextromethorphan/phenylpropanolamine is used to treat nasal congestion, sinusitis (inflammation of the sinuses), and coughs associated with allergies, hay fever, and the common cold.
Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.
Brompheniramine/dextromethorphan/phenylpropanolamine may also be used for purposes other than those listed in this medication guide.
Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.
Do not take more of this medication than is recommended. If your symptoms do not improve, or if they worsen, talk to your doctor.
Before taking this medication, tell your doctor if you have
diabetes,
glaucoma,
any type of heart disease or high blood pressure,
thyroid disease,
emphysema or chronic bronchitis, or
difficulty urinating or have an enlarged prostate.
You may not be able to take brompheniramine/dextromethorphan/phenylpropanolamine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.
Take brompheniramine/dextromethorphan/phenylpropanolamine exactly as directed. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.
To ensure that you get a correct dose, measure the liquid forms of brompheniramine/dextromethorphan/phenylpropanolamine with a special dose-measuring spoon or cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.
Do not take brompheniramine/dextromethorphan/phenylpropanolamine for longer than 7 days in a row. If your symptoms do not improve, if they get worse, or if you have a fever, talk to your doctor.
Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.
Symptoms of a brompheniramine/dextromethorphan/phenylpropanolamine overdose include dry mouth, large pupils, flushing, nausea, vomiting, hyperactivity, or hallucinations.
Brompheniramine/dextromethorphan/phenylpropanolamine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if brompheniramine/dextromethorphan/phenylpropanolamine is taken with any of these medications.
Other, less serious side effects may be more likely to occur. Continue to take brompheniramine/dextromethorphan/phenylpropanolamine and talk to your doctor or try another similar medication if you experience
dryness of the eyes, nose, and mouth;
drowsiness or dizziness;
blurred vision;
difficulty urinating; or
excitation in children.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
Do not take other over-the-counter cough, cold, allergy, diet, or sleep aids while taking brompheniramine/dextromethorphan/phenylpropanolamine without first talking to your doctor or pharmacist. Other medications may also contain brompheniramine, dextromethorphan, phenylpropanolamine, or other similar drugs. You may accidentally take too much of these medicines.
Brompheniramine/dextromethorphan/phenylpropanolamine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if brompheniramine/dextromethorphan/phenylpropanolamine is taken with any of these medications.
Drugs other than those listed here may also interact with brompheniramine/dextromethorphan/phenylpropanolamine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.
Brompheniramine/dextromethorphan/phenylpropanolamine is available over the counter and with a prescription in many different formulations. Ask your pharmacist any questions you have about this medication, especially if it is new to you.
Generic Name: triamcinolone (Topical application route)
trye-am-SIN-oh-lone a-SEET-oh-nide
In the U.S.
In Canada
Available Dosage Forms:
Therapeutic Class: Corticosteroid, Intermediate
Pharmacologic Class: Triamcinolone
Triamcinolone topical is used to help relieve redness, itching, swelling, or other discomfort caused by skin conditions. This medicine is a corticosteroid (cortisone-like medicine or steroid).
This medicine is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of triamcinolone topical in the pediatric population. However, because of this medicine's toxicity, it should be used with caution. Children may absorb large amounts through the skin, which can cause serious side effects. If your child is using this medicine, follow your doctor's instructions very carefully.
No information is available on the relationship of age to the effects of triamcinolone topical in geriatric patients.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain triamcinolone. It may not be specific to Triaderm Mild Cream. Please read with care.
It is very important that you use this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects or skin irritation.
This medicine is for use on the skin only. Do not get it in your eyes. Do not use it on skin areas that have cuts, scrapes, or burns. If it does get on these areas, rinse it off right away with water.
If you or your child are using the spray form on or near the face, protect your nose to avoid breathing it in and make sure that your eyes are covered.
This medicine should only be used for skin conditions that your doctor is treating. Check with your doctor before using it for other conditions, especially if you think that a skin infection may be present. This medicine should not be used to treat certain kinds of skin infections or conditions, such as severe burns.
Do not use the spray on the groin or underarms unless directed to do so by your doctor.
To use:
The spray form is flammable until it dries on the skin. Do not use it near heat, an open flame, or while smoking. Do not puncture, break, or burn the aerosol can.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Store the canister at room temperature, away from heat and direct light. Do not freeze. Do not keep this medicine inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
It is very important that your doctor check the progress of you or your child at regular visits for any problems that may be caused by this medicine. Blood and urine tests may be needed to check for unwanted effects.
If your or your child's symptoms do not improve within a few weeks, or if they become worse, check with your doctor.
Using too much of this medicine or using it for a long time may increase your risk of having adrenal gland problems. The risk is greater for children and patients who use large amounts for a long time. Talk to your doctor right away if you or your child have more than one of these symptoms while you are using this medicine: blurred vision; dizziness or fainting; a fast, irregular, or pounding heartbeat; increased thirst or urination; irritability; or unusual tiredness or weakness.
Stop using this medicine and check with your doctor right away if you or your child have a skin rash, burning, stinging, swelling, or irritation on the skin.
Do not use this medication with other corticosteroid (eg, hydrocortisone) containing products without checking with your doctor first. .
Do not use cosmetics or other skin care products on the treated areas.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
Klorhex may be available in the countries listed below.
Chlorhexidine digluconate (a derivative of Chlorhexidine) is reported as an ingredient of Klorhex in the following countries:
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In the US, Ixempra (ixabepilone systemic) is a member of the drug class mitotic inhibitors and is used to treat Breast Cancer and Breast Cancer - Metastatic.
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Desferrioxamine Mesilate 500 mg and 2 g Powder for Injection.
Desferrioxamine mesilate 500 mg or 2 g per vial.
Following reconstitution, each ml of solution contains 100 mg desferrioxamine mesilate.
For a full list of excipients, see section 6.1.
Powder for solution for injection or infusion.
White to cream powder or lyophilised plug.
Iron overload - acute iron poisoning; primary and secondary haemochromatosis including thalassaemia and transfusional haemosiderosis; in patients in whom concomitant disorders (e.g. severe anaemia, hypoproteinaemia, renal or cardiac failure) preclude phlebotomy; and for the diagnosis of iron storage disease and sideroblastic anaemia, auto-immune haemolytic anaemia and other chronic anaemias.
Aluminium overload - in patients on maintenance dialysis for end stage renal failure where preventative measures (e.g. reverse osmosis) have failed and with proven aluminium-related bone disease and/or anaemia, dialysis encephalopathy; and for diagnosis of aluminium overload.
Desferrioxamine mesilate may be administered intramuscularly, intravenously, or subcutaneously. When administered subcutaneously the needle should not be inserted too close to the dermis.
Desferrioxamine mesilate has limited efficacy in children under three years of age.
Treatment of acute iron poisoning: Adults, adolescents and children: desferrioxamine mesilate may be administered parenterally (intramuscularly, intravenously, or subcutaneously). It is important to initiate treatment as soon as possible.
Patients with -
?.- serum iron levels > 500 µg/dl (89.5 µmol/l), or
?.- serum iron levels> 350 µg/dl (62.6 µmol/l) with evidence of free iron, or
?.- with signs and symptoms of acute iron poisoning, should be given desferrioxamine mesilate, either intramuscularly or intravenously to eliminate iron that has already been absorbed. The dosage and route of administration should be adapted to the severity of the poisoning.
Dose: The normal dose is 2 g for an adult and adolescent, and 1 g for a child, administered as a single dose by intramuscular injection.
If the patient is hypotensive or in shock, the intravenous route of administration is recommended. Initially the maximum rate of intravenous administration should be 15 mg/kg/hr. It should be reduced after 4-6 hours so that the total dose does not exceed 80 mg/kg/24 hours. However, in the absence of adverse reactions, much larger doses may be tolerated.
Therapy should be continued until serum iron levels are less than the total iron binding capacity.
The effectiveness of treatment is dependent on an adequate urine output in order that the iron complex (ferrioxamine) is excreted from the body. Therefore, if oliguria or anuria develop, peritoneal dialysis or haemodialysis may become necessary to remove ferrioxamine.
It should be noted that the serum iron level may rise sharply when the iron is released from the tissues.
100 mg desferrioxamine mesilate can chelate 8.5 mg of ferric iron.
Primary and secondary haemochromatosis including thalassaemia, in patients in whom concomitant disorders (e.g. severe anaemia, hypoproteinaemia) preclude phlebotomy: The main aim of therapy in younger patients is to achieve an iron balance and prevent haemosiderosis, whilst in the older patient a negative iron balance is desirable in order to slowly deplete the increased iron stores and to prevent the toxic effects of iron.
Adults, adolescents and children: Desferrioxamine mesilate therapy should be commenced after the first 10-15 blood transfusions, or when serum ferritin levels reach 1,000 ng/ml. The dose and route of administration should be individually adapted according to the degree of iron overload.
Dose: The lowest effective dose should be used. The average daily dose will lie between 20 and 60 mg/kg. Patients with serum ferritin levels of < 2,000 ng/ml should require about 25 mg/kg/day, and those with levels between 2,000 and 3,000 ng/ml about 35 mg/kg/day. Higher doses should only be employed if the benefit for the patient outweighs the risk of adverse events.
To assess the chelation therapy, 24 hour urinary iron excretion should initially be monitored daily. Starting with a dose of 500 mg daily the dose should be raised until a plateau of iron excretion is reached. Once the appropriate dose has been established, urinary iron excretion can be assessed at intervals of a few weeks.
Mode of administration: Slow subcutaneous infusions by means of a portable, light-weight, infusion pump over a period of 8-12 hours is effective and particularly convenient for ambulant patients. It may be possible to achieve a further increase in iron excretion by infusing the same daily dose over a 24 hour period. Patients should be treated 4-7 times a week depending on the degree of iron overload.
As intramuscular injections are less effective, they should be given only when subcutaneous infusions are not appropriate.
Desferrioxamine mesilate can be administered by intravenous infusion during blood transfusion.
Continuous intravenous infusion is recommended for patients incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. Implanted intravenous systems can be used when intensive chelation is carried out at home.
Diagnosis of iron storage disease and certain anaemias: The desferrioxamine mesilate test for iron overload is based on the principle that normal subjects do not excrete more than a fraction of a milligram of iron in their urine daily, and that a standard intramuscular injection of 500 mg of desferrioxamine mesilate will not increase this above 1 mg (18 µmol). In iron storage diseases, however, the increase may be well over 1.5 mg (27 µmol). It should be borne in mind that the test only yields reliable results when renal function is normal.
Desferrioxamine mesilate is administered as a 500 mg intramuscular injection. Urine is then collected for a period of 6 hours and its iron content determined. Excretion of 1-1.5 mg (18-27 µmol) of iron during this 6-hour period is suggestive of iron overload; values greater than 1.5 mg (27 µmol) can be regarded as pathological.
Use in the elderly: No special dosage regime is necessary but concurrent renal insufficiency should be taken into account.
Treatment for aluminium overload in patients with end-stage renal failure: Patients should receive desferrioxamine mesilate if:
?.-they have symptoms or evidence of organ impairment due to aluminium overload
?.-they are asymptomatic but their serum aluminium levels are consistently above 60 ng/ml and associated with a positive desferrioxamine mesilate test (see below), particularly if a bone biopsy provides evidence of aluminium related bone disease.
The iron– and aluminium complexes are dialyzable. Their excretion can be increased by dialysis in patients with renal failure.
Adults, adolescents and children: Patients on maintenance haemodialysis or haemofiltration: 5 mg/kg once a week administered during the last hour of a dialysis as a slow intravenous infusion (to reduce loss of free active substance in the dialysate).
Four weeks after the completion of a 3-month course of desferrioxamine mesilate treatment, a desferrioxamine mesilate infusion test should be performed, followed by a second test 1 month later. Serum aluminium increases above baseline of less than 75 ng/ml measured in 2 successive infusion tests indicate that further desferrioxamine mesilate treatment is not necessary.
Patients on CAPD (Continuous ambulatory peritoneal dialysis) or CCPD (Continuous cyclic peritoneal dialysis): 5 mg/kg once a week prior to the final exchange of the day. Desferrioxamine mesilate may be administered intravenously (by slow infusion), intramuscularly, subcutaneously or intraperitoneally; the intraperitoneal route is recommended for these patients.
Diagnosis of aluminium overload in patients with end-stage renal failure: A desferrioxamine mesilate infusion test is recommended in patients with serum aluminium levels > 60 ng/ml associated with serum ferritin levels > 100 ng/ml.
Serum aluminium values should be determined from blood samples taken: -immediately before a haemodialysis session (baseline); 5 mg/kg should then be administered as a slow intravenous infusion during the last hour of the dialysis
-at the start of the next haemodialysis session.
An increase in serum aluminium above baseline of more than 150 ng/ml is suggestive of aluminium overload. It should be noted that a negative test does not completely exclude the possibility of aluminium overload.
100 mg desferrioxamine mesilate can bind 4.1 mg Al+++.
Hypersensitivity to desferrioxamine mesilate unless the patient can be desensitised.
Desferrioxamine mesilate should be used with caution in patients with renal impairment since the metal complexes are excreted mainly via the kidneys. In these patients, dialysis will increase the elimination of chelated iron and aluminium.
Used alone desferrioxamine mesilate may exacerbate neurological impairment in patients with aluminium-related encephalopathy. This deterioration (manifest as seizures) is probably related to an acute increase in brain aluminium secondary to elevated circulating levels. Pre-treatment with clonazepam has been shown to afford protection against such impairment.
Treatment with desferrioxamine mesilate by the intravenous route should only be administered in the form of slow infusions. If an intramuscular injection is accidentally given intravenously, this may lead to circulatory collapse.
Desferrioxamine mesilate should not be administered subcutaneously in concentrations and/or doses higher than those recommended as otherwise local irritation at the site of administration may occur more frequently.
Patients suffering from iron overload are particularly susceptible to infection. There have been reports of desferrioxamine mesilate promoting some infections such as Yersinia enterocolitica and Y. Pseudotuberculosis. If patients develop fever with pharyngitis, diffuse abdominal pain or enteritis/enterocolitis, desferrioxamine mesilate therapy should be stopped, and appropriate treatment with antibiotics should be instituted. Desferrioxamine mesilate therapy may be resumed once the infection has cleared.
In patients undergoing haemodialysis while receiving desferrioxamine mesilate, there have been rare reports of severe fungal infection (i.e. cases of mucormycosis). If any characteristic signs or symptoms occur desferrioxamine mesilate treatment should be discontinued, mycological tests carried out and appropriate treatment immediately instituted. Mucormycosis has been reported to occur in dialysis patients not receiving desferrioxamine mesilate, thus no causal link with the use of the medicinal product has been established.
Disturbances of vision and hearing have been reported during prolonged desferrioxamine mesilate therapy. In particular this has occurred in patients on higher than recommended doses, or in patients with low serum ferritin levels. Therefore, ophthalmological and audiological tests should be carried out both prior to the institution of long-term therapy with desferrioxamine mesilate and at 3-monthly intervals during treatment. A detailed ophthalmological assessment is recommended (visual field measurements, funduscopy, colour vision testing using pseudoisochromatic plates and the Farnsworth D-15 colour test, slit lamp investigation, visual evoked potential studies).
If disturbances of vision or hearing do occur, treatment with desferrioxamine mesilate should be stopped. Such disturbances may be reversible. If desferrioxamine mesilate therapy is re-instituted later at a lower dosage, close monitoring of ophthalmological/auditory function should be carried out with due regard to the risk-benefit ratio.
The use of inappropriately high doses of desferrioxamine mesilate in patients with low ferritin levels or young children (<3 years at commencement of treatment) has also been associated with growth retardation; dose reduction has been found to restore the growth rate to pre-treatment levels in some cases. Three monthly checks on body weight and height are recommended in children.
Growth retardation, if associated with excessive doses of desferrioxamine mesilate, must be distinguished from growth retardation from iron overload. Growth retardation from desferrioxamine mesilate use is rare if the dose is kept below 40 mg/kg; if growth retardation has been associated with doses above this value, then reduction of the dose may result in return in growth velocity, however, predicted adult height is not attained.
Oral administration of vitamin C (up to a maximum of 200 mg daily, given in divided doses) may serve to enhance excretion of the iron complex in response to desferrioxamine mesilate; larger doses of vitamin C fail to produce an additional effect. Monitoring of cardiac function is indicated during such combined therapy. Vitamin C should be given only if the patient is receiving desferrioxamine mesilate regularly, and should not be administered within the first month of desferrioxamine mesilate therapy. In patients with severe chronic iron-storage disease undergoing combined treatment with desferrioxamine mesilate and high doses of vitamin C (more than 500 mg daily) impairment of cardiac function has been encountered; this proved reversible when the vitamin C was withdrawn. Vitamin C supplements should not therefore be given to patients with cardiac failure.
Desferrioxamine mesilate should not be used in combination with prochlorperazine (a phenothiazine derivative) since prolonged unconsciousness may result. Caution is advised when desferrioxamine mesilate is used in combination with any phenothiazine.
Gallium67 imaging results may be distorted because of the rapid urinary excretion of desferrioxamine-bound radiolabel. Discontinuation of desferrioxamine mesilate 48 hours prior to scintigraphy is advised.
There is evidence that aluminium intoxication causes reduced erythropoiesis. In dialysed patients with aluminium and/or iron overload treated with desferrioxamine mesilate and erythropoietin some dosage adjustment of the latter may be necessary. Regular monitoring of iron stores should also be carried out.
Desferrioxamine mesilate has caused teratogenic effects in animals when given during pregnancy (see also section 5.3).
It is not known whether desferrioxamine mesilate is excreted into the breast milk.
Desferrioxamine mesilate should not be given to pregnant or lactating women unless in the judgement of the physician, the expected benefits to the mother outweigh the potential risk to the child. This particularly applies to the first trimester.
Desferrioxamine mesilate has a major influence on the ability to drive and use machines in patients experiencing CNS effects such as dizziness or impaired vision/hearing.
The following adverse events have been reported:
Frequency estimate: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000) including isolated reports.
Blood and the lymphatic system disorders: Rare: blood dyscrasias
(e.g. thrombocytopenia), aplastic anaemia.
Immune system disorders: Rare: anaphylactic/anaphylactoid reactions with or without shock, angioedema including laryngeal oedema.
Endocrine disorders: Rare: growth retardation.
Nervous system disorders: Rare: neurological disturbances, dizziness, convulsions, exacerbation of neurological impairment in aluminium-related encephalopathy.
Isolated cases: precipitation of dialysis dementia, peripheral sensory neuropathy, paraesthesia.
Eye disorders: Rare: Blurred vision, decreased visual acuity, loss of vision, impairment of colour vision, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration of the retina), optic neuritis, cataracts, corneal opacities.
Ear and labyrinth disorders: Uncommon: Tinnitus; hearing loss (including high frequency sensorineural hearing loss).
Cardiac disorders: Rare: hypotension.
Respiratory, thoracic and mediastinal disorders: Very Rare: adult respiratory distress syndrome (with dyspnoea, cyanosis and interstitial pulmonary infiltrates); following excessively high intravenous doses of desferrioxamine mesilate.
Gastrointestinal disorders: Rare: nausea, vomiting, diarrhoea, abdominal cramps.
Hepato-biliary disorders: Rare: impaired hepatic function.
Musculoskeletal, connective tissue and bone disorders: Growth retardation and bone changes (e.g. metaphyseal dysplasia) are common in chelated patients given doses of 60 mg/kg especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk is considerably reduced. Rare: Leg cramps and bone pain have also been reported in isolated cases.
Renal and urinary disorders: Very Rare: impaired renal function.
General disorders and administration site conditions: Common: pain, swelling, induration, erythema, burning, pruritus, wheals, rash at the injection/infusion site, occasionally accompanied by fever, chills and malaise.
Skin and subcutaneous disorders: Rare: generalised rash, pruritus, urticaria.
Some of the adverse events mentioned above must be considered as signs and symptoms of the underlying disease. Excretion of iron complex during treatment with desferrioxamine mesilate causes reddish-brown discolouration of the urine.
Desferrioxamine mesilate is usually administered parenterally and acute poisoning is unlikely to occur
Signs and symptoms: Tachycardia, hypotension and gastrointestinal symptoms have occasionally occurred in patients who received an overdose of desferrioxamine mesilate. Accidental administration of desferrioxamine mesilate by the intravenous route may be associated with acute but transient loss of vision, aphasia, agitation, headache, nausea, bradycardia and hypotension.
Treatment: There is no specific antidote to desferrioxamine mesilate but signs and symptoms may be eliminated by reducing the dosage and desferrioxamine mesilate is dialysable. Appropriate supportive therapy should be instituted.
Pharmacotherapeutic group: Iron chelating agents, ATC Code: V03A C01
Desferrioxamine mesilate is a chelating agent for trivalent iron and aluminium ions; the resulting chelates (ferrioxamine and aluminoxamine) are stable and non-toxic. Neither chelate undergoes significant intestinal absorption, and any formed systemically as a result of parenteral administration is rapidly excreted via the kidneys without deleterious effects. Desferrioxamine mesilate takes up iron either free or bound to ferritin and haemosiderin. Similarly it mobilises and chelates tissue bound aluminium. It does not remove iron from haemin containing substances including haemoglobin and transferrin. Since both ferrioxamine and aluminoxamine are completely excreted, desferrioxamine mesilate promotes the excretion of iron and aluminium in urine and faeces thus reducing pathological iron or aluminium deposits in the organs and tissues.
Desferrioxamine mesilate is rapidly absorbed following intramuscular or subcutaneous administration. In healthy volunteers peak plasma concentrations of desferrioxamine (15.5 µmol/l / 8.7 µg/ml) and ferrioxamine (3.7 µmol/l / 2.3 µg/ml) were observed at 30 minutes and 1 hour respectively, following an injection (10 mg/kg) of desferrioxamine mesilate. It is only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.
Serum protein binding of desferrioxamine is less than 10 % in vitro.
Four metabolites of desferrioxamine mesilate were isolated and identified from urine of patients with iron overload. The following biotransformation reactions were found to occur with desferrioxamine: transamination and oxidation yielding an acid metabolite, beta-oxidation also yielding an acid metabolite, decarboxylation and N-hydroxylation yielding neutral metabolites.
In healthy subjects elimination is biphasic, first phase half-lives for desferrioxamine and ferrioxamine are 1 hour and 2.4 hours, respectively. In the second phase both compounds have a half-life of 6 hours. Of the injected dose 22 % appears in the urine as desferrioxamine and 1 % as ferrioxamine, after 6 hours.
In patients with haemochromatosis peak plasma levels of 7.0 µmol/l (3.9 µg/ml) were measured for desferrioxamine, and 15.7 µmol/l (9.6 µg/ml) for ferrioxamine, 1 hour after intramuscular injection of 10 mg/kg desferrioxamine mesilate. These patients eliminated desferrioxamine and ferrioxamine with half-lives of 5.6 and 4.6 hours, respectively. Six hours after the injection 17 % of the dose was excreted in the urine as desferrioxamine and 12 % as ferrioxamine.
In patients dialysed for renal failure who received 40 mg/kg desferrioxamine mesilate infused intravenously within 1 hour, the plasma concentration at the end of the infusion was 152 µmol/l (85.2 µg/ml) when the infusion was given between dialysis sessions. Plasma concentrations of desferrioxamine were between 13 % and 27 % lower when the infusion was administered during dialysis. Concentrations of ferrioxamine were in all cases approx. 7.0 µmol/l (4.3 µg/ml) with concomitant aluminoxamine levels of 2-3 µmol/litre (1.2-1.8 µg/ml). After the infusion was discontinued, the plasma concentration of desferrioxamine decreased rapidly with a half-life of 20 minutes. A smaller fraction of the dose was eliminated with a longer half-life of 14 hours. Plasma concentrations of aluminoxamine continued to increase for up to 48 hours post-infusion and reached values of approx. 7 µmol/l (4 µg/ml). Following dialysis the plasma concentration of aluminoxamine fell to 2.2 µmol/l
(1.3 µg/ml), indicating that the aluminoxamine complex is dialysable.
During peritoneal dialysis desferrioxamine is absorbed if administered in the dialysis fluid.
In rabbits desferrioxamine mesilate caused skeletal malformations. However, these teratogenic effects in the fetuses were observed at doses which were toxic to the mother animal. In mice and rats desferrioxamine mesilate appears to be free of teratogenic activity.
Long-term carcinogenicity studies have not been performed.
Evidence of mutagenicity has been observed in mouse lymphoma cells.
None
Heparin is pharmaceutically incompatible with desferrioxamine mesilate solutions.
30 months
In use: Following dilution in water for injections, chemical and physical in-use stability has been demonstrated for up to 48 hours at 20ºC. From a microbiological point of view, however, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and dilution should take place in controlled and validated aseptic conditions.
Do not store above 25°C.
After opening: use immediately.
After dilution: do not refrigerate or freeze.
Type I glass vials with bromobutyl rubber stoppers containing 500 mg or 2 g of powder.
500 mg vial: Cartons of 10 vials.
2 g vial: Cartons of 1 vial.
For parenteral administration: The medicinal product should preferably be employed in the form of a 10 % solution, e.g. by dissolving the contents of one 500 mg vial in 5 ml of Water for Injections. The 10 % desferrioxamine mesilate solution can be diluted with routinely employed infusion solutions (sodium chloride 9 mg/ml (0.9 %), glucose 50 mg/ml (5 %), or sodium chloride 1.8 mg/ml (0.18 %) and glucose 40 mg/ml (4 %)), although these should not be used as solvent for the dry substance. Dissolved desferrioxamine mesilate can also be added to dialysis fluid and given intraperitoneally to patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD).
Only clear pale yellow desferrioxamine mesilate solutions should be used. Opaque, cloudy or discoloured solutions should be discarded.
Unused portions of opened vials must not be stored and should be discarded immediately.
Hospira UK Limited
Queensway,
Royal Leamington Spa, Warwickshire
CV313RW
PL 04515/0103
9 January 2001
January 2008
