Complegel may be available in the countries listed below.
Ingredient matches for Complegel
Citicoline
Citicoline is reported as an ingredient of Complegel in the following countries:
- Argentina
- Colombia
International Drug Name Search
Tuesday, 28 December 2010
Sunday, 26 December 2010
Cipamox
Cipamox may be available in the countries listed below.
Ingredient matches for Cipamox
Amoxicillin
Amoxicillin trihydrate (a derivative of Amoxicillin) is reported as an ingredient of Cipamox in the following countries:
- Portugal
International Drug Name Search
RoxiHefa
RoxiHefa may be available in the countries listed below.
Ingredient matches for RoxiHefa
Roxithromycin
Roxithromycin is reported as an ingredient of RoxiHefa in the following countries:
- Romania
International Drug Name Search
Friday, 24 December 2010
Colestilan Chloride
Colestilan Chloride may be available in the countries listed below.
Ingredient matches for Colestilan Chloride
Colestilan
Colestilan Chloride (USAN) is also known as Colestilan (Rec.INN)
International Drug Name Search
Glossary
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Click for further information on drug naming conventions and International Nonproprietary Names.
Thursday, 23 December 2010
Cyanokit
Cyanokit is a brand name of hydroxocobalamin, approved by the FDA in the following formulation(s):
CYANOKIT (hydroxocobalamin - injectable; injection)
Manufacturer: MERCK SANTE SAS
Approval date: April 8, 2011
Strength(s): 5GM/VIAL (5GM/KIT) [RLD]
Has a generic version of Cyanokit been approved?
No. There is currently no therapeutically equivalent version of Cyanokit available.
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Cyanokit. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
Related Patents
Patents are granted by the U.S. Patent and Trademark Office at any time during a drug's development and may include a wide range of claims.
Dosage form of hydroxocobalamin and its use in cyanide poisoning
Patent 5,834,448
Issued: November 10, 1998
Inventor(s): Pouchol; Gerard & Bonhomme; Yves & Poulain; Marie-Laure & Duran; Michel
Assignee(s): Merck Patent Gesellschaft mit beschrankter Haftung
The invention relates to a new dosage form of hydroxocobalamin which serves in the treatment of cyanide poisoning and contains hydroxocobalamin in freeze-dried form. The hydroxocobalamin is freeze-dried in an acidic medium so as to be practically instantly redissolved in a neutral saline solution. The present invention also relates to a process for producing hydroxocobalamin-based pharmaceutical compositions as well as to first aid kits containing these compositions and methods of using such kits for the treatment of cyanide poisoning.Patent expiration dates:
- November 14, 2016✓
- November 14, 2016✓✓
- November 14, 2016
Related Exclusivities
Exclusivity is exclusive marketing rights granted by the FDA upon approval of a drug and can run concurrently with a patent or not. Exclusivity is a statutory provision and is granted to an NDA applicant if statutory requirements are met.
- Exclusivity expiration dates:
- December 15, 2013 - ORPHAN DRUG EXCLUSIVITY
See also...
- Cyanokit Consumer Information (Drugs.com)
- Cyanokit Kit Consumer Information (Wolters Kluwer)
- Cyanokit injection Consumer Information (Cerner Multum)
- Hydroxocobalamin Consumer Information (Wolters Kluwer)
- Hydroxocobalamin Kit Consumer Information (Wolters Kluwer)
- Hydroxocobalamin injection Consumer Information (Cerner Multum)
Wednesday, 22 December 2010
Noviana
Noviana may be available in the countries listed below.
Ingredient matches for Noviana
Estradiol
Estradiol is reported as an ingredient of Noviana in the following countries:
- Slovakia
Norethisterone
Norethisterone 17ß-acetate (a derivative of Norethisterone) is reported as an ingredient of Noviana in the following countries:
- Slovakia
International Drug Name Search
Monday, 20 December 2010
Bumetanide Tablets
Dosage Form: tablet
Bumetanide Tablets USP
Rx only
WARNING
Bumetanide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required, and dose and dosage schedule have to be adjusted to the individual patient’s needs (see DOSAGE AND ADMINISTRATION).
Bumetanide Tablets Description
Bumetanide is a loop diuretic, available as scored tablets. Each tablet for oral administration contains 0.5 mg, 1 mg or 2 mg of bumetanide. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, corn starch, magnesium stearate, microcrystalline cellulose, pregelatinized starch, talc, with the following dye systems: 0.5 mg- D&C yellow No. 10 aluminum lake, FD&C blue No. 1 aluminum lake and FD&C red No. 40 aluminum lake; 1 mg- D&C yellow No. 10 aluminum lake; 2 mg- synthetic black iron oxide, synthetic red iron oxide and synthetic yellow iron oxide.
Chemically, bumetanide is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is a practically white powder having a calculated molecular weight of 364.42, and the following structural formula:
C17H20N2O5S
Bumetanide Tablets - Clinical Pharmacology
Bumetanide is a loop diuretic with a rapid onset and short duration of action. Pharmacological and clinical studies have shown that 1 mg bumetanide has a diuretic potency equivalent to approximately 40 mg furosemide. The major site of bumetanide action is the ascending limb of the loop of Henle.
The mode of action has been determined through various clearance studies in both humans and experimental animals. Bumetanide inhibits sodium reabsorption in the ascending limb of the loop of Henle, as shown by marked reduction of free-water clearance (cH2O) during hydration and tubular free-water reabsorption (TcH2O) during hydropenia. Reabsorption of chloride in the ascending limb is also blocked by bumetanide, and bumetanide is somewhat more chloruretic than natriuretic.
Potassium excretion is also increased by bumetanide, in a dose-related fashion.
Bumetanide may have an additional action in the proximal tubule. Since phosphate reabsorption takes place largely in the proximal tubule, phosphaturia during bumetanide-induced diuresis is indicative of this additional action. This is further supported by the reduction in the renal clearance of bumetanide by probenecid, associated with diminution in the natriuretic response. This proximal tubular activity does not seem to be related to an inhibition of carbonic anhydrase. Bumetanide does not appear to have a noticeable action on the distal tubule.
Bumetanide decreases uric acid excretion and increases serum uric acid. Following oral administration of bumetanide the onset of diuresis occurs in 30 to 60 minutes. Peak activity is reached between 1 and 2 hours. At usual doses (1 mg to 2 mg) diuresis is largely complete within 4 hours; with higher doses, the diuretic action lasts for 4 to 6 hours. Diuresis starts within minutes following an intravenous injection and reaches maximum levels within 15 to 30 minutes.
Several pharmacokinetic studies have shown that bumetanide, administered orally or parenterally, is eliminated rapidly in humans, with a half-life of between 1 and 1½ hours. Plasma protein-binding is in the range of 94% to 96%.
Oral administration of carbon-14 labeled bumetanide to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Urinary and biliary metabolites identified in this study were formed by oxidation of the N-butyl side chain. Biliary excretion of bumetanide amounted to only 2% of the administered dose.
Pediatric Pharmacology
Elimination of bumetanide appears to be considerably slower in neonatal patients compared with adults, possibly because of immature renal and hepatobiliary function in this population. Small pharmacokinetic studies of intravenous bumetanide in preterm and full-term neonates with respiratory disorders have reported an apparent half-life of approximately 6 hours with a range up to 15 hours and a serum clearance ranging from 0.2 mL/min/kg to 1.1 mL/min/kg. In a population of neonates receiving bumetanide for volume overload, mean serum clearance rates were 2.17 mL/min/kg in patients less than 2 months of age and 3.8 mL/min/kg in patients aged 2 to 6 months. Mean serum half-life of bumetanide was 2.5 hours and 1.5 hours in patients aged less than 2 months and those aged 2 to 6 months, respectively. Elimination half-life decreased considerably during the first month of life, from a mean of approximately 6 hours at birth to approximately 2.4 hours at 1 month of age.
In preterm neonates, mean serum concentrations following a single 0.05 mg/kg dose ranged from 126 µg/L at 1 hour to 57 µg/L at 8 hours. In another study, mean serum concentrations following a single 0.05 mg/kg dose were 338 ng/mL at 30 minutes and 176 ng/mL after 4 hours. A single dose of 0.1 mg/kg produced mean serum levels of 314 ng/mL at 1 hour, and 195 ng/mL at 6 hours. Mean volume of distribution in neonates and infants has been reported to range from 0.26 L/kg to 0.39 L/kg.
The degree of protein binding of bumetanide in cord sera from healthy neonates was approximately 97%, suggesting the potential for bilirubin displacement. A study using pooled sera from critically ill neonates found that bumetanide at concentrations of 0.5 µg/mL to 50 µg/mL, but not 0.25 µg/mL, caused a linear increase in unbound bilirubin concentrations.
In 56 infants aged 4 days to 6 months, bumetanide doses ranging from 0.005 mg/kg to 0.1 mg/kg were studied for pharmacodynamic effect. Peak bumetanide excretion rates increased linearly with increasing doses of drug. Maximal diuretic effect was observed at a bumetanide excretion rate of about 7 µg/kg/hr, corresponding to doses of 0.035 mg/kg to 0.040 mg/kg. Higher doses produced a higher bumetanide excretion rate but no increase in diuretic effect. Urine flow rate peaked during the first hour after drug administration in 80% of patients and by 3 hours in all patients.
Geriatric Pharmacology
In a group of ten geriatric subjects between the ages of 65 and 73 years, total bumetanide clearance was significantly lower (1.8 ± 0.3 mL/min•kg) compared with younger subjects (2.9 ± 0.2 mL/min•kg) after a single oral bumetanide 0.5 mg dose. Maximum plasma concentrations were higher in geriatric subjects (16.9 ± 1.8 ng/mL) compared with younger subjects (10.3 ± 1.5 ng/mL). Urine flow rate and total excretion of sodium and potassium were increased less in the geriatric subjects compared with younger subjects, although potassium excretion and fractional sodium excretion were similar between the two age groups. Nonrenal clearance, bioavailability, and volume of distribution were not significantly different between the two groups.
Indications and Usage for Bumetanide Tablets
Bumetanide Tablets USP are indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease, including the nephrotic syndrome.
Almost equal diuretic response occurs after oral and parenteral administration of bumetanide. Therefore, if impaired gastrointestinal absorption is suspected or oral administration is not practical, bumetanide should be given by the intramuscular or intravenous route.
Successful treatment with Bumetanide Tablets USP following instances of allergic reactions to furosemide suggests a lack of cross-sensitivity.
Contraindications
Bumetanide is contraindicated in anuria. Although bumetanide can be used to induce diuresis in renal insufficiency, any marked increase in blood urea nitrogen or creatinine, or the development of oliguria during therapy of patients with progressive renal disease, is an indication for discontinuation of treatment with bumetanide. Bumetanide is also contraindicated in patients in hepatic coma or in states of severe electrolyte depletion until the condition is improved or corrected. Bumetanide is contraindicated in patients hypersensitive to this drug.
Warnings
Volume and Electrolyte Depletion
The dose of bumetanide should be adjusted to the patient’s need. Excessive doses or too frequent administration can lead to profound water loss, electrolyte depletion, dehydration, reduction in blood volume and circulatory collapse with the possibility of vascular thrombosis and embolism, particularly in elderly patients.
Hypokalemia
Hypokalemia can occur as a consequence of bumetanide administration. Prevention of hypokalemia requires particular attention in the following conditions: patients receiving digitalis and diuretics for congestive heart failure, hepatic cirrhosis and ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, certain diarrheal states, or other states where hypokalemia is thought to represent particular added risks to the patient, i.e., history of ventricular arrhythmias.
In patients with hepatic cirrhosis and ascites, sudden alterations of electrolyte balance may precipitate hepatic encephalopathy and coma. Treatment in such patients is best initiated in the hospital with small doses and careful monitoring of the patient’s clinical status and electrolyte balance. Supplemental potassium and/or spironolactone may prevent hypokalemia and metabolic alkalosis in these patients.
Ototoxicity
In cats, dogs and guinea pigs, bumetanide has been shown to produce ototoxicity. In these test animals bumetanide was 5 to 6 times more potent than furosemide and, since the diuretic potency of bumetanide is about 40 to 60 times furosemide, it is anticipated that blood levels necessary to produce ototoxicity will rarely be achieved. The potential exists, however, and must be considered a risk of intravenous therapy, especially at high doses, repeated frequently in the face of renal excretory function impairment. Potentiation of aminoglycoside ototoxicity has not been tested for bumetanide. Like other members of this class of diuretics, bumetanide probably shares this risk.
Allergy to Sulfonamides
Patients allergic to sulfonamides may show hypersensitivity to bumetanide.
Thrombocytopenia
Since there have been rare spontaneous reports of thrombocytopenia from postmarketing experience, patients should be observed regularly for possible occurrence of thrombocytopenia.
Precautions
General
Serum potassium should be measured periodically and potassium supplements or potassium-sparing diuretics added if necessary. Periodic determinations of other electrolytes are advised in patients treated with high doses or for prolonged periods, particularly in those on low-salt diets.
Hyperuricemia may occur; it has been asymptomatic in cases reported to date. Reversible elevations of the BUN and creatinine may also occur, especially in association with dehydration and particularly in patients with renal insufficiency. Bumetanide may increase urinary calcium excretion with resultant hypocalcemia.
Diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Laboratory Tests
Studies in normal subjects receiving bumetanide revealed no adverse effects on glucose tolerance, plasma insulin, glucagon and growth hormone levels, but the possibility of an effect on glucose metabolism exists. Periodic determinations of blood sugar should be done, particularly in patients with diabetes or suspected latent diabetes.
Patients under treatment should be observed regularly for possible occurrence of blood dyscrasias, liver damage or idiosyncratic reactions, which have been reported occasionally in foreign marketing experience. The relationship of these occurrences to bumetanide use is not certain.
Drug Interactions
Drugs with Ototoxic Potential
(See WARNINGS)
Especially in the presence of impaired renal function, the use of parenterally administered bumetanide in patients to whom aminoglycoside antibiotics are also being given should be avoided, except in life-threatening conditions.
Drugs with Nephrotoxic Potential
There has been no experience with the concurrent use of bumetanide with drugs known to have a nephrotoxic potential. Therefore, the simultaneous administration of these drugs should be avoided.
Lithium
Lithium should generally not be given with diuretics (such as bumetanide) because they reduce its renal clearance and add a high risk of lithium toxicity.
Probenecid
Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by bumetanide. This antagonistic effect of probenecid on bumetanide natriuresis is not due to a direct action on sodium excretion but is probably secondary to its inhibitory effect on renal tubular secretion of bumetanide. Thus, probenecid should not be administered concurrently with bumetanide.
Indomethacin
Indomethacin blunts the increases in urine volume and sodium excretion seen during bumetanide treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent therapy with bumetanide is thus not recommended.
Antihypertensives
Bumetanide may potentiate the effect of various antihypertensive drugs, necessitating a reduction in the dosage of these drugs.
Digoxin
Interaction studies in humans have shown no effect on digoxin blood levels.
Anticoagulants
Interaction studies in humans have shown bumetanide to have no effect on warfarin metabolism or on plasma prothrombin activity.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Bumetanide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system. An 18-month study showed an increase in mammary adenomas of questionable significance in female rats receiving oral doses of 60 mg/kg/day (2000 times a 2-mg human dose). A repeat study at the same doses failed to duplicate this finding.
Reproduction studies were performed to evaluate general reproductive performance and fertility in rats at oral dose levels of 10 mg/kg/day, 30 mg/kg/day, 60 mg/kg/day or 100 mg/kg/day. The pregnancy rate was slightly decreased in the treated animals; however, the differences were small and not statistically significant.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Bumetanide is neither teratogenic nor embryocidal in mice when given in doses up to 3400 times the maximum human therapeutic dose.
Bumetanide has been shown to be nonteratogenic, but it has a slight embryocidal effect in rats when given in doses of 3400 times the maximum human therapeutic dose and in rabbits at doses of 3.4 times the maximum human therapeutic dose. In one study, moderate growth retardation and increased incidence of delayed ossification of sternebrae were observed in rats at oral doses of 100 mg/kg/day, 3400 times the maximum human therapeutic dose. These effects were associated with maternal weight reductions noted during dosing. No such adverse effects were observed at 30 mg/kg/day (1000 times the maximum human therapeutic dose). No fetotoxicity was observed at 1000 to 2000 times the human therapeutic dose.
In rabbits, a dose-related decrease in litter size and an increase in resorption rate were noted at oral doses of 0.1 mg/kg/day and 0.3 mg/kg/day (3.4 and 10 times the maximum human therapeutic dose). A slightly increased incidence of delayed ossification of sternebrae occurred at 0.3 mg/kg/day; however, no such adverse effects were observed at the dose of 0.03 mg/kg/day. The sensitivity of the rabbit to bumetanide parallels the marked pharmacologic and toxicologic effects of the drug in this species. Bumetanide was not teratogenic in the hamster at an oral dose of 0.5 mg/kg/day (17 times the maximum human therapeutic dose). Bumetanide was not teratogenic when given intravenously to mice and rats at doses up to 140 times the maximum human therapeutic dose.
There are no adequate and well-controlled studies in pregnant women. A small investigational experience in the United States and marketing experience in other countries to date have not indicated any evidence of adverse effects on the fetus, but these data do not rule out the possibility of harmful effects. Bumetanide should be given to a pregnant woman only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while the patient is on bumetanide since it may be excreted in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 have not been established.
In vitro studies using pooled sera from critically ill neonates have shown bumetanide to be a potent displacer of bilirubin (see CLINICAL PHARMACOLOGY: Pediatric Pharmacology). The administration of bumetanide could present a particular concern if given to critically ill or jaundiced neonates at risk for kernicterus.
Geriatric Use
Clinical studies of bumetanide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, 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.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Adverse Reactions
The most frequent clinical adverse reactions considered probably or possibly related to bumetanide are muscle cramps (seen in 1.1% of treated patients), dizziness (1.1%), hypotension (0.8%), headache (0.6%), nausea (0.6%) and encephalopathy (in patients with preexisting liver disease) (0.6%). One or more of these adverse reactions have been reported in approximately 4.1% of patients treated with bumetanide.
Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in association with bumetanide use.
Less frequent clinical adverse reactions to bumetanide are impaired hearing (0.5%), pruritus (0.4%), electrocardiogram changes (0.4%), weakness (0.2%), hives (0.2%) abdominal pain (0.2%), arthritic pain (0.2%), musculoskeletal pain (0.2%), rash (0.2%) and vomiting (0.2%). One or more of these adverse reactions have been reported in approximately 2.9% of patients treated with bumetanide.
Other clinical adverse reactions, which have each occurred in approximately 0.1% of patients, are vertigo, chest pain, ear discomfort, fatigue, dehydration, sweating, hyperventilation, dry mouth, upset stomach, renal failure, asterixis, itching, nipple tenderness, diarrhea, premature ejaculation and difficulty maintaining an erection.
Laboratory abnormalities reported have included hyperuricemia (in 18.4% of patients tested), hypochloremia (14.9%), hypokalemia (14.7%), azotemia (10.6%), hyponatremia (9.2%), increased serum creatinine (7.4%), hyperglycemia (6.6%), and variations in phosphorus (4.5%), CO2 content (4.3%) bicarbonate (3.1%) and calcium (2.4%). Although manifestations of the pharmacologic action of bumetanide, these conditions may become more pronounced by intensive therapy.
Also reported have been thrombocytopenia (0.2%) and deviations in hemoglobin (0.8%), prothrombin time (0.8%), hematocrit (0.6%), WBC (0.3%) and differential counts (0.1%). There have been rare spontaneous reports of thrombocytopenia from post-marketing experience.
Diuresis induced by bumetanide may also rarely be accompanied by changes in LDH (1.0%), total serum bilirubin (0.8%), serum proteins (0.7%), SGOT (0.6%), SGPT (0.5%), alkaline phosphatase (0.4%), cholesterol (0.4%) and creatinine clearance (0.3%). Increases in urinary glucose (0.7%) and urinary protein (0.3%) have also been seen.
Overdosage
Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels.
Bumetanide Tablets Dosage and Administration
Dosage should be individualized with careful monitoring of patient response.
Oral Administration
The usual total daily dosage of Bumetanide Tablets is 0.5 mg to 2 mg and in most patients is given as a single dose.
If the diuretic response to an initial dose of Bumetanide Tablets is not adequate, in view of its rapid onset and short duration of action, a second or third dose may be given at 4 to 5 hour intervals up to a maximum daily dose of 10 mg. An intermittent dose schedule, whereby Bumetanide Tablets is given on alternate days or for 3 to 4 days with rest periods of 1 to 2 days in between, is recommended as the safest and most effective method for the continued control of edema. In patients with hepatic failure, the dosage should be kept to a minimum, and if necessary, dosage increased very carefully.
Because cross-sensitivity with furosemide has rarely been observed, Bumetanide Tablets can be substituted at approximately a 1:40 ratio of Bumetanide Tablets to furosemide in patients allergic to furosemide.
Parenteral Administration: Bumetanide injection may be administered parenterally (IV or IM) to patients in whom gastrointestinal absorption may be impaired or in whom oral administration is not practical.
Parenteral treatment should be terminated and oral treatment instituted as soon as possible.
How is Bumetanide Tablets Supplied
Bumetanide Tablets USP, for oral administration, are available as:
0.5 mg: Green, round, biconvex, bisected and debossed “E” above and “128” below the bisect on one side and plain on the reverse side and supplied as:
NDC 0185-0128-01 bottles of 100
NDC 0185-0128-05 bottles of 500
1 mg: Yellow, round, biconvex, bisected and debossed “E” above and “129” below the bisect on one side and plain on the reverse side and supplied as:
NDC 0185-0129-01 bottles of 100
NDC 0185-0129-05 bottles of 500
2 mg: Beige to light brown, round, biconvex, bisected and debossed “E” above and “130” below the bisect on one side and plain on the reverse side and supplied as:
NDC 0185-0130-01 bottles of 100
NDC 0185-0130-05 bottles of 500
Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Sandoz Inc.
Princeton, NJ 08540
OS7071
Rev. 04/11
MF0128REV04/11
MG # 16922
0.5 mg Label
NDC 0185-0128-01
Bumetanide
Tablets, USP
0.5 mg
Rx only
100 Tablets
Sandoz
mg Label
NDC 0185-0129-01
Bumetanide
Tablets, USP
1 mg
Rx only
100 Tablets
Sandoz
mg Label
NDC 0185-0130-01
Bumetanide
Tablets, USP
2 mg
Rx only
100 Tablets
Sandoz
| BUMETANIDE bumetanide tablet | ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA074700 | 11/21/1996 | |
| BUMETANIDE bumetanide tablet | ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| ||||||||||||||||||||
| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA074700 | 11/21/1996 | |
| BUMETANIDE bumetanide tablet | ||||||||||||||||||||||
| ||||||||||||||||||||||
| ||||||||||||||||||||||
| ||||||||||||||||||||||
| ||||||||||||||||||||||
| ||||||||||||||||||||||
| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA074700 | 11/21/1996 | |
| Labeler - Eon Labs, Inc. (012656273) |
More Bumetanide Tablets resources
- Bumetanide Tablets Side Effects (in more detail)
- Bumetanide Tablets Dosage
- Bumetanide Tablets Use in Pregnancy & Breastfeeding
- Drug Images
- Bumetanide Tablets Drug Interactions
- Bumetanide Tablets Support Group
- 1 Review for Bumetanides - Add your own review/rating
Compare Bumetanide Tablets with other medications
- Ascites
- Edema
- Pulmonary Edema
Sunday, 19 December 2010
Cacelmin
Cacelmin may be available in the countries listed below.
Ingredient matches for Cacelmin
Kallidinogenase
Kallidinogenase is reported as an ingredient of Cacelmin in the following countries:
- Japan
International Drug Name Search
Byetta
Generic Name: exenatide
Dosage Form: injection
FULL PRESCRIBING INFORMATION
Indications and Usage for Byetta
Type 2 Diabetes Mellitus
Byetta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
Byetta is not a substitute for insulin. Byetta should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of Byetta with prandial insulin has not been studied and cannot be recommended.
Based on postmarketing data Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Byetta has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Byetta. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
Byetta Dosage and Administration
Recommended Dosing
Byetta should be initiated at 5 mcg administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. Based on clinical response, the dose of Byetta can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix Byetta with insulin. Do not transfer Byetta from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Byetta.
Use Byetta only if it is clear, colorless and contains no particles.
Dosage Forms and Strengths
Byetta is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide in the following packages:
- 5 mcg per dose, 60 doses, 1.2 mL prefilled pen
- 10 mcg per dose, 60 doses, 2.4 mL prefilled pen
Contraindications
Hypersensitivity
Byetta is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.
Warnings and Precautions
Acute Pancreatitis
Based on postmarketing data Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of Byetta, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, Byetta should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Byetta should not be restarted. Consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis.
Use with Medications Known to Cause Hypoglycemia
The risk of hypoglycemia is increased when Byetta is used in combination with a sulfonylurea. Therefore, patients receiving Byetta and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.
When Byetta is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin [see Adverse Reactions (6.1)]. The concurrent use of Byetta with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of Byetta with other glucose-independent insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia.
For additional information on glucose dependent effects see Mechanism of Action (12.1).
Renal Impairment
Byetta should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6)]. In patients with end-stage renal disease receiving dialysis, single doses of Byetta 5 mcg were not well-tolerated due to gastrointestinal side effects. Because Byetta may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min).
There have been postmarketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including Byetta. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.
Gastrointestinal Disease
Byetta has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because Byetta is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of Byetta is not recommended in patients with severe gastrointestinal disease.
Immunogenicity
Patients may develop antibodies to exenatide following treatment with Byetta. Antibody levels were measured in 90% of subjects in the 30-week, 24-week and 16-week studies of Byetta. In 3%, 4% and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1)].
Hypersensitivity
There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylaxis and angioedema) in patients treated with Byetta. If a hypersensitivity reaction occurs, the patient should discontinue Byetta and other suspect medications and promptly seek medical advice [see Adverse Reactions (6.2)].
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Byetta or any other antidiabetic drug.
Adverse Reactions
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypoglycemia
Table 1 summarizes the incidence and rate of hypoglycemia with Byetta in six placebo-controlled clinical trials.
| Byetta | |||
|---|---|---|---|
| Placebo twice daily | 5 mcg twice daily | 10 mcg twice daily | |
| N = The number of Intent-to-Treat subjects in each treatment group. | |||
| |||
| Monotherapy (24 Weeks) | |||
| N | 77 | 77 | 78 |
| % Overall | 1.3% | 5.2% | 3.8% |
| Rate (episodes/patient-year) | 0.03 | 0.21 | 0.52 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin (30 Weeks) | |||
| N | 113 | 110 | 113 |
| % Overall | 5.3% | 4.5% | 5.3% |
| Rate (episodes/patient-year) | 0.12 | 0.13 | 0.12 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With a Sulfonylurea (30 Weeks) | |||
| N | 123 | 125 | 129 |
| % Overall | 3.3% | 14.4% | 35.7% |
| Rate (episodes/patient-year) | 0.07 | 0.64 | 1.61 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin and a Sulfonylurea (30 Weeks) | |||
| N | 247 | 245 | 241 |
| % Overall | 12.6% | 19.2% | 27.8% |
| Rate (episodes/patient-year) | 0.58 | 0.78 | 1.71 |
| % Severe | 0.0% | 0.4% | 0.0% |
| With a Thiazolidinedione (16 Weeks) | |||
| N | 112 | not evaluated | 121 |
| % Overall | 7.1% | not evaluated | 10.7% |
| Rate (episodes/patient-years) | 0.56 | not evaluated | 0.98 |
| % Severe | 0.0% | not evaluated | 0.0% |
| With Insulin Glargine (30 Weeks) † | |||
| N | 122 | not evaluated | 137 |
| % Overall | 29.5% | not evaluated | 24.8% |
| Rate (episodes/patient-years) | 1.58 | not evaluated | 1.61 |
| % Severe | 0.8% | not evaluated | 0.0% |
Immunogenicity
Antibodies were assessed in 90% of subjects in the 30-week, 24-week and 16-week studies of Byetta. In the 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to Byetta; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
In the 16-week trial of Byetta add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall) had an attenuated glycemic response to Byetta; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
In the 24-week trial of Byetta used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to Byetta; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
Antibodies to exenatide were not assessed in the 30-week trial of Byetta used in combination with insulin glargine.
Two hundred and ten patients with antibodies to exenatide in the Byetta clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross reactive antibodies were observed across the range of titers.
Other Adverse Reactions
Monotherapy
For the 24-week placebo-controlled study of Byetta used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| Monotherapy | Placebo BID N = 77 % | All Byetta BID N = 155 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 0 | 8 |
| Vomiting | 0 | 4 |
| Dyspepsia | 0 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with Byetta, nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with Byetta withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions.
Combination Therapy
Add-on to metformin and/or sulfonylurea
In the three 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients [see Warnings and Precautions (5.2)] are summarized in Table 3.
| Placebo BID N = 483 % | All Byetta BID N = 963 % | |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 18 | 44 |
| Vomiting | 4 | 13 |
| Diarrhea | 6 | 13 |
| Feeling Jittery | 4 | 9 |
| Dizziness | 6 | 9 |
| Headache | 6 | 9 |
| Dyspepsia | 3 | 6 |
| Asthenia | 2 | 4 |
| Gastroesophageal Reflux Disease | 1 | 3 |
| Hyperhidrosis | 1 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for Byetta-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting.
Add-on to thiazolidinedione with or without metformin
For the 16-week placebo-controlled study of Byetta add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| With a TZD or TZD/MET | Placebo N = 112 % | All Byetta BID N = 121 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 15 | 40 |
| Vomiting | 1 | 13 |
| Dyspepsia | 1 | 7 |
| Diarrhea | 3 | 6 |
| Gastroesophageal Reflux Disease | 0 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions (n = 2) occurred only in Byetta-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the Byetta arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for Byetta-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.
Add-on to insulin glargine with or without metformin and/or thiazolidinedione
For the 30-week placebo-controlled study of Byetta as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| With Insulin Glargine | Placebo N = 122 % | All Byetta BID N = 137 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 8 | 41 |
| Vomiting | 4 | 18 |
| Diarrhea | 8 | 18 |
| Headache | 4 | 14 |
| Constipation | 2 | 10 |
| Dyspepsia | 2 | 7 |
| Asthenia | 1 | 5 |
| Abdominal Distention | 1 | 4 |
| Decreased Appetite | 0 | 3 |
| Flatulence | 1 | 2 |
| Gastroesophageal Reflux Disease | 1 | 2 |
The most frequently reported adverse reactions leading to withdrawal for Byetta-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting.
Post-Marketing Experience
The following additional adverse reactions have been reported during post-approval use of Byetta. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction [see Warnings and Precautions (5.6)].
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see Drug Interactions (7.2)].
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Limitations of Use (1.2) and Warnings and Precautions (5.1)].
Neurologic: dysgeusia; somnolence
Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction [see Warnings and Precautions (5.3)].
Skin and Subcutaneous Tissue Disorders: alopecia
Drug Interactions
Orally Administered Drugs
The effect of Byetta to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. Byetta should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption [see Adverse Reactions (6.2)]. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before Byetta injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Byetta is not administered [see Clinical Pharmacology (12.3)].
Warfarin
There are postmarketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Byetta [see Adverse Reactions (6.2)]. In a drug interaction study, Byetta did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of Byetta therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Byetta use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
Pregnancy Registry
Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
Nursing Mothers
It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when Byetta is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Byetta have not been established in pediatric patients.
Geriatric Use
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology (12.3)]. Byetta was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.
Renal Impairment
Byetta is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of Byetta is required in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating or escalating doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide [see Clinical Pharmacology (12.3)].
Overdosage
In a clinical study of Byetta, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
Byetta Description
Byetta (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
H - His - Gly - Glu - Gly - Thr - Phe - Thr - Ser - Asp - Leu - Ser - Lys - Gln - Met - Glu - Glu - Glu - Ala - Val - Arg - Leu - Phe - Ile - Glu - Trp - Leu - Lys - Asn - Gly - Gly - Pro - Ser - Ser - Gly - Ala - Pro - Pro - Pro - Ser - NH2
Byetta is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).
Byetta - Clinical Pharmacology
Mechanism of Action
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Byetta is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
Byetta improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.
Pharmacodynamics
Glucose-dependent insulin secretion: Byetta has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Byetta does not impair the normal glucagon response to hypoglycemia.
First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Byetta at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Byetta compared with saline (p <0.001 for both).
Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects
Glucagon secretion: In patients with type 2 diabetes, Byetta moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.
Gastric emptying: Byetta slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.
Postprandial Glucose
In patients with type 2 diabetes, Byetta reduces postprandial plasma glucose concentrations (Figure 2).
Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Byettaa Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)
Fasting Glucose
In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of Byetta. Plasma glucose concentrations were significantly reduced with Byetta compared with placebo (Figure 3).
Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Byettaa or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)
Cardiac Electrophysiology
The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms. Thus, Byetta (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.
Pharmacokinetics
Absorption
Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or upper arm.
Distribution
The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.
Metabolism and Elimination
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.
Drug Interactions
Acetaminophen
When 1000 mg acetaminophen elixir was given with 10 mcg Byetta (0 h) and 1 hour, 2 hours, and 4 hours after Byetta injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before Byetta injection.
Digoxin
Administration of repeated doses of Byetta (10 mcg BID) 30 minutes before oral digoxin (0.25 mg QD) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed.
Lovastatin
Administration of Byetta (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of Byetta, the use of Byetta in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.
Lisinopril
In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), Byetta (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-h mean systolic and diastolic blood pressure.
Oral Contraceptives
The effect of Byetta (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after Byetta administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to Byetta administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. Byetta did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after Byetta administration injection as compared to when the OC was given alone. The effect of Byetta on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to Byetta injection.
Warfarin
Administration of warfarin (25 mg) 35 minutes after repeated doses of Byetta (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Byetta did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions (7.2)].
Specific Populations
Renal Impairme
Subscribe to:
Posts (Atom)