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Deramaxx

Dosage Form: FOR ANIMAL USE ONLY
Deramaxx

Deramaxx Chewable Tablets

For Oral Use In Dogs Only

Caution: 

Federal Law (U.S.) restricts this drug to use by or on the order of a licensed veterinarian.

Description:

Deramaxx (deracoxib) is a non-narcotic, non-steroidal anti-inflammatory drug (NSAID) of the coxib class. Deramaxx tablets are round, biconvex, chewable tablets that contain deracoxib formulated with beefy flavoring. The molecular weight of deracoxib is 397.38. The empirical formula is C17-H14-F3-N3-O3-S. Deracoxib is 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl] benzenesulfonamide, and can be termed a diaryl substituted pyrazole. The structural formula is:

Clinical Pharmacology

Mode of Action:

Deramaxx tablets are a member of the coxib class of non-narcotic, non-steroidal, cyclooxygenase-inhibiting anti-inflammatory drugs for the control of postoperative pain and inflammation associated with orthopedic surgery and for the control of pain and inflammation associated with osteoarthritis in dogs.

Data indicate that deracoxib inhibits the production of PGE1 and 6-keto PGF1 by its inhibitory effects on prostaglandin biosynthesis.1 Deracoxib inhibited COX-2 mediated PGE2 production in LPS-stimulated human whole blood.2

Cyclooxygenase-1 (COX-1) is the enzyme responsible for facilitating constitutive physiological processes (e.g., platelet aggregation, gastric mucosal protection, renal perfusion).3 Cyclooxygenase-2 (COX-2) is responsible for the synthesis of inflammatory mediators.4 Both COX isoforms are constitutively expressed in the canine kidney.5 At doses of 2-4 mg/kg/day, Deramaxx tablets do not inhibit COX-1 based on in vitro studies using cloned canine cyclooxygenase.6 The clinical relevance of this in vitro data has not been shown.

Although the plasma terminal elimination half-life for Deramaxx tablets is approximately 3 hours, a longer duration of clinical effectiveness is observed.

Summary pharmacokinetics of Deramaxx tablets are listed in Table 1.

Table 1: Pharmacokinetics of Deracoxib

Parameter	Value
Tmaxa	2 hours
Oral Bioavailability (F)a	> 90% at 2 mg/kg
Terminal elimination half-lifeb	3 hours at 2-3 mg/kg
	19 hours at 20 mg/kg
Systemic Clearanceb	~ 5 ml/kg/min at 2 mg/kg
	~1.7 ml/kg/min at 20 mg/kg
Volume of Distributionc	~ 1.5 L/kg
Protein bindingd	> 90%

a Values obtained following a single 2.35 mg/kg dose

b Estimates following IV administration of deracoxib as an aqueous solution

c Based upon a dose of 2 mg/kg of deracoxib

d Based upon in vitro plasma concentrations of 0.1, 0.3, 1.0, 3.0, 10.0 µg/ml

Non-linear elimination kinetics are exhibited at doses above 8 mg/kg/day, at which competitive inhibition of constitutive COX-1 may occur.

Deracoxib is not excreted as parent drug in the urine. The major route of elimination of deracoxib is by hepatic biotransformation producing four major metabolites, two of which are characterized as products of oxidation and o-demethylation. The majority of deracoxib is excreted in feces as parent drug or metabolite.

Large intersubject variability was observed in drug metabolite profiles of urine and feces. No statistically significant differences between genders were observed.

Indications and Usage:

Always provide “Information for Dog Owners” Sheet with prescription. Carefully consider the potential benefits and risk of Deramaxx and other treatment options before deciding to use DERMAXX. Use the lowest effective dose for the shortest duration consistent with individual response.

Osteoarthritis Pain and Inflammation:

Deramaxx Chewable Tablets are indicated for the control of pain and inflammation associated with osteoarthritis in dogs.

Dosage and Administration:

Osteoarthritis Pain and Inflammation: 0.45 – 0.91 mg/lb/day (1 to 2 mg/kg/day) as a single daily dose, as needed.

Postoperative Orthopedic Pain and Inflammation:

Deramaxx Chewable Tablets are indicated for the control of postoperative pain and inflammation associated with orthopedic surgery in dogs ≥ 4 lbs (1.8 kg).

Dosage and Administration:

Postoperative Orthopedic Pain and Inflammation: 1.4–1.8 mg/lb/day (3 to 4 mg/kg/day) as a single daily dose, as needed, not to exceed 7 days of administration.

Since Deramaxx tablet bioavailability is greatest when taken with food, post-prandial administration is preferable. However, Deramaxx tablets have been shown to be effective under both fed and fasted conditions; therefore, they may be administered in the fasted state if necessary. For postoperative orthopedic pain, administer Deramaxx tablets prior to the procedure. Tablets are scored and dosage should be calculated in half-tablet increments. In clinical practice it is recommended to adjust the individual patient dose while continuing to monitor the dog's status until a minimum effective dose has been reached.

Contraindications:

Dogs with known hypersensitivity to deracoxib should not receive Deramaxx.

Warnings:

Not for use in humans. Keep this and all medications out of reach of children. Consult a physician in case of accidental ingestion by humans. For use in dogs only.

All dogs should undergo a thorough history and physical examination before the initiation of NSAID therapy. Appropriate laboratory tests to establish hematological and serum biochemical baseline data prior to, and periodically during, administration of any NSAID is recommended. Owners should be advised to observe for signs of potential drug toxicity (see Adverse Reactions, Animal Safety and Post-Approval Experience) and be given an “Information for Dog Owners” Sheet.

Precautions:

Since NSAIDs possess the potential to produce gastrointestinal ulceration and/or perforation, concomitant use of Deramaxx tablets with other anti-inflammatory drugs, such as NSAIDs or corticosteroids, should be avoided. As a class, NSAIDs may be associated with gastrointestinal, renal and hepatic toxicity. Sensitivity to drug-associated adverse events varies with the individual patient. Dogs that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Patients at greatest risk for adverse events are those that are dehydrated, on concomitant diuretic therapy, or those with existing renal, cardiovascular, and/or hepatic dysfunction. Plasma levels of deracoxib may increase in a greater than dose-proportional fashion above 8 mg/kg/day. Deramaxx tablets have been safely used during field studies in conjunction with other common medications, including heartworm preventatives, anthelmintics, anesthetics, pre-anesthetic medications, and antibiotics. If additional pain medication is needed after a daily dose of Deramaxx tablets, a non-NSAID/non-corticosteroid class of analgesic may be necessary. It is not known whether dogs with history of hypersensitivity to sulfonamide drugs will exhibit hypersensitivity to Deramaxx tablets. The safe use of DERMAXX tablets in dogs younger than 4 months of age, dogs used for breeding, or in pregnant or lactating dogs has not been evaluated.

NSAIDs may inhibit the prostaglandins which maintain normal homeostatic function. Such anti-prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease that has not been previously diagnosed. Appropriate monitoring procedures should be employed during all surgical procedures. The use of parenteral fluids during surgery should be considered to decrease potential renal complications when using NSAIDs perioperatively. Concurrent administration of potentially nephrotoxic drugs should be carefully approached.

The use of concomitantly protein-bound drugs with Deramaxx tablets has not been studied in dogs. Commonly used protein-bound drugs include cardiac, anticonvulsant and behavioral medications. The influence of concomitant drugs that may inhibit metabolism of Deramaxx tablets has not been evaluated. Drug compatibility should be monitored in patients requiring adjunctive therapy. Consider appropriate washout times when switching from one NSAID to another or when switching from corticosteroid use to NSAID use.

Animal Safety:

In a 6-month study, dogs were dosed with Deramaxx at 0, 2, 4, 6, 8 and 10 mg/kg with food once daily for 6 consecutive months. There were no abnormal feces, and no abnormal findings on clinical observations, food and water consumption, body weights, physical examinations, ophthalmoscopic evaluations, macroscopic pathological examinations, hematology, or buccal bleeding time. Urinalysis results showed hyposthenuria (specific gravity <1.005) and polyuria in one male and one female in the 6 mg/kg group after 6 months of treatment. After 6 months of treatment, the mean BUN values for dogs treated with 6, 8, or 10 mg/kg/day were 30.0, 35.3, and 48.2 mg/dL respectively. No effects were seen on any other clinical chemistry parameters, including other variables associated with renal physiology (serum creatinine, serum electrolytes, and urine sediment evaluation). Dose dependent focal renal tubular degeneration/regeneration was seen in some dogs treated at 6, 8, and 10 mg/kg/day. Focal renal papillary necrosis was seen in 3 dogs dosed at 10 mg/kg/day and in one dog dosed at 8 mg/kg/day. No renal lesions were seen at the label doses of 2 and 4 mg/kg/day. There was no evidence of gastrointestinal, hepatic, or hematopoietic pathology at any of the doses tested.

In a laboratory study, healthy young dogs were dosed with deracoxib tablets once daily, within 30 minutes of feeding, at doses of 0, 4, 6, 8, and 10 mg/kg body weight for 21 consecutive days. No adverse drug events were reported. There were no abnormal findings reported for clinical observations, food and water consumption, body weights, physical examinations, ophthalmic evaluations, organ weights, macroscopic pathologic evaluation, hematology, urinalyses, or buccal mucosal bleeding time. In the clinical chemistry results there was a statistically significant (p<0.0009) dose-dependent trend toward increased levels of blood urea nitrogen (BUN). Mean BUN values remained within historical normal limits at the label dose. No effects on other clinical chemistry values associated with renal function were reported. There was no evidence of renal, gastrointestinal, hepatic or biliary lesions noted during gross necropsy. Renal histopathology revealed trace amounts of tubular degeneration/regeneration in all dose groups including placebo, but no clear dose relationship could be determined. There was no histopathologic evidence of gastrointestinal, hepatic or biliary lesions.

In another study, micronized deracoxib in gelatin capsules was administered once daily to healthy young dogs at doses of 10, 25, 50, and 100 mg/kg body weight for periods up to 14 consecutive days. Food was withheld prior to dosing. Non-linear elimination kinetics occurred at all doses. At doses of 25, 50, and 100 mg/kg, reduced body weight, vomiting, and melena occurred. Necropsy revealed gross gastrointestinal lesions in dogs from all dose groups. The frequency and severity of the lesions increased with escalating doses. At 10 mg/kg, moderate diffuse congestion of gut associated lymphoid tissues (GALT) and erosions/ulcers in the jejunum occurred. At 100 mg/kg, all dogs exhibited gastric ulcers and erosions/ulcerations of the small intestines. There were no hepatic or renal lesions reported at any dose in this study. In a 13-week study, deracoxib in gelatin capsules was administered to healthy dogs at doses of 0, 2, 4, and 8 mg/kg/day. No test-article related changes were identified in clinical observations, physical exams, or any of the other parameters measured. One dog in the 8 mg/kg dose group died from bacterial septicemia secondary to a renal abscess. The relationship between deracoxib administration and the renal abscess is not clear.

Palatability:

Deramaxx tablets were evaluated for palatability in 100 client-owned dogs of a variety of breeds and sizes. Dogs received two doses of Deramaxx tablets, one on each of two consecutive days. Deramaxx tablets were accepted by 94% of dogs on the first day of dosing and by 92% of dogs on the second day of dosing.

Effectiveness:

Deramaxx tablets were evaluated in masked, placebo-controlled multi-site field studies involving client-owned animals to determine effectiveness.

Postoperative Orthopedic Pain and Inflammation Field Study:

In this study, 207 dogs admitted to veterinary hospitals for repair of a cranial cruciate injury were randomly administered Deramaxx tablets or a placebo. Drug administration started the evening before surgery and continued once daily for 6 days postoperatively. Effectiveness was evaluated in 119 dogs and safety was evaluated in 207 dogs. Statistically significant differences in favor of Deramaxx tablets were found for lameness at walk and trot, and pain on palpation values at all post-surgical time points. The results of this field study demonstrate that Deramaxx tablets, when administered daily for 7 days are effective for the control of postoperative pain and inflammation associated with orthopedic surgery.

Adverse Reactions:

A total of 207 dogs of forty three (43) different breeds, 1-15 years old, weighing 7-141 lbs were included in the field safety analysis. The following table shows the number of dogs displaying each clinical observation.

Abnormal Health Findings in The Postoperative Orthopedic Pain Field Study1
Clinical Observation	Deramaxx (deracoxib) tablets N = 105	Placebo N = 102
Vomiting	11	6
Diarrhea	6	7
Hematochezia	4	0
Melena	0	1
Anorexia	0	4
Incision site lesion (drainage, oozing)	11	6
Non-incision skin lesions (moist dermatitis, pyoderma)	2	0
Otitis externa	2	0
Positive joint culture	1	0
Phlebitis	1	0
Hematuria	2	0
Conjunctivitis	1	2
Splenomegaly	1	0
Hepatomegaly	1	0
Death	0	1

1Dogs may have experienced more than one of the observations during the study.

This table does not include one dog that was dosed at 16.92 mg/kg/day for the study duration. Beginning on the last day of treatment, this dog experienced vomiting, diarrhea, increased water intake and decreased appetite. Hematology and clinical chemistry values were unremarkable. The dog recovered uneventfully within 3 days of cessation of dosing.

Incisional drainage was most prevalent in dogs enrolled at a single study site. There were no statistically significant changes in the mean values for hepatic or renal clinical pathology indices between Deramaxx tablet- and placebo-treated dogs. Four Deramaxx tablet-treated dogs and two placebo-treated dogs exhibited elevated bilirubin during the dosing phase. One Deramaxx tablet-treated dog exhibited elevated ALT, BUN and total bilirubin and a single vomiting event. None of the changes in clinical pathology values were considered clinically significant.

The results of this clinical study demonstrate that Deramaxx tablets, when administered daily for 7 days to control postoperative orthopedic pain and inflammation in dogs, are well tolerated.

Osteoarthritis Pain and Inflammation Field Study:

Two hundred and nine (209) client-owned dogs with clinical and radiographic signs of osteoarthritis of at least one appendicular joint were enrolled in this study. A total of 194 dogs were included in the safety evaluation and a total of 181 dogs were included in the effectiveness evaluation. The effectiveness of Deramaxx tablets in the control of pain and inflammation associated with osteoarthritis was demonstrated in a placebo-controlled, masked study evaluating the anti-inflammatory and analgesic effects of Deramaxx tablets. Tablets were administered by the owner at approximately 1-2 mg/kg/day for forty-three (43) consecutive days.

In general, statistically significant (p≤ 0.05) differences in favor of Deramaxx were seen for force plate parameters (vertical impulse area, peak vertical force) and owner evaluations (quality of life, lameness and overall level of activity).

The results of this field study demonstrate that Deramaxx tablets, when administered at 1-2 mg/kg/day for 43 days, are effective for the control of pain and inflammation associated with osteoarthritis.

Adverse Reactions:

Deramaxx was well tolerated and the incidence of clinical adverse reactions was comparable in Deramaxx and placebo-treated animals. A total of 209 dogs of 41 breeds, 1-14 years old, weighing 17-177 lbs were included in the field safety analysis. The following table shows the number of dogs displaying each clinical observation.

Abnormal Health Findings in The Osteoarthritis Field Study1
Clinical Observation	Deramaxx (deracoxib) tablets N = 105	Placebo N = 104
Vomiting	3	4
Diarrhea/soft stool	3	2
Weight loss	1	0
Abdominal pain (splinting)	0	1
Seizure	1	0
Lethargy	0	1
Pyoderma/Dermatitis	2	0
Unilateral conjunctivitis	1	0
Scleral injection	0	1
Hematuria/UTI	1	0
Splenomegaly*	1	0
Grade II murmur systolic	1	0

1Dogs may have experienced more than one of the observations during the study.

*This dog was less active and eating less on enrollment, with elevated WBC, amylase, and AST and died 1 month after exiting the study. The dog was withdrawn from the study on Day 17 with anorexia, lethargy and a suspicion of diarrhea. Follow-up laboratory analyses revealed hypoalbuminemia, hyperphosphatemia, elevated AST and decreased BUN. Follow-up treatment included other anti-inflammatories and antibiotics.

Complete blood count, serum chemistry, and buccal bleeding time analysis were conducted at the beginning and end of the trial. Mean values of all CBC and chemistry results for both Deramaxx and placebo-treated dogs were within normal limits. There was no statistically significant difference in the buccal bleeding time between Deramaxx and placebo-treated dogs before or after the study, and all results remained within normal limits (less than 5 minutes). The results of this field study demonstrate that Deramaxx is safe and effective for the control of pain and inflammation associated with osteoarthritis in dogs.

During this trial, dogs were safely treated with a variety of commonly used medications, including antibiotics, anti-parasiticides, topical flea adulticides and thyroid supplements.

The results of this field study demonstrate that Deramaxx tablets are well tolerated when administered at 1-2 mg/kg/day for up to 43 days for the control of pain and inflammation associated with osteoarthritis.

Post Approval Experience:

The following adverse reactions are based on voluntary post-approval reporting. The categories are listed in decreasing order of frequency by body system.

Gastrointestinal: Vomiting, anorexia, diarrhea, melena, inappetence, hematemesis, hematochezia, weight loss, nausea, gastrointestinal ulceration, gastrointestinal perforation, salivation.

Hematological: Anemia, thrombocytopenia.

Hepatic: Hepatic enzyme elevations, decreased or increased total protein and globulin, decreased albumin, decreased BUN, hyperbilirubinemia, icterus, ascites, pancreatitis.

Neurological: Lethargy, weakness, seizure, ataxia, tremor, nystagmus, mydriasis.

Sensory: Vestibular signs, glazed eyes, uveitis.

Behavioral: Aggression, apprehension.

Urinary: Azotemia, polydipsia, polyuria, hematuria, low specific gravity, urinary incontinence, urinary tract infection, renal failure.

Cardiovascular: Bradycardia.

Respiratory: Tachypnea, coughing.

Dermatological/Immunological: Fever, edema, facial/muzzle edema, pruritis, urticaria, moist dermatitis, erythema, dermal ulceration/necrosis.

In rare situations, death has been reported as an outcome of the adverse events listed above.

For technical assistance or to report suspected adverse events, call 1-800-332-2761.

Information for Dog Owners:

Deramaxx, like other drugs of its class, is not free from adverse reactions. Owners should be advised of the potential for adverse reactions and be informed of the clinical signs associated with drug intolerance. Adverse reactions may include vomiting, diarrhea, decreased appetite, dark or tarry stools, increase water consumption, increased urination, anemia, yellowing of gums, skin or white of the eye due to jaundice, lethargy, incoordination, seizure, or behavioral changes. Serious adverse reactions associated with this drug class can occur without warning and in rare situations result in death (see Warnings, Post-Approval Experience and Adverse Reactions). Owners should be advised to discontinue Deramaxx therapy and contact their veterinarian immediately if signs of intolerance are observed. The vast majority of patients with drug related adverse reactions have recovered when the signs are recognized, the drug is withdrawn, and veterinary care, if appropriate, is initiated. Owners should be advised of the importance of periodic follow up for all dogs during administration of any NSAID.

Storage Conditions:

Deramaxx tablets should be stored at room temperature between 59° and 86°F

(15-30°C).

Keep this and all medications out of reach of children.

How Supplied:

Deramaxx tablets are available as 25 mg, 50mg, 75 mg and 100 mg round, brownish, half-scored tablets in 7, 30, and 90 count bottles.

Manufactured for: Novartis Animal Health US, Inc.

Greensboro, NC 27408 USA

Deramaxx Chewable Tablets are under the following U.S. patent numbers:

U.S. Patent Number              Date of Expiration

5,521,207                   November 30, 2013

5,756,529                   September 29, 2015

5,892,053                   May 25, 2015

5,910,597                   May 25, 2015

References:

1. Data on File
   


2. Data on File
   


3. Smith, et al.: “Pharmacological Analysis of Cyclo-oxygenase -1 in Inflammation,” Proc. Natl. Acad. Sci. USA (October 1998) 95: 13313-13318, Pharmacology.
   


4. Zhang, et al.: “Inhibition of Cyclo-oxygenase -2 Rapidly Reverses Inflammatory Hyperalgesia and Prostaglandin E2 Production,” JPET, (1997) 283: 1069-1075.
   


5. Verburg, KM et al. “Cox-2 Specific Inhibitors: Definition of a New Therapeutic Concept.” Amer J of Therapeutics 8, 49-64, 2001.
   


6. Data on File

NADA # 141-203, Approved by FDA

© 2008 Novartis Animal Health US, Inc.

NAH/DXB-T/PI/6 07/08

INFORMATION FOR DOG OWNERS

Deramaxx Chewable Tablets are for the control of pain and inflammation due to osteoarthritis or following orthopedic surgery.

This summary contains important information about Deramaxx tablets. You should read this information before starting your dog on Deramaxx tablets. This sheet is provided only as a summary and does not take the place of instructions from your veterinarian. Talk to your veterinarian if you do not understand any of this information or you want to know more about Deramaxx tablets.

What is Deramaxx?

Deramaxx tablets are a prescription non-steroidal anti-inflammatory drug (NSAID) of the coxib class. They are indicated for the control of postoperative pain and inflammation associated with orthopedic (bone) surgery in dogs and for the control of pain and inflammation (soreness) associated with osteoarthritis in dogs. The tablets are flavored to make administration more convenient.

What kind of results can I expect when my dog takes Deramaxx tablets for postoperative orthopedic pain and inflammation?

Deramaxx tablets allow your dog to recover more comfortably by controlling pain and inflammation that follow orthopedic surgery.

• Control of pain and inflammation may vary from dog to dog.
  


• If Deramaxx tablets are not given according to your veterinarian's directions, your dog's pain may return.
  


• Consult your veterinarian if your dog appears to be uncomfortable.

What kind of results can I expect when my dog takes Deramaxx tablets for pain and inflammation due to osteoarthritis?

Osteoarthritis is a painful condition caused by damage to cartilage and other parts of the joint that may result in the following changes or signs in your dog:

• Limping or lameness
  


• Decreased activity or exercise (reluctance to stand, climb stairs, jump or run, or difficulty in performing these activities)
  


• Stiffness or decreased movement of joints

While Deramaxx is not a cure for osteoarthritis, it can control the pain and inflammation of osteoarthritis and improve your dog's mobility. Response may vary from dog to dog but can be quite dramatic. Deramaxx tablets may need to be given on a periodic basis for the animal's lifetime. Use the lowest dose to provide adequate relief. Always consult with your veterinarian before altering the dose.

What dogs should not take Deramaxx tablets?

Your dog should not be given Deramaxx tablets if s/he:

• Has had an allergic reaction to deracoxib, the active ingredient in Deramaxx tablets
  


• Has had an allergic reaction (such as hives, facial swelling, or red or itchy skin) to aspirin or other NSAIDs
  


• Is presently taking aspirin, other NSAIDs, or corticosteroids (unless directed by your veterinarian)
  


• Has bloody stool or vomit
  


• Has a pre-existing kidney or liver condition
  


• Has any condition predisposing to dehydration
  


• Is anorexic (loss of appetite)

Deramaxx tablets should only be given to dogs.

People should not take Deramaxx tablets. Keep Deramaxx tablets and all medication out of reach of children. Call your physician immediately if you accidentally take Deramaxx tablets.

What to discuss with your veterinarian before giving Deramaxx tablets?

Tell your veterinarian about:

• Any side effects your dog has experienced from Deramaxx tablets or other NSAIDs
  


• Any digestive upset (vomiting or diarrhea) your dog has had
  


• Any kidney disease your dog has had
  


• Any other medical problems or allergies that your dog has now or has had in the past
  


• All medications that you are giving your dog or plan to give your dog, including those you can get without prescription and any dietary supplements
  


• If you plan to breed your dog, or if your dog is pregnant or nursing

Talk to your veterinarian about:

• The orthopedic surgery your dog will undergo
  


• What tests might be done before surgery is performed or Deramaxx tablets are prescribed
  


• The signs of pain or inflammation that may occur after surgery
  


• Normal events that can be expected after your dog undergoes surgery
  


• The proper amount of exercise after surgery to aid recovery
  


• The signs of osteoarthritis you have observed (for example, limping or stiffness)
  


• The importance of weight control, physical therapy and exercise in the management of osteoarthritis
  


• How often your dog may need to be examined by your veterinarian
  


• The risks and benefits of using Deramaxx tablets

How to give Deramaxx tablets to your dog.

Deramaxx tablets should be given according to your veterinarian's instructions. Your veterinarian will tell you what amount of Deramaxx tablets is right for your dog and for how long they should be given. Do not change the way you give Deramaxx tablets to your dog without first speaking with your veterinarian. Deramaxx tablets should be given by mouth and may be given with or without food, although with food is preferable.

What are the possible side effects that may occur in my dog during therapy with Deramaxx tablets?

Deramaxx tablets, like all other drugs, may cause some side effects in individual dogs. These are normally mild, but rare serious side effects have been reported in dogs taking non-steroidal anti-inflammatory drugs (NSAIDs) including Deramaxx. Serious side effects can, in rare situations, result in death. It is important to stop the medication and contact your veterinarian immediately if you think your dog may have a medical problem or side effect while on Deramaxx tablets. If you have additional questions about possible side effects, talk with your veterinarian or call 1-800-332-2761.

Look for the following side effects that may indicate that your dog is having a problem with Deramaxx tablets or may have another medical problem:

• Vomiting
  


• Change in bowel movements such as diarrhea or change in stool color
  


• Change in drinking or urination
  


• Decrease in appetite
  


• Change in behavior, such as depression or restlessness

Can Deramaxx tablets be given with other medications?

Deramaxx tablets should not be given with other non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids (for example, aspirin, carprofen, etodolac, prednisone).

Tell your veterinarian about all medications that you have given your dog in the past, and any medications that you are planning to give with Deramaxx tablets. This should include any medications that you can get without a prescription and any dietary supplements. Your veterinarian may want to evaluate the potential for any drug interactions and to assure drug compatability.

What can I do in case my dog eats more than the prescribed amount of Deramaxx tablets?

Contact your veterinarian immediately if your dog eats more than the prescribed amount of Deramaxx tablets.

What else should I know about Deramaxx tablets?

This sheet provides a summary of information about Deramaxx tablets. If you have any questions or concerns about Deramaxx tablets, postoperative orthopedic pain and inflammation, or osteoarthritis, talk to your veterinarian.

As with all prescribed medications, Deramaxx tablets should only be given to the dog for which they are prescribed. They should be given to your dog only for the condition for which they were prescribed, at the prescribed dose, as directed by your veterinarian. It is important to periodically discuss your dog's response to Deramaxx tablets at regular checkups. Your veterinarian will best determine if your dog is responding as expected and if your dog should continue receiving Deramaxx tablets.

NADA 141-203, Approved by FDA

© 2008 Novartis Animal Health US, Inc.

PRINCIPAL DISPLAY PANEL

Package Label – 25 mg

Deramaxx® 

(deracoxib)

7 chewable tablets

A coxib-class NSAID

For Use in Dogs Only

Caution: Federal Law (U.S.) restricts

this drug to use by or on the order

of a licensed veterinarian.

NADA#141-203, Approved by FDA.

Made in Canada. Manufactured for

Novartis Animal Health US, Inc.

Greensboro, NC 27408

NOVARTIS 25 mg

PRINCIPAL DISPLAY PANEL

Package Label – 75 mg

Deramaxx® 

(deracoxib)

7 chewable tablets

A coxib-class NSAID

For Use in Dogs Only

Caution: Federal Law (U.S.) restricts

this drug to use by or on the order

of a licensed veterinarian.

NADA#141-203, Approved by FDA.

Made in Canada. Manufactured for

Novartis Animal Health US, Inc.

Greensboro, NC 27408

NOVARTIS 75 mg

ANIMAL HEALTH

PRINCIPAL DISPLAY PANEL

Package Label – 100 mg

Deramaxx® 

(deracoxib)

7 chewable tablets

A coxib-class NSAID

For Use in Dogs Only

Caution: Federal Law (U.S.) restricts

this drug to use by or on the order

of a licensed veterinarian.

NADA#141-203, Approved by FDA.

Made in Canada. Manufactured for

Novartis Animal Health US, Inc.

Greensboro, NC 27408

NOVARTIS 100 mg

PRINCIPAL DISPLAY PANEL – BULK PRODUCT

Bulk Product – 40 KILOGRAM DRUM

DERACOXIB MICRO.

NOA 448123 B

PROD. NO. 80025

CAS-NO 169590-41-4

DANGEROUS FOR THE ENVIRONMENT

HARMFUL

NEW ANIMAL DRUG

NADA 141-203

ISSUED BY U.S. FDA, CENTER FOR VETERINARY MEDICINE

U.S. CONSIGNEE

NOVARTIS ANIMAL HEALTH US, INC.

GREENSBORO, NC

REGULATORY AFFAIRS 336-387-1000

THIS PRODUCT IS REGULATED BY FDA. IN THE EVENT THAT U.S. CUSTOMS REQUIRES SAMPLING OR CONTAINER INSPECTION, CONTACT CONSIGNEE IMMEDIATELY.

Manufactured by

DOTTIKON EXCLUSIVE SYNTHESIS AG

CH-5605 Dottikon

Switzerland

Milled by

Micro-Macinazione SA

CH-6995 Molinazzo di Monteggio

Switzerland

IN EMERGENCY DIAL

CH 4161-696-3333

US 1-800-424-9300

602374/NAH/DER/BULK/03/08

Deramaxx  deracoxib  tablet, chewable

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 58198-5215 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DERACOXIB (DERACOXIB) DERACOXIB 25 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color BROWN (speckled with white, brown or tan) Score 2 pieces Shape ROUND (biconvex) Size 11mm Flavor MEAT Imprint Code NA;AF Contains

Packaging # NDC Package Description Multilevel Packaging 1 58198-5215-2 7 TABLET In 1 BOTTLE None 2 58198-5215-3 30 TABLET In 1 BOTTLE None 3 58198-5215-4 90 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141203	08/21/2008

Deramaxx  deracoxib  tablet, chewable

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 58198-5217 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DERACOXIB (DERACOXIB) DERACOXIB 75 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color BROWN (speckled with white, brown or tan) Score 2 pieces Shape ROUND (biconvex) Size 16mm Flavor MEAT Imprint Code NA;DH Contains

Packaging # NDC Package Description Multilevel Packaging 1 58198-5217-2 7 TABLET In 1 BOTTLE None 2 58198-5217-3 30 TABLET In 1 BOTTLE None 3 58198-5217-4 90 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141203	06/13/2007

Deramaxx  deracoxib  tablet, chewable

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 58198-5216 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DERACOXIB (DERACOXIB) DERACOXIB 100 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color BROWN (speckled with white, brown or tan) Score 2 pieces Shape ROUND (biconvex) Size 17mm Flavor MEAT Imprint Code NA;BD Contains

Packaging # NDC Package Description Multilevel Packaging 1 58198-5216-2 7 TABLET In 1 BOTTLE None 2 58198-5216-3 30 TABLET In 1 BOTTLE None 3 58198-5216-4 90 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	N

Mykoderm

Mykoderm may be available in the countries listed below.

Ingredient matches for Mykoderm

Miconazole

Miconazole is reported as an ingredient of Mykoderm in the following countries:

• Germany

Miconazole nitrate (a derivative of Miconazole) is reported as an ingredient of Mykoderm in the following countries:

• Germany

International Drug Name Search

Pentox-CT

Pentox-CT may be available in the countries listed below.

Ingredient matches for Pentox-CT

Pentoxifylline

Pentoxifylline is reported as an ingredient of Pentox-CT in the following countries:

• Germany


• Luxembourg

International Drug Name Search

Tyklopidyna Anpharm

Tyklopidyna Anpharm may be available in the countries listed below.

Ingredient matches for Tyklopidyna Anpharm

Ticlopidine

Ticlopidine hydrochloride (a derivative of Ticlopidine) is reported as an ingredient of Tyklopidyna Anpharm in the following countries:

• Poland

International Drug Name Search

Loosyn

Loosyn may be available in the countries listed below.

Ingredient matches for Loosyn

Letrozole

Letrozole is reported as an ingredient of Loosyn in the following countries:

• Slovakia

International Drug Name Search

Gammaxol

Gammaxol may be available in the countries listed below.

Ingredient matches for Gammaxol

Ambroxol

Ambroxol hydrochloride (a derivative of Ambroxol) is reported as an ingredient of Gammaxol in the following countries:

• Italy

International Drug Name Search

Apo-Metoprolol

Apo-Metoprolol may be available in the countries listed below.

Ingredient matches for Apo-Metoprolol

Metoprolol

Metoprolol tartrate (a derivative of Metoprolol) is reported as an ingredient of Apo-Metoprolol in the following countries:

• Canada


• Czech Republic


• Singapore

International Drug Name Search

Cefoxin

Cefoxin may be available in the countries listed below.

Ingredient matches for Cefoxin

Cefoxitin

Cefoxitin sodium salt (a derivative of Cefoxitin) is reported as an ingredient of Cefoxin in the following countries:

• Thailand

International Drug Name Search

Altrenogest

In some countries, this medicine may only be approved for veterinary use.

Scheme

Rec.INN

CAS registry number (Chemical Abstracts Service)

0000850-52-2

Chemical Formula

C21-H26-O2

Molecular Weight

310

Therapeutic Category

Progestin

Chemical Name

Estra-4,9,11-trien-3-one, 17-hydroxy-17-(2-propenyl)-, (17ß)-

Foreign Names

• Altrenogestum (Latin)
• Altrenogest (German)
• Altrénogest (French)
• Altrenogest (Spanish)

Generic Names

• Altrenogest (OS: BAN, USAN)
• Altrénogest (OS: DCF)
• A 35957 (IS)
• A 41300 (IS)
• RH 2267 (IS)
• RU 2267 (IS: RousselUclaf)

Brand Names

• Altresyn (veterinary use)
  Ceva, France; Ceva Animal Health, Poland



• FolliPlan (veterinary use)
  Intervet, France; Veterinaria, Switzerland



• Matrix (veterinary use)
  Intervet, United States



• Reg U Late (veterinary use)
  Caledonian Holdings, New Zealand



• Regu Mate (veterinary use)
  Intervet, United States



• Regumate (veterinary use)
  Intervet, Austria; Intervet, Belgium; Intervet, Germany; Intervet, Finland; Intervet, France; Intervet, United Kingdom; Intervet, Ireland; Intervet, Italy; Intervet, Netherlands; Intervet, South Africa; Intervet / Schering-Plough Animal Health, New Zealand; Intervet International B.V., Luxembourg; Intervet Schering-Plough Animal Health, Portugal; Intervet/Schering-Plough Animal Health, Australia; Janssen Animal Health, Belgium; Janssen Animal Health, Germany; Janssen Santé Animale, France; Veterinaria, Switzerland

International Drug Name Search

Glossary

BAN	British Approved Name
DCF	Dénomination Commune Française
IS	Inofficial Synonym
OS	Official Synonym
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.

Ledermix

Ledermix may be available in the countries listed below.

Ingredient matches for Ledermix

Demeclocycline

Demeclocycline calcium (a derivative of Demeclocycline) is reported as an ingredient of Ledermix in the following countries:

• Germany


• Switzerland

Demeclocycline hydrochloride (a derivative of Demeclocycline) is reported as an ingredient of Ledermix in the following countries:

• Germany


• Switzerland

Triamcinolone

Triamcinolone 16α,17α-acetonide (a derivative of Triamcinolone) is reported as an ingredient of Ledermix in the following countries:

• Germany


• Switzerland

International Drug Name Search

RT

RT may be available in the countries listed below.

Ingredient matches for RT

Ranitidine

Ranitidine is reported as an ingredient of RT in the following countries:

• Bangladesh

International Drug Name Search

Vitac

Vitac may be available in the countries listed below.

Ingredient matches for Vitac

Ascorbic Acid

Ascorbic Acid is reported as an ingredient of Vitac in the following countries:

• Chile

International Drug Name Search

R-X

R-X may be available in the countries listed below.

Ingredient matches for R-X

Barium Sulfate

Barium Sulfate is reported as an ingredient of R-X in the following countries:

• Turkey

International Drug Name Search

Eqizolin

Eqizolin may be available in the countries listed below.

Ingredient matches for Eqizolin

Cefazolin

Cefazolin sodium salt (a derivative of Cefazolin) is reported as an ingredient of Eqizolin in the following countries:

• Turkey

International Drug Name Search

Nizofenone

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

N06BX10

CAS registry number (Chemical Abstracts Service)

0054533-85-6

Chemical Formula

C21-H21-Cl-N4-O3

Molecular Weight

412

Therapeutic Categories

Nootropic

Vasodilator, cerebral

Chemical Name

Methanone, (2-chlorophenyl)[2-[2-[(diethylamino)methyl]-1H-imidazol-1-yl]-5-nitrophenyl]-

Foreign Names

• Nizofenonum (Latin)
• Nizofenon (German)
• Nizofenone (French)
• Nizofenona (Spanish)

Generic Names

• Y 9179 (IS: Yoshitomi)
• Nizofenone Fumarate (OS: JAN)
• Midafenone fumarate (IS)

Brand Name

• Ekonal
  Tanabe Mitsubishi, Japan

International Drug Name Search

Glossary

IS	Inofficial Synonym
JAN	Japanese Accepted Name
OS	Official Synonym
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)

Click for further information on drug naming conventions and International Nonproprietary Names.

Darbepoetin Alfa

Class: Hematopoietic Agents
VA Class: BL400
Chemical Name: Erythropoietin [30-asparagine, 32-threonine, 87-valine, 88-asparagine, 90-threonine] (human)
Molecular Formula: C₈₀₀H₁₃₀₀N₂₂₈O₂₂₄S₅
CAS Number: 209810-58-2
Brands: Aranesp

Special Alerts:

[Posted 06/24/2011] ISSUE: FDA notified healthcare professionals that new, modified recommendations for more conservative dosing of Erythropoiesis-Stimulating Agents (ESAs) in patients with chronic kidney disease (CKD) have been approved to improve the safe use of these drugs. FDA has made these recommendations because of data showing increased risks of cardiovascular events with ESAs in this patient population. The new dosing recommendations are based on clinical trials showing that using ESAs to target a hemoglobin level of greater than 11 g/dL in patients with CKD provides no additional benefit than lower target levels, and increases the risk of experiencing serious adverse cardiovascular events, such as heart attack or stroke.

BACKGROUND: ESAs treat certain types of anemia by stimulating the bone marrow to produce red blood cells and by decreasing the need for blood transfusions. The manufacturer has revised the Boxed Warning, Warnings and Precautions, and Dosage and Administration sections of the labels for the ESAs to include this new information.

RECOMMENDATION: Healthcare professionals should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions in CKD patients against the increased risks for serious cardiovascular events, and should inform their patients of the current understanding of potential risks and benefits. Therapy should be individualized to the patient and the lowest possible ESA dose given to reduce the need for transfusions. See the Drug Safety Communication for additional information including a table of key trials and other supporting references. Treatment with ESAs in CKD was discussed at the Drug Safety and Risk Management Advisory Committee, held October 18, 2010. For summary minutes of that Advisory Committee, see the following link: . For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for darbepoetin to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of darbepoetin and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Increased Mortality, Serious Cardiovascular Events, Thromboembolic Events, Stroke, and Increased Risk of Tumor Progression or Recurrence


• 
  

  Increased risk of death, serious cardiovascular events, and stroke reported in patients with chronic renal failure (CRF) receiving therapy with darbepoetin alfa or other erythropoiesis-stimulating agents (ESAs) targeted to hemoglobin concentrations ≥13 g/dL in clinical studies.^{1 19 20 21 22 23 24 25 28 29 30 31 38 39 40 45 620 622} (See Increased Mortality and Cardiovascular and Thromboembolic Events under Cautions.)

  
  


• 
  

  Individualize dosing of ESAs in CRF patients to achieve and maintain hemoglobin concentrations within 10–12 g/dL.^{1 28 29}

  
  

  ESA therapy shortened overall survival and/or increased risk of tumor progression or recurrence in some studies in patients with breast, non-small cell lung, head and neck, lymphoid, or cervical cancers.^{1 24 25 28 29 34 35 38 39 40 41 42 43 49} (See Increased Mortality and/or Tumor Progression under Cautions.)

  
  


• 
  

  To decrease these risks and risk of serious cardiovascular and thromboembolic events in anemic patients with cancer, titrate ESA dosage to lowest hemoglobin concentration sufficient to avoid RBC transfusion.^{1 20 21 22 23 24 25 28 29}

  
  


• 
  

  Darbepoetin alfa may be prescribed and/or dispensed to cancer patients only by clinicians and institutions enrolled in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program.^{1 619} (See Risk Management Plan under Dosage and Administration.)

  
  


• 
  

  Use ESAs in cancer patients only for treatment of anemia caused by concomitant myelosuppressive chemotherapy.^{1 24 25 28 29 38 39 40 41}

  
  


• 
  

  ESAs not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure of the underlying malignancy.^{1 28 29 54}

  
  


• 
  

  Discontinue ESAs following completion of a course of chemotherapy.^{1 28 29}

  
  

Introduction

Biosynthetic (recombinant DNA origin) form of the glycoprotein hormone erythropoietin, a hematopoietic agent that principally affects erythropoiesis.^{1 2 9 10}

Uses for Darbepoetin Alfa

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Anemia of Chronic Renal Failure

Treatment of anemia associated with CRF in patients who currently are undergoing hemodialysis or peritoneal dialysis therapy, as well as those who do not yet require maintenance dialysis (predialysis patients).^{13 4 5 9 13}

Some evidence suggests once-weekly darbepoetin alfa has similar safety and efficacy as equivalent doses of epoetin alfa given 2 or 3 times weekly in patients with CRF who are undergoing hemodialysis or peritoneal dialysis.^{1 6 7 9 11 12} In addition, administration of darbepoetin alfa once every other week appears to have similar efficacy as equivalent doses of sub-Q epoetin alfa administered once weekly.^{11 58 59 60}

ESAs, including darbepoetin alfa, may increase risk for death and serious cardiovascular events when targeted to hemoglobin concentrations ≥13 g/dL.^{1 19 20 21 22 23 24 25 28 29 30 38 39 40 620 622} (See Boxed Warning.) FDA has issued public health advisories regarding risks with ESAs;^{19 20 21 22 23 24 25 38 39 40} FDA cautions that dosage of these drugs in patients with CRF should be individualized to achieve and maintain hemoglobin concentrations of 10–12 g/dL.^{1 28 29} Renal Physicians Association (RPA) states that the clinical standard of care in patients with chronic kidney disease or end-stage renal failure now advocated by the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) is use of lowest ESA dosage that will gradually increase target hemoglobin concentration to 11–12 g/dL and not exceed 13 g/dL.^{26 48 50} RPA advises consideration of individual patient risks and benefits and use of evidence-based guidelines in changing anemia management regimens to avoid unacceptably low hemoglobin concentrations in CRF patients.²⁶

Chemotherapy-induced Anemia in Patients with Nonmyeloid Malignancies

Treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies;¹ used to decrease the need for blood transfusions in patients receiving therapy with antineoplastic agents.^{1 14 62}

Correction of hemoglobin to concentrations >12 g/dL not recommended because of the risk of adverse effects, including death and serious and/or life-threatening cardiovascular events.^{19 20 21 22 23 24 25 28 29 30} (See Boxed Warning.)

ESAs not indicated in patients with chemotherapy-induced anemia when the anticipated outcome is cure of the underlying malignancy.^{1 54} ESAs do not improve outcomes of cancer chemotherapy (e.g., in terms of greater tumor shrinkage, delayed tumor progression, increased survival).^{1 24 25 34 35 38 39 40 43 44 49} Not established that ESAs improve health-related quality of life, including effects on fatigue, energy, or strength, in patients with chemotherapy-induced anemia.^{24 25}

Chronic Anemia Associated with Malignancy

Darbepoetin alfa and other ESAs not indicated for use in anemic patients with active malignant disease who are not receiving cancer chemotherapy†.^{1 28 29} ESAs shorten the time to death and/or tumor progression in such patients when therapy is targeted to hemoglobin concentrations >12 g/dL^{1 24 25 28 29}

Darbepoetin Alfa Dosage and Administration

General

• 
  

  Administer under the supervision of a health-care professional.¹ (See Advice to Patients.)

  
  


• 
  

  Monitor hemoglobin concentration twice weekly until stabilized during initiation of therapy and at regular intervals thereafter.¹ Following dosage adjustment, monitor hemoglobin concentrations weekly for ≥4 weeks until stabilized, then at regular intervals thereafter.¹ Titrate to the lowest dosage that will gradually increase hemoglobin to the lowest concentration sufficient to avoid red blood cell transfusion.^{1 9 19 22 24 25} Do not exceed a hemoglobin concentration of 12 g/dL or a rate of increase in hemoglobin concentration of 1 g/dL in any 2-week period.^{1 9 19 22 24 25}

  
  

Risk Management Plan

• 
  

  A required risk management plan (Risk Evaluation and Mitigation Strategy, REMS) has been developed for all ESAs.^{1 619}

  
  


• 
  

  A medication guide explaining the risks and benefits of ESA therapy must be distributed to and discussed with all patients receiving these drugs.^{55 619 621}

  
  


• 
  

  In addition, the APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program has been created to minimize risk of decreased survival and poor tumor response in cancer patients receiving ESAs.^{1 619} Clinicians and institutions must enroll in and comply with all requirements of the program (e.g., training module, signed acknowledgment of patient counseling) before they can prescribe and/or dispense ESAs to patients with cancer; participants must re-enroll every 3 years.^{1 619} For additional information or to enroll in the ESA APPRISE Oncology program, contact 866-284-8089 or visit www.esa-apprise.com.^{1 619}

  
  

Anemia of Chronic Renal Failure

• 
  

  Predialysis patients may be more responsive to hematopoietic effects; judicious monitoring of BP, hemoglobin, renal function, and fluid and electrolyte balance and lower maintenance dosages may be required compared with dialysis patients.¹

  
  


• 
  

  Appreciable changes in hemoglobin not evident for 2–6 weeks following any dosage adjustment; allow sufficient time (≥1 month) to determine response before adjusting dosage.¹

  
  


• 
  

  Maintenance dosage will be lower than initial dosage in many patients.¹ Some patients also may benefit from less frequent administration of maintenance doses (e.g., sub-Q administration once every 2 weeks).¹

  
  

Administration

Administer by IV or sub-Q injection.^{1 8 9}

IV or Sub-Q Administration

Do not expose to light or shake prior to use; vigorous shaking and exposure to light may physically denature the glycoprotein structure and inactivate the molecule.^{1 32}

Do not dilute injection further prior to administration.¹

Do not administer in the same syringe with other drug solutions.¹

Observe strict aseptic technique; drug contains no preservative.¹ Once dose has been withdrawn from the single-use vial, prefilled syringes, or autoinjection device, administer promptly and discard any unused portion of the solution or discard the device.^{1 13 32 33} Unused portions of vials and syringes should not be pooled.¹

Sub-Q injections are preferred by some clinicians for predialysis and peritoneal dialysis patients because of the lack of existing accessible IV sites in such patients.⁸

Darbepoetin alfa may be self-administered in a home-care setting by patients if they are judged competent to do so by their clinician.¹ For sub-Q injection using an autoinjection device (SureClick autoinjector), inject into front center of thighs, abdomen, or back of upper arms (only if caregiver is available to administer the injection).³² For sub-Q injection using a vial and a disposable syringe or prefilled syringe, inject into the outer area of the upper arms, abdomen (except the 2-inch area around the navel), front of middle thighs, or upper outer areas of the buttocks.³³ Rotate injection sites; do not inject into areas where skin is tender, bruised, red, or hard.^{32 33} Avoid injecting into areas with scars or stretch marks.^{32 33}

Before using the prefilled syringe, check to see that the needle cover is on and the yellow needle guard is covering the barrel of the syringe.³³ If the needle guard is covering the needle, discard the syringe.³³ Do not slide the needle guard over the needle cover before injection; the sliding motion will lock the needle guard prematurely.³³

Following administration from the prefilled syringe, activate the needle guard to prevent accidental needle sticks.^{1 33} To activate the needle guard, hold the finger grip of the syringe with one hand and grasp the needle guard with the other hand.³³ Slide the guard completely over the needle until the needle guard clicks into place.³³

Prior to use of the autoinjection device, remove the grey needle shield; do not recap the device with the needle shield.³² Place the open end of the autoinjection device at 90° to the injection site and unlock the safety needle cover by pushing the cover firmly against the skin.³² Press the red button at the top of the autoinjection device and release the thumb from the red button.³² Wait to hear a second click and verify that the inspection window on the side of the autoinjection device has changed from clear to yellow before lifting the device away from the skin.³²

Because the prefilled autoinjection device is designed to deliver the full contents, use such devices only for patients who need the full dose.¹

The manufacturer recommends IV administration in patients with CRF undergoing hemodialysis.¹

When switching from epoetin alfa to darbepoetin alfa, administer darbepoetin alfa by the same route of administration (IV or sub-Q) that epoetin alfa was administered.^{1 9} Administer darbepoetin alfa once weekly if epoetin alfa was administered 2 or 3 times weekly.^{1 9} Administer darbepoetin alfa once every 2 weeks if epoetin alfa was administered once weekly.^{1 9} Administer first dose of darbepoetin alfa in place of epoetin alfa at the time of the next scheduled dose.⁸

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

Anemia of Chronic Renal Failure

IV or Sub-Q

In pediatric patients >1 year of age currently receiving epoetin alfa, the manufacturer of darbepoetin alfa recommends the following initial dosage of darbepoetin alfa based on the weekly epoetin alfa dosage at the time of substitution (See Table 1):¹

For pediatric patients receiving a weekly epoetin alfa dosage of <1500 units/week, data are insufficient to determine initial darbepoetin alfa dosage.

Table 1.

Previous Weekly Epoetin Alfa Dosage (units/week)	Initial Weekly Darbepoetin Alfa Dosage (mcg/week)
<1500
1500–2499	6.25
2500–4999	10
5000–10,999	20
11,000–17,999	40
18,000–33,999	60
34,000–89,999	100
≥90,000	200

Dosage adjustments should not be made more frequently than once a month.¹

If hemoglobin has increased by <1 g/dL during initial 4 weeks of therapy and iron stores are adequate, increase dosage by approximately 25% of the previous dosage.^{1 8 9} Dosage may be increased at intervals of ≥4 weeks until the lowest hemoglobin concentration that will avoid the need for blood transfusion (not to exceed 12 g/dL) is attained.^{1 9 24 25}

If hemoglobin concentration is increasing and approaching 12 g/dL, decrease dosage by approximately 25% of the previous dosage.^{1 9} If the hemoglobin concentration continues to increase, temporarily withhold therapy until hemoglobin concentration begins to decrease, at which point reinitiate therapy at a dosage approximately 25% below the previous dosage.^{1 9} If the hemoglobin concentration increases by >1 g/dL in any 2-week period, decrease dosage by approximately 25%.^{1 9}

Patients who fail to respond or maintain a response to dosages >1.5 mcg/kg per week may be resistant to the drug; failure or lack of response to darbepoetin alfa should be evaluated to determine causative factors.^{1 9} (See Lack or Loss of Response to Therapy under Cautions.)

Predialysis patients may require lower maintenance dosages compared with dialysis patients.¹

Adults

Anemia of Chronic Renal Failure

IV or Sub-Q

Initially, 0.45 mcg/kg administered as a single IV or sub-Q injection once weekly.^{1 9}

In patients currently receiving epoetin alfa, the manufacturer of darbepoetin alfa recommends the following initial dosage of darbepoetin alfa based on the weekly epoetin alfa dosage at the time of substitution (See Table 2):^{1 9}

Table 2.

Previous Weekly Epoetin Alfa Dosage (units/week)	Initial Weekly Darbepoetin Alfa Dosage (mcg/week)
<1500	6.25
1500–2499	6.25
2500–4999	12.5
5000–10,999	25
11,000–17,999	40
18,000–33,999	60
34,000–89,999	100
≥90,000	200

Dosage adjustments should not be made more frequently than once a month.¹

If hemoglobin has increased by <1 g/dL during initial 4 weeks of therapy and iron stores are adequate, increase dosage by approximately 25% of the previous dosage.^{1 8 9} Dosage may be increased at intervals of ≥4 weeks until the lowest hemoglobin concentration that will avoid the need for blood transfusion (not to exceed 12 g/dL) is attained.^{1 9 24 25}

If hemoglobin concentration is increasing and approaching 12 g/dL, decrease dose by approximately 25% of the previous dosage.^{1 9} If the hemoglobin concentration continues to increase, temporarily withhold therapy until hemoglobin concentration begins to decrease, at which point reinitiate therapy at a dosage approximately 25% below the previous dosage.^{1 9} If the hemoglobin concentration increases by >1 g/dL in any 2-week period, decrease dosage by approximately 25% of the previous dosage.^{1 9}

Patients who fail to respond or maintain a response to dosages >1.5 mcg/kg per week may be resistant to the drug; failure or lack of response to darbepoetin alfa should be evaluated to determine causative factors.^{1 9} (See Lack or Loss of Response to Therapy under Cautions.)

Predialysis patients may require lower maintenance dosages compared with dialysis patients.¹

Chemotherapy-induced anemia in Patients with Nonmyeloid Malignancies

Sub-Q

2.25 mcg/kg once weekly.¹

Alternatively, 500 mcg once every 3 weeks.¹

Weekly dosage regimen: If hemoglobin concentration increases by <1 g/dL during the initial 6 weeks of therapy, increase dosage up to 4.5 mcg/kg weekly.¹

Weekly or every 3 weeks dosage regimen: If hemoglobin concentration increases by >1 g/dL in any 2-week period or exceeds 11 g/dL, decrease dosage by approximately 40% of the previous dosage.¹

Weekly or every 3 weeks dosage regimen: If the hemoglobin concentration is >12 g/dL, withhold therapy until hemoglobin concentration decreases to 11 g/dL, at which point reinstitute at a dosage 40% below the previous dosage.¹

Cautions for Darbepoetin Alfa

Contraindications

• 
  

  Uncontrolled hypertension.^{1 33} (See Hypertension and Seizures under Cautions.)

  
  


• 
  

  Known hypersensitivity to darbepoetin alfa or any ingredient in the formulation.^{1 33}

  
  

Warnings/Precautions

Warnings

Increased Mortality and Cardiovascular and Thromboembolic Events

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased risk of death and serious cardiovascular events (MI, stroke, CHF, hemodialysis graft occlusion) in patients receiving ESAs targeted to hemoglobin concentrations >12 g/dL.^{1 19 20 21 22 23 24 25 30 31 55 620 622} Patients with CRF and an insufficient hemoglobin response to ESA therapy may be at greater risk for cardiovascular events and mortality than other patients.¹

Increased incidence of thrombotic events (pulmonary embolism, thromboembolism, thrombophlebitis [deep and/or superficial], thrombosis) in cancer patients receiving darbepoetin alfa or other ESAs (epoetin alfa).^{1 24 25 46}

Increased incidence of thromboembolism in patients undergoing surgical procedures without prophylactic anticoagulation and receiving another ESA, epoetin alfa, to reduce allogeneic RBC transfusion requirements†.^{1 24 25 28 29 47} Darbepoetin alfa not FDA-labeled for reduction of allogeneic RBC transfusions in patients undergoing surgery.¹

Increased mortality reported in hemodialysis patients receiving another ESA, epoetin alfa, with clinically evident cardiac disease treated to a target hemoglobin concentration of 14 g/dL compared with similar patients treated to a target hemoglobin concentration of 10 g/dL.¹ Reason for increased mortality not known; incidence of nonfatal MI, vascular access thrombosis, and all other thrombotic events higher in those treated to a target hemoglobin concentration of 14 g/dL.¹

Increased risk of stroke observed in patients with type 2 diabetes, anemia, and non-dialysis-dependent CRF receiving darbepoetin alfa targeted to a hemoglobin concentration of 13 g/dL.^{1 620 622}

Increased incidence of fatal thromboembolic/vascular events and overall mortality reported in women with metastatic breast cancer who received epoetin alfa targeted to a hemoglobin concentration of 12–14 g/dL.^{1 24 25} (See Boxed Warning for cardiovascular and thromboembolic events in other patient populations.)

Correction of hemoglobin to concentrations above those currently recommended (i.e., 12 g/dL) may increase the risk of serious and life-threatening cardiovascular events.^{1 19 20 21 23 61} The manufacturer recommends that the target hemoglobin concentration not exceed 12 g/dL and the rate of rise of hemoglobin concentrations not exceed 1 g/dL in any 2-week period.¹ Guidelines for dosage and frequency of dosage adjustment should be followed closely.¹ (See Dosage and Administration.)

Increased Mortality and/or Tumor Progression

Shortened overall survival and increased incidence of death attributed to disease progression observed in women with metastatic breast cancer receiving cancer chemotherapy and ESAs targeted to hemoglobin concentration >12 g/dL.^{1 24 28 29} (See Boxed Warning.)

A shortened time to tumor progression was observed in patients with advanced head and neck cancer receiving radiation therapy and ESAs targeted to hemoglobin concentration >12 g/dL.^{1 24 28 29 34 35}

Increased risk of death in patients with cancer-related anemia who were not receiving cancer chemotherapy or radiation therapy† while receiving darbepoetin alfa.^{1 24 25 46} ESAs are not FDA-labeled for use in patients with cancer-related anemia who are not receiving myelosuppressive chemotherapy.^{1 24 25 38 39 40 41}

ESAs, including darbepoetin alfa, can only be prescribed and dispensed to cancer patients by authorized clinicians and institutions enrolled in the ESA APPRISE Oncology program.^{1 619} (See Risk Management Plan under Dosage and Administration and also see Boxed Warning.)

Hypertension and Seizures

BP may increase during treatment with darbepoetin alfa.¹ Use is contraindicated in patients with uncontrolled hypertension; BP should be under control before initiation of therapy.¹ Monitor and aggressively control BP, particularly during first several months of therapy.¹ If BP is difficult to control with antihypertensive therapy or dietary measures, reduce dosage of or withhold darbepoetin alfa.¹

Seizures and hypertensive encephalopathy reported in patients with CRF during treatment.¹ Monitor BP and neurologic status during the first several months of therapy.¹ Guidelines for dosage and frequency of dosage adjustment should be closely followed.¹ (See Dosage under Dosage and Administration.)

Pure Red Cell Aplasia

Pure red cell aplasia (PRCA) and severe anemia with or without other cytopenias in association with neutralizing antibodies to endogenous erythropoietin reported during postmarketing experience in a limited number of patients.^{1 16 56 57} PRCA occurred predominantly in patients with CRF receiving darbepoetin alfa by sub-Q administration.^{1 16}

Antibody-induced PRCA also reported in patients with hepatitis C virus (HCV) infection receiving ESAs concomitantly with ribavirin and interferon alfa (nonconjugated or pegylated).^{1 56 57}

Investigate the etiology of any loss of response to therapy accompanied by severe anemia and low reticulocyte counts.^{1 16 56} If anti-erythropoietin antibody-associated anemia is suspected, withhold darbepoetin alfa and other ESAs.^{1 16 56} Contact the manufacturer (1-800-77AMGEN) to perform assays for binding and neutralizing antibodies.^{1 16 56}

Discontinue therapy permanently in any patient with antibody-mediated anemia.^{1 16 56} Do not switch to other ESAs as antibodies may cross-react.^{1 16 56}

Potential for Viral Transmission

Theoretical risk of transmission of Creutzfeldt-Jakob disease (CJD) associated with darbepoetin alfa formulation containing albumin human; however, transmission of CJD or viral diseases to a human recipient via administration of albumin human has not been reported.¹

Sensitivity Reactions

Hypersensitivity Reactions

Potentially serious hypersensitivity reactions including rash and urticaria occur rarely.¹ Recurrence of manifestations following rechallenge has occurred, suggesting a causal relationship.¹ If a serious hypersensitivity or anaphylactic reaction occurs, discontinue immediately and institute appropriate and symptomatic care as indicated.¹

Latex Sensitivity

The needle cover of the prefilled syringe contains natural latex proteins in the form of dry natural rubber (latex).^{1 51 52 53} Individuals sensitive to latex should not handle the needle cover.^{1 51 52 53} Rarely, hypersensitivity reactions to natural latex proteins have been fatal.^{52 53}

General Precautions

Concomitant Diseases

Safety and efficacy of darbepoetin alfa not established in patients with underlying hematologic diseases (e.g., hemolytic anemia, sickle cell anemia,⁸ thalassemia, porphyria).^{1 9} Use with caution in patients with epilepsy.¹

Lack or Loss of Response to Therapy

A lack of response or failure to maintain a hemoglobin response with usual dosages of darbepoetin alfa should prompt evaluation for potential causative factors (e.g., PRCA).¹

Depending on the clinical setting, underlying infections, inflammatory or malignant processes, osteitis fibrosa cystica,¹³ occult blood loss, hemolysis, severe aluminum toxicity, and bone marrow fibrosis may compromise erythropoietic response.¹ Deficiencies of folic acid or vitamin B₁₂ should be excluded or corrected prior to initiation of therapy.¹ In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietins.¹ (See Pure Red Cell Aplasia under Cautions.)

Patient Monitoring

To ensure effective erythropoiesis, evaluate iron stores in all patients prior to and periodically during therapy.^{1 8 9} Supplemental iron therapy is recommended for all patients whose serum ferritin concentration is <100 mg/L or whose serum transferrin saturation is <20%.^{1 8}

Patients with CRF: Evaluate hemoglobin concentrations weekly during initiation of therapy and at regular intervals thereafter.¹ Following dosage adjustment, monitor hemoglobin concentrations weekly for ≥4 weeks until stabilized, then at regular intervals thereafter.¹ Monitor hemoglobin concentrations carefully to ensure that hemoglobin does not exceed 12 g/dL.^{1 24 25 27}

Dialysis Management

May reduce dialysis efficiency; patients who are marginally dialyzed may require adjustments in dialysis parameters.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether darbepoetin alfa is distributed into milk;^{1 32} use with caution in nursing women.¹

Pediatric Use

Safety and efficacy in the initial treatment of anemia of CRF not established.¹ Safety and efficacy of transferring from another erythropoietin in patients >1 year of age with CRF similar to adults.¹ Safety and efficacy of transferring from another erythropoietin not established in pediatric patients <1 year of age.¹

Safety and efficacy in pediatric cancer patients not established.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Use with caution.⁸

Common Adverse Effects

Adult patients with CRF: Infection,¹ hypertension,¹ hypotension,¹ myalgia,¹ headache,¹ diarrhea.¹

Pediatric patients with CRF: Fever, headache, upper respiratory infection, hypertension, hypotension, injection site pain, cough.¹

Patients with cancer: Fatigue,¹ diarrhea,¹ edema,¹ fever.¹

Interactions for Darbepoetin Alfa

No formal drug interaction studies have been performed.¹

Darbepoetin Alfa Pharmacokinetics

Absorption

Bioavailability

Approximately 37% (range 30–50%) or 54% (range 32–70%) in adult or pediatric patients, respectively, with CRF following sub-Q administration.¹

Absorption is slow and rate limiting following sub-Q administration.¹

Distribution

Extent

Not known whether darbepoetin alfa is distributed into milk.¹

Elimination

Half-life

Following sub-Q administration: 49 hours (range: 27–89 hours) in adult patients with CRF.¹

Pediatric patients (3–16 years of age) with CRF with or without dialysis following a single IV or sub-Q dose: Half-life similar to that in adults.¹

Patients with cancer following a single sub-Q dose: 74 hours (range: 24–144 hours).¹

Following IV administration: Distribution half-life is approximately 1.4 hours and terminal half-life is approximately 21 hours.¹

Stability

Storage

Parenteral

Injection

2–8°C; protect from light.^{1 32 33} Do not freeze or shake.^{1 32 33} Discard autoinjection device, vial, or prefilled syringe that has been frozen, exposed to light, or improperly refrigerated.^{32 3} For a more comfortable sub-Q injection, refrigerated autoinjection device (SureClick autoinjector), vial, or prefilled syringe may be allowed to stand protected from light at room temperature for about 30 minutes prior to injection; do not warm autoinjection device.^{32 33}

Actions

• 
  

  Has pharmacologic actions identical to those of endogenous erythropoietin;^{1 2 10} interacts with progenitor stem cells to increase red cell production.¹

  
  


• 
  

  Erythropoietin deficiency is the primary cause of anemia in patients with CRF.¹

  
  


• 
  

  In patients with cancer receiving concomitant chemotherapy, etiology of anemia is multifactorial.¹

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of informing patients about the increased risks of death, serious cardiovascular effects, thromboembolic events, and tumor progression in certain patient populations.^{1 32 33} (See Increased Mortality and Cardiovascular and Thromboembolic Events under Cautions and also see Boxed Warning.)

  
  


• 
  

  Provide a copy of the patient instructions for use and medication guide provided by the manufacturer prior to initiating therapy and each time drug is dispensed.^{1 55 619}