Label: OSPHOS- clodronate disodium injection, solution
- NDC Code(s): 17033-460-15
- Packager: Dechra Veterinary Products
- Category: PRESCRIPTION ANIMAL DRUG LABEL
Drug Label Information
Updated July 29, 2020
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DESCRIPTION
DESCRIPTION: Clodronate disodium is a non-amino, chloro-containing bisphosphonate. Chemically, clodronate disodium is (dichloromethylene) diphosphonic acid disodium salt and is manufactured from the tetrahydrate form.
The structural formula of clodronate disodium is:
Molecular Formula: CH2Cl2Na2O6P2 Molecular Weight: 288.85
Active substance clodronate disodium tetrahydrate 74.98 mg/mL corresponds to clodronate disodium 60.0 mg/mL. Each mL contains 60 mg clodronate disodium, sodium hydroxide (to adjust pH) and water for injection.
- VETERINARY INDICATIONS
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DOSAGE & ADMINISTRATION
DOSAGE AND ADMINISTRATION: Administer 1.8 mg/kg by intramuscular injection up to a maximum dose of 900 mg per horse. Divide the total volume evenly into three separate injection sites. Discard unused vial contents. OSPHOS is provided in a single use vial and does not contain a preservative.
Clinical improvement is most evident at 2 months post-treatment (see EFFECTIVENESS). Of the horses that responded to treatment with OSPHOS in the field study, 65% maintained their level of improvement through the 6 month evaluation.
If there is no response to initial therapy, the horse should be re-evaluated. For horses that initially respond to OSPHOS but do not maintain their clinical improvement for 6 months, OSPHOS may be re-administered at 3 to 6 month intervals based on recurrence of clinical signs. For horses that respond to OSPHOS and maintain clinical improvement for 6 months, OSPHOS should be re-administered after clinical signs recur.
- CONTRAINDICATIONS
- WARNINGS
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PRECAUTIONS
PRECAUTIONS: OSPHOS has been associated with renal toxicity. Concurrent administration of other potentially nephrotoxic drugs should be approached with caution and renal function should be monitored. Use of bisphosphonates in patients with conditions or diseases affecting renal function is not recommended.
Horses should be well-hydrated prior to and after the administration of OSPHOS due to the potential for adverse renal events. Water intake and urine output should be monitored for 3-5 days post-treatment and any changes from baseline should elicit further evaluation.
As a class, bisphosphonates may be associated with gastrointestinal and renal toxicity. Sensitivity to drug associated adverse reactions varies with the individual patient. Renal and gastrointestinal adverse reactions may be associated with plasma concentrations of the drug. Bisphosphonates are excreted by the kidney; therefore, conditions causing renal impairment may increase plasma bisphosphonate concentrations resulting in an increased risk for adverse reactions.
Administration of bisphosphonates has been associated with abdominal pain (colic), discomfort, and agitation in horses. Clinical signs usually occur shortly after drug administration and may be associated with alterations in intestinal motility. In horses treated with OSPHOS these clinical signs usually began within 2 hours of treatment. Horses should be monitored for at least 2 hours following administration of OSPHOS.
Bisphosphonates affect plasma concentrations of some minerals and electrolytes such as calcium, magnesium and potassium, immediately post-treatment, with effects lasting up to several hours. Caution should be used when administering bisphosphonates to horses with conditions affecting mineral or electrolyte homeostasis (e.g. hyperkalemic periodic paralysis, hypocalcemia, etc.).
The safe use of OSPHOS has not been evaluated in horses less than 4 years of age. The effect of bisphosphonates on the skeleton of growing horses has not been studied; however, bisphosphonates inhibit osteoclast activity which impacts bone turnover and may affect bone growth.
Bisphosphonates should not be used in pregnant or lactating mares, or mares intended for breeding. The safe use of OSPHOS has not been evaluated in breeding horses or pregnant or lactating mares. Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of months to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Bisphosphonates have been shown to cause fetal developmental abnormalities in laboratory animals. The uptake of bisphosphonates into fetal bone may be greater than into maternal bone creating a possible risk for skeletal or other abnormalities in the fetus. Many drugs, including bisphosphonates, may be excreted in milk and may be absorbed by nursing animals.
Increased bone fragility has been observed in animals treated with bisphosphonates at high doses or for long periods of time. Bisphosphonates inhibit bone resorption and decrease bone turnover which may lead to an inability to repair microdamage within the bone. In humans, atypical femur fractures have been reported in patients on long term bisphosphonate therapy; however, a causal relationship has not been established.
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ADVERSE REACTIONS
ADVERSE REACTIONS: One hundred forty-six horses (111 OSPHOS, 35 saline control) of various breeds, 4 to 22 years of age, and weighing 807 to 1,322 pounds were included in the field study safety analysis.
Following treatment on Day 0, 10 horses had clinical signs of discomfort or nervousness, cramping, pawing, and/or colic within 2 hours post-treatment. One horse experiencing colic and hives required treatment with supportive care to resolve clinical signs. In 8 of the 10 horses, 10 to 15 minutes of hand walking resulted in resolution of clinical signs. In one horse, clinical signs resolved without hand walking. Three additional horses experienced lip licking, yawning, and/or head shaking. Adverse reactions occurring within 2 hours post-treatment with OSPHOS or the saline control are summarized in Table 1.
Table 1: Adverse Reactions Occurring within 2 Hours Post-treatment Clinical Sign OSPHOS (n=111) Control (n=35) - *
- This horse experienced colic and hives and recovered with supportive treatment.
Uncomfortable, Nervous, Colic, and/or Pawing 9.0% (10) 0% (0) Lip licking 5.4% (6) 0% (0) Yawning 4.5% (5) 0% (0) Head shaking 2.7% (3) 0% (0) Injection site swelling 1.8% (2) 2.9% (1) Colic requiring treatment* 0.9% (1) 0% (0) Hives/Pruritus 0.9% (1) 0% (0) POST-APPROVAL EXPERIENCE (December 2018): The following adverse events are based on post-approval adverse drug experience reporting. Not all adverse events are reported to FDA/CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data.
The following adverse events are listed in decreasing order of reporting frequency: renal failure, polyuria, polydipsia, abdominal pain, anorexia, lethargy, hypercalcemia, behavioral disorder (e.g.: head shaking, flehmen response, lip licking), discomfort, hyperkalemia, hyperactivity, recumbency, hyperthermia, injection site reactions (pain, edema, inflammation), muscle tremor, urticaria, hyperglycemia, and fracture.
In some cases, death has been reported as an outcome of the adverse events listed above (See PRECAUTIONS).
Contact Information: For a copy of the SDS or to report suspected adverse drug events, contact Dechra at (866) 933-2472. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth.
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INFORMATION FOR OWNERS/CAREGIVERS
INFORMATION FOR HORSE OWNERS: Owners should be advised to:
- NOT administer NSAIDs.
- Ensure horses have access to adequate water before and after administration of OSPHOS.
- Observe their horse for at least 2 hours post-treatment for signs of colic, agitation, and/or abnormal behavior.
- If a horse appears uncomfortable, nervous, or experiences cramping post-treatment, hand walk the horse for 15 minutes. If signs do not resolve contact the veterinarian.
- Monitor water intake and urine output for 3-5 days post-treatment.
- Contact their veterinarian if the horse displays abnormal clinical signs such as changes in drinking and urination, appetite, and attitude.
(See PRECAUTIONS and Post-Approval Experience sections.)
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CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY: Clodronate disodium is a non-nitrogen containing bisphosphonate that inhibits bone resorption by binding to calcium phosphate crystals (inhibiting their formation and dissolution), and by exerting direct cellular effects on osteoclasts (inhibiting osteoclast cell function)1. Bound to bone matrix, clodronate disodium enters resorbing osteoclasts, alters their morphology and reduces the number of active osteoclasts, regardless of the cause of osteoclast activity2,3.
In humans, 60 to 80% of clodronate disodium administered intravenously is eliminated unchanged in the urine and 5% in the feces2; the remainder of the administered dose is distributed to bone. The bone residence time in horses could not be estimated. However, in numerous studies, the half-life of clodronate disodium in rodent bone (long bones and lumbar vertebrae) has been estimated to be months to years.
After intramuscular injection, clodronate disodium is rapidly absorbed and cleared from the plasma. Within a dosing range of 1.8 to 5.4 mg/kg (n=8 per dose group), the Cmax values increased in proportion to the dose. However, dose related changes were observed after the third administration of a regimen consisting of a single 5.4 mg/kg intramuscular injection administered once every 28 days. In this 3× dose group, a decrease in apparent total systemic clearance (CL/F) was seen (0.08 mL/hr + 0.02; mean + standard deviation), resulting in a greater than proportional increase in systemic drug exposure (AUC, 62.49 hr*mcg/mL ± 18.52) and plasma elimination T ½ (2.89 hours ± 1.33). In comparison, the estimated mean CL/F in horses receiving the 1× (1.8 mg/kg) dose was 0.12 mL/hr + 0.02 (mean + standard deviation) and the corresponding mean pharmacokinetic parameters were 5.36 ± 0.98 mcg/mL (Cmax), 12.15 ± 1.83 hr*mcg/mL (AUC), 1.65 ± 0.52 hours (T ½) and 20 minutes (Tmax).
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EFFECTIVENESS: A double masked 3:1 randomized, negative control, multi-site field study evaluated the effectiveness of a single dose of 1.4 mg/kg OSPHOS (maximum dose of 900 mg/horse) for the control of clinical signs associated with navicular syndrome in horses. Enrolled horses had a unilateral or bilateral forelimb lameness of Grade ≥ 2 on the AAEP lameness scale (Grade 0 to 5) and a diagnosis of navicular syndrome based on lameness exam, diagnostic nerve blocks, and radiographic signs indicative of the bony changes associated with navicular syndrome. Horses with radiographic signs indicating concurrent soft tissue injury, osteoarthritis, fractures, or any condition other than the bony changes related to navicular syndrome were not eligible for enrollment. A horse was considered a treatment success if the lameness grade in the primarily affected limb improved by at least 1 AAEP grade and there was no worsening of lameness grade in the other forelimb on Day 56 post-treatment as compared to the pre-treatment assessment. Lameness scores were also recorded on Day 28 and Day 180.
Of the 211 horses screened for enrollment, 146 horses received treatment (111 OSPHOS and 35 saline control). 29% of horses screened for enrollment were not eligible based on radiographic findings. 114 horses (86 OSPHOS, 28 saline control) were included in the statistical analysis. Effectiveness was evaluated on Day 56 post-treatment. On Day 56, 68 of the 86 OSPHOS treated horses and 1 out of 28 saline treated horses were treatment successes. Based on the statistical analysis, the estimated least squares mean success rates are 74.7% and 3.3% for the OSPHOS and saline treated groups, respectively. The difference in success rates is significant at P=0.0028.
Table 2: Day 56 Treatment Success Rate Study Day OSPHOS Saline P Value* - *
- P value and estimated success rates are based on back-transformed mean estimates from the statistical analysis.
56 74.7% 3.3% 0.0028 Treatment success based on Day 28 and Day 180 lameness scores was also assessed but not statistically analyzed. At Day 28, 67.4% (60/89) OSPHOS treated horses were considered successes, compared to 20.7% (6/29) in the saline treated group. Day 56 treatment successes were followed to the Day 180 assessment, and Day 56 treatment failures were also considered failures at Day 180. Of the 68 OSPHOS treated horses that were deemed treatment successes on Day 56, 60 were evaluable at Day 180. Of these 60 horses, 51 remained treatment successes at Day 180 based on improvement in lameness grade as compared to Day 0. However, 21 of these 60 evaluable horses demonstrated an increase in lameness grade at Day 180 as compared to their Day 56 evaluation. Including the 18 treatment failures at Day 56, the estimated overall success rate for OSPHOS at Day 180 is 65.4% (51/78).
Table 3: Day 28 and Day 180 Treatment Success Rates Study Day OSPHOS Saline - *
- The 18 horses that were treatment failures on Day 56 were considered to remain treatment failures at Day 180. No Day 180 lameness evaluation was performed on these horses. 60 horses (all OSPHOS treated horses) completed the Day 180 lameness evaluation.
28 67.4% (60/89) 20.7% (6/29) 180 65.4% (51/78)* None evaluable -
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ANIMAL SAFETY: Two studies were conducted to assess the safety of OSPHOS in horses, a six month target animal safety (TAS) study and a two phase study evaluating the safety of concurrent use of the recommended dose of OSPHOS with an NSAID and a single 5× (9 mg/kg) dose of OSPHOS.
Target Animal Safety Study: In the TAS study, OSPHOS was administered to 32 healthy adult horses at 0, 1.8, 3.6 and 5.4 mg/kg (0, 1, 2, and 3× the recommended dose) every 28 days for 6 consecutive months. OSPHOS was administered by intramuscular injection with the total volume divided evenly into at least three separate injection sites with a maximum of 15 mL per injection site.
In the TAS study, the most common post-treatment observations were clinical signs related to abdominal discomfort (colic) and the central nervous system. The incidence of colic was dose related. In the TAS study, colic was observed following 94% (45/48) of 3× treatment administrations, 54% (26/48) of 2× treatment administrations, 4% (2/48) of 1× treatment administrations, and 8% (4/48) of 0× treatment administrations. 80% (36/45) of the 3× horses, 31% (8/26) of 2× horses and none of the 1× (0/2) and 0× (0/4) horses required hand walking to relieve clinical signs associated with colic. In the 3× group, clinical signs of colic often persisted after hand walking and horses were often walked more than once. Colic related clinical signs began shortly after administration (ranging from 1 to 227 minutes post-treatment). No horses in any treatment group received medical treatment and all horses returned to normal within 5.5 hours post-treatment.
In the TAS study, post-treatment clinical signs also included yawning, flehmen, tongue rolling, head shaking and neck writhing. The signs were observed in 50% (4/8) of 0×, 100% (8/8) of 1×, 88% (7/8) of 2×, and 100% (8/8) of 3× horses. All horses returned to normal within 5.5 hours post-treatment.
Table 4: Incidence of Abnormal Clinical Signs in the TAS Study Number of Observations per Treatment Group
(N=48 treatment administrations per group)Clinical Sign 0× 1× 2× 3× - *
- Signs of colic included repeated lying down and rising, rolling, kicking at the abdomen, stretching of the abdomen and/or other typical signs of abdominal discomfort.
Colic* 4 2 26 45 Colic requiring hand walking 0 0 8 36 Yawning 5 17 16 30 Flehmen 0 0 8 2 Tongue rolling 1 10 8 10 Head shaking 1 5 3 7 Neck writhing 0 0 0 6 Pawing 4 4 12 23 Agitation 1 1 7 10 Depression 0 2 5 21 Muscle fasciculations/Trembling 0 0 1 4 Injection site reactions were identified in three 0×, four 1×, two 2×, and one 3× horse. One 1× horse had injection site reactions on two separate treatment days. Injection site reactions in OSPHOS treated horses were characterized by soft or firm swellings, ranged in size from 0.5 cm diameter to 7 × 28 cm, and resolved within 10 days. Clinical pathology evaluations showed a dose related trend for increases in BUN and creatinine post-treatment with the 2× and 3× dose groups having statistically significant elevations as compared to the 0× dose group. Horses in all OSPHOS treated groups had dose dependent elevations in BUN concentrations above the reference range (up to 41 mg/dL; reference range 8-25 mg/dL). Three 3× horses had creatinine concentrations above the reference range (up to 2.5 mg/dL; reference range 0.9-1.9 mg/dL) for up to 12 hours post-treatment. A dose related trend for an increase in potassium was observed for up to 6 hours post-treatment. Individual animal potassium concentrations were within the reference range with the exception of two 3× horses with post-treatment potassium concentrations up to 5.3 mg/dL (reference range 3-5 mg/dL). Decreases in chloride and increases in glucose, creatine kinase, and aspartate aminotransferase were also observed post-treatment. End of study evaluations concluded that bone density (bone mineral concentration) and bone strength (mechanical testing of cortical bone) remained similar between all dose groups.
Two Phase Pilot Study: In Phase I of a two phase pilot study, six horses were administered phenylbutazone orally twice a day at a dose of 4.4 mg/kg on Days 0 to 3, administered OSPHOS at 1.8 mg/kg (1×) by intramuscular injection into 3 sites once on Day 4, and continued on phenylbutazone orally twice a day at a dose of 2.2 mg/kg on Days 4 to 6. In Phase II of the pilot study, after a 15 day washout, the same six horses were administered a single dose of OSPHOS at 9 mg/kg (5×) by intramuscular injection divided evenly into 5 separate injection sites. No NSAIDs were administered in Phase II.
In Phase I, three horses had post-treatment elevations in BUN above the reference range (up to 42 mg/dL; reference range 8-25 mg/dL). BUN concentrations returned to normal prior to Phase II of the study. In Phase II, five out of six horses developed changes in attitude associated with signs of agitation or nervousness including pawing, circling, and tail twitching within 6 minutes of dosing. Four of six horses also developed clinical signs including excessive yawning, flehmen, tongue rolling, head shaking, and head bobbing. All six horses developed mild to moderate muscle fasciculations between 2 and 30 minutes post-treatment. By 30 minutes post-treatment, four out of six horses also developed signs of discomfort and possible abdominal pain including full body stretching, repetitive lying down and rising, and kicking at the abdomen. At approximately one hour post-treatment, one horse exhibited agitation and clinical signs of colic requiring medical therapy. The horse responded to medical therapy and was clinically normal at 7 hours post-treatment. Three out of six horses developed temporary gait abnormalities that included mild to moderate hypermetria, spasticity, or mild ataxia. Four out of six horses developed mildly elevated BUN concentrations by 48 hours post-treatment and one horse had a creatinine concentration slightly above the reference range (2.0 mg/dL; reference range 0.9-1.9 mg/dL) for 12 hours post-treatment.
- STORAGE AND HANDLING
- HOW SUPPLIED
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MANUFACTURED FOR:
Dechra Veterinary Products
7015 College Boulevard, Suite 525
Overland Park, KS 66211 USAFor a copy of the Safety Data Sheet (SDS) or to report adverse reactions call Dechra Veterinary Products at (866) 933-2472.
Manufactured in Canada.
Approved by FDA under NADA # 141-427
US Patent 7,781,420
OSPHOS is a registered trademark of Dechra Ltd. All rights reserved.
© 2018 Dechra Ltd.
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REFERENCES
- 1
- Fleisch H. 1987. Bisphosphonates-history and experimental basis. Bone 8: S23-28.
- 2
- Plosker GL, Goa KL. 1994. Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 47: 945-982.
- 3
- Flanagan AM, Chambers TJ. 1989. Dichloromethylene bisphosphonate (Cl2MBP) inhibits bone resorption through injury to osteoclasts that resorb Cl2MBP-coated bone. Bone Miner: 6:33-43.
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- PRINCIPAL DISPLAY PANEL - 15 mL Vial Carton
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INGREDIENTS AND APPEARANCE
OSPHOS
clodronate disodium injection, solutionProduct Information Product Type PRESCRIPTION ANIMAL DRUG Item Code (Source) NDC:17033-460 Route of Administration INTRAMUSCULAR Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLODRONATE DISODIUM (UNII: N030400H8J) (CLODRONIC ACID - UNII:0813BZ6866) CLODRONATE DISODIUM 60 mg in 1 mL Inactive Ingredients Ingredient Name Strength Sodium Hydroxide (UNII: 55X04QC32I) Water (UNII: 059QF0KO0R) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17033-460-15 1 in 1 CARTON 1 15 mL in 1 VIAL, SINGLE-USE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NADA NADA141427 08/01/2014 Labeler - Dechra Veterinary Products (362142734) Registrant - Dechra Ltd (641097493)
