Chymodiactin (Chymopapain)

CHYMODIACTIN®

Knoll

Chymopapain

Proteolytic Enzyme

Action And Clinical Pharmacology: Chymopapain for intradiscal injection is injected into the herniated nucleus pulposus of the lumbar intervertabral disc resulting in rapid hydrolysis of the noncollagenous polypeptides or proteins that maintain the tertiary structure of the chondromucoprotein. This lessens the intradiscal osmotic activity, thereby decreasing fluid absorption and reducing intradiscal pressure. The foregoing mechanism of action is based on animal in vitro and in vivo data. Although the mechanism of action in the human has not been established directly, operative findings in patients who have come to surgery following injection have usually revealed the nucleus pulposus to be absent from its former site.

Indications And Clinical Uses: For the treatment of patients with documented herniated lumbar intervertebral discs whose symptoms and signs, particularly sciatica, have not responded to an adequate period or periods of conservative therapy. Chymopapain has not been studied in the treatment of herniated discs in areas other than the lumbar spine. Chymopapain should only be used in hospitals by physicians who routinely care for the patients described above, who are qualified by training and experience to perform laminectomy, discectomy, or other spinal procedures and who have received specialized training in chemonucleolysis. The appropriate use of chymopapain in chemonucleolysis requires precise diagnosis and the ability to employ skillfully all appropriate diagnostic and treatment modalities necessary, including surgical interventions other than chemonucleolysis (laminectomy/discectomy) and all aspects of pre- and postoperative patient management. Proper selection of patients for whom chemonucleolysis is applicable requires extensive training and experience in the diagnosis and management of all spinal disorders, since there are circumstances in which nerve root compression resulting from conditions other than herniated disc can produce similar signs and symptoms.

In hospitals where chymopapain is used, the supporting personnel, as well as physicians, should be qualified in the diagnosis and management of all potential complications of the use of chymopapain including anaphylaxis.

Clinical observations suggest that female patients are more likely to develop anaphylactic reactions secondary to chymopapain (see Warnings).

Contra-Indications: Patients with a known sensitivity to chymopapain, papaya or papaya derivatives, including papain containing contact lens cleaners, or meat tenderizer preparations.

Other contraindications are severe spondylolisthesis; severe, progressing paralysis as indicated by rapidly progressing neurologic dysfunction; and in patients with evidence of spinal cord tumor or other lesions producing spinal motor or sensory dysfunction (e.g. cauda equina lesion).

Patients who have previously been injected with any form of chymopapain.

Chymopapain has not been studied in regions of the spine other than the lumbar area; therefore, its use is contraindicated in any spinal region other than the lumbar area.

Children: Safety and effectiveness of chymopapain has not been studied in pediatric patients, therefore, the drug should not be used in children.

Pregnancy: Chymopapain has not been evaluated for possible teratogenic effects. Since animal reproduction studies have not been conducted, chymopapain is not recommended for use in pregnant women.

Manufacturers’ Warnings In Clinical States: Anaphylaxis of a severe to mild nature has been observed after injection of chymopapain in about 0.5% of patients and may be life threatening if not treated promptly and correctly. At least 1 open i.v. line must always be in place to permit rapid and adequate management of such an occurrence. The reaction can be immediate or delayed up to 2 hours after injection and can last for minutes to several hours or longer. The patient may present with almost immediate hypotension and/or bronchospasm, the former being more common. These may proceed to laryngeal edema, cardiac arrhythmia, cardiac arrest, coma and death. Speed in diagnosis and treatment is of the essence since the clinical signs, severity, progression, and duration of an anaphylactic reaction are highly unpredictable. Other signs of allergic response, such as erythema, pilomotor erection, rash, pruritic urticaria, conjunctivitis, vasomotor rhinitis, angioedema, or various gastrointestinal disturbances, must also be watched for.

U.S. post marketing surveillance data confirm that females are more likely to develop an anaphylactic reaction secondary to chymopapain (observed rate of 0.8% vs 0.3% in males). These data have also shown a statistically significant difference in the frequency of anaphylaxis in patients receiving local anesthesia vs those receiving general anesthesia (0.4% vs 0.6% respectively); however, a direct cause and effect relationship has not been established. In the population where race has been reported the incidence is statistically higher in black females.

Clinical judgment, speed of therapy, and choice of agents all enter into the treatment of anaphylaxis. Epinephrine is the definitive therapeutic agent in the immediate treatment of anaphylaxis. Substitution of other agents such as steroids should be reserved for cases where epinephrine is not appropriate.

In cases where the risk-benefit ratio of chemonucleolysis is dubious, allergy or immunology consultation before attempting this procedure is recommended. Documentation on the usefulness of in vitro chymopapain – specific lgE test or in vivo skin test as predictors for anaphylactic reactions is still inconclusive.

Acute transverse myelitis/acute transverse myelopathy has been reported in association with the injection of chymopapain at a rate of about 1 in 18 000. Although cause and effect relationship to the injection of chymopapain itself has not been established, the reported rate is significantly higher than the incidence reported in the medical literature. These patients are characterized clinically by the delayed (2 to 3 weeks) onset of paraplegia or paraparesis without prior signs or symptoms. Patients receiving injections at 2 or more disc spaces following discography appear to be at increased risk.

It is recommended that discography not be performed as part of the chemonucleolysis procedure unless the operating surgeon determines that the risks of discography are outweighed by the benefits in the particular clinical situation. Serious neurotoxicity from the injection of radiological contrast agents into the spinal fluid followed by chymopapain has been observed in studies with baboons. A water acceptance test or discometry may be used as an alternative to discography for assessment of the disc abnormality and to attempt reproduction of sciatic pain in the patients under local anesthesia. Certain radiopaque contrast media are neurotoxic. The toxicity of these materials may be enhanced by intrathecal bleeding. If chymopapain is then inadvertently administered intrathecally, disruption of the capillaries may occur, resulting in intrathecal bleeding.

Paraplegia/paraparesis (e.g., as are seen in the cauda equina syndrome), other serious neurologic adverse events, and subarachnoid and intracerebral hemorrhage and seizures have been observed soon (within hours or days) after chymopapain injection at a rate of about 1 in 2 000. Causal relationships to the drug when properly injected have not been established. Needle trauma and/or injection of chymopapain and contrast media into the spinal fluid may be causes in some of these reported cases. Other less severe neurologic reactions have included burning sacral, leg pain, hypalgesia, leg weakness, foot drop, cramping in both calves, pain in the opposite leg, paresthesia, tingling in legs, and numbness of legs/toes.

The drug is extremely toxic when injected intrathecally in animals. Therefore, great caution must be exercised in assuring the chymopapain is not injected intrathecally into dural canal.

Chemonucleolysis is not recommended during active inflammatory episodes and/or infections.

Patients using beta-blocking agents should be weaned from these agents prior to chemonucleolysis.

Precautions: Because of the potential for anaphylaxis resulting from the intradiscal injection of chymopapain the following precautions should be observed in the use of the drug:

Patient Selection: A careful history should be obtained to determine if the patient has multiple allergies, especially a known allergy to papaya or papaya derivatives. In patients allergic to iodine, discography must not be performed and absorbable iodine must not be used during myelography.

The use of chymopapain in a lumbar disc which has previously undergone surgical treatment has not been systematically studied. Therefore, chemonucleolysis at that disc level is not recommended.

Females, particularly black females, are more likely to develop anaphylactic reactions secondary to chymopapain (see Warnings).

In case of anaphylaxis, beta-blocker therapy may inhibit the action of epinephrine.

Pretreatment: Patients may be pretreated prior to the injection of chymopapain with histamine receptor (H1 and H2) antagonists to lessen the severity of an anaphylactic reaction. One regimen that is widely used is cimetidine 300 mg orally every 6 hours and diphenhydramine 50 mg orally every 6 hours for 24 hours prior to chemonucleolysis.

Because of the abrupt decrease in intravascular volume during anaphylaxis, patients should be well hydrated with oral or i.v. fluids prior to chemonucleolysis. At least 1 open i.v. line must always be in place to permit rapid and adequate management of such an occurrence.

Procedure: The choice of anesthetic for a specific patient should be made by the attending surgeon and anesthesiologist. However, it is recommended that local or supplemented local anesthetic be used whenever possible.

The advantages of local or supplemental local anesthesia are thought to be: a lower anaphylaxis rate (0.4%); possible ease of recognition of impending anaphylaxis because earliest symptoms can be reported by an awake patient; possible correlation of sciatic pain with a specific disc because the patient is awake; and possible decreased risk of experiencing a serious neurologic adverse event secondary to difficult needle placement (see Warnings).

The advantages of general anesthesia are thought to be: ease of airway management if anaphylaxis should develop; more precise patient positioning for injection; and less patient discomfort. A disadvantage of general anesthesia is a higher rate of anaphylaxis (0.5%). If halothane anesthesia is used, it should be noted that if epinephrine HCl is required for treatment of an anaphylactic reaction, there is a potential arrhythmogenic interaction of the 2 drugs.

Needle placement for the intradiscal administration of chymopapain should be made by physicians experienced in needle placement via the lateral approach to avoid puncture of the dura mater. Clinical trials have not been conducted using the posterior approach for needle placement and serious neurologic toxicity has been reported using the posterior transdural approach; therefore, this method of needle placement must be avoided. Surgeons performing chemonucleolysis may wish to consider the injection of saline or water into the nucleus pulposus (saline or water acceptance test) as an alternative to discography. The use of this test plus careful evaluation of high quality AP and lateral x-ray views of the disc are sufficient to confirm proper needle placement in the nucleus pulposus. If discography is performed (see Warnings) at least 15 minutes should elapse after the administration of radiopaque contrast media to allow for diffusion and absorption of the media before injection of chymopapain through the same needle after removal of the obturator. If high quality x-ray equipment including an image intensifier is not available to perform chemonucleolysis, the procedure should not be carried out. If there is any question about satisfactory needle placement or if needle placement is difficult, requiring repeated attempts, the procedure should be aborted.

Based on the increased frequency of neurological adverse reaction in patients with 2 or more disc level injections chemonucleolysis should be limited to the 1 disc producing the patient’s symptoms unless definitive signs, symptoms and diagnostic procedures indicate that more than 1 disc is at fault.

For 3 minutes prior to chymopapain injection, 100% O2 may be administered to the patient by the anesthesiologist to maximize oxygenation in case of anaphylaxis.

A test dose injection of 0.2 mL of chymopapain followed by a 10 to 15 minute wait is recommended prior to the injection of the full therapeutic dose. The purpose of the test dose is to help identify those patients who are most sensitive to chymopapain. Patients who develop signs and/or symptoms of anaphylaxis following the test dose must not receive the therapeutic dose. However, some patients have been reported who failed to react to the test dose, but developed anaphylaxis to the therapeutic dose suggesting that sensitivity to chymopapain may be dose related.

Patient Instructions: Patients should be instructed that after injection they may experience back pain or involuntary muscle spasm in the lower area of the back for several days. This is not uncommon nor is a residual stiffness or soreness of the low back which may persist for several months.

Patients should be instructed to anticipate the possibility of any of the following delayed allergic reactions which may occur as late as 15 days after injection: rash of any type, urticaria or itching. If any of these occur patients should contact their physician.

Patients should be adequately advised of the potential benefits and risks associated with chemonucleolysis using chymopapain.

Adverse Reactions: The most serious adverse reactions encountered with the use of chymopapain have been anaphylactic in nature. Based on U.S. postmarketing surveillance reports, the overall frequency of anaphylaxis is 0.5% or 1 in 200 patients. The frequency in females is approximately 0.8%, in males approximately 0.3%. The frequency when general anesthesia is employed is 0.5%, when local anesthesia is employed 0.4%. These differences are statistically significant.

Several deaths have been reported in association with chymopapain injection. Some of these fatalities, such as those due to anaphylaxis or complications of anaphylaxis, disc space infection, or CNS hemorrhage, may be associated with either the drug or the procedure. Others appear to be coincidental. The overall mortality rate following chymopapain injection is approximately 1 in 5 000 patients (0.02%). For purposes of comparison, mortality associated with laminectomy has been reported to range from 0.02% to 0.1%.

Paraplegia/paraparesis (20 cases), other serious neurologic adverse events in 30 patients out of 80 000 treated with chymopapain, intracerebral hemorrhage (8 cases), quadriplegia (1 case) and hemiparesis (1 case). Causal relationships to the drug when properly injected have not been established. Needle trauma and/or injection of chymopapain and contrast media into the spinal fluid may be causes in some of these reported cases. Other less severe neurologic reactions have included burning sacral, leg pain, hypalgesia, leg weakness, foot drop, cramping in both calves, pain in the opposite leg, paresthesia, tingling in legs, and numbness of legs/toes.

Acute transverse myelitis/acute transverse myelopathy has been reported in association with the injection of chymopapain at a rate of about 1 in 18 000. Although cause and effect relationship to the injection of chymopapain itself has not been established, the reported rate is significantly higher than the incidence, reported in the medical literature. These patients are characterized clinically by the delayed (2 to 3 weeks) onset of paraplegia or paraparesis without prior signs or symptoms.

Discitis, both bacterial and aseptic, has been reported.

Less severe, but more frequent adverse reactions include back pain/stiffness/soreness in approximately 50% of treated patients and/or back spasm in approximately 30%. Less frequent adverse reactions, occurring in less than 1% of patients studied include rash, itching, urticaria, nausea, paralytic ileus, urinary retention, headache and dizziness.

Dosage And Administration: Each 2 mL vial of Chymodiactin contains 4 nKat units of enzyme and should be reconstituted with 2 mL sterile water for injection, USP. Each 5 mL vial of Chymodiactin contains 10 nKat units of the enzyme and should be reconstituted with 5 mL sterile water for injection, USP. The concentration of solution in the reconstituted vial is 2 nKat units of chymopapain per mL. Recommended dosage is 1 to 4 nKat units per disc, usually 3 nKat units per disc or a volume of injection of 0.5 to 2 mL, usually 1.5 mL per disc. Maximum dose in a single patient with multiple disc herniation is 8 nKat units. However, based on the increased frequency of neurological reaction in patients with two or more disc level injections (see Warnings), chemonucleolysis should be limited to the 1 disc producing the patient’s symptoms, unless definitive signs, symptoms and diagnostic procedures indicate that more than 1 disc is at fault.

Note: Alcohol should be used to cleanse the vial stopper prior to insertion of needles into the vial. However, since residual alcohol may inactivate the enzyme, it should be allowed to air dry before continuing with the reconstitution process.

Bacteriostatic Water for Injection USP, must not be used because it may inactivate the enzyme.

As with all parenteral drug products, chymopapain should be visually inspected for particulate matter and discoloration prior to administration. Care should be exercised in the selection of proper size and use of needles inserted into the vials in the reconstitution process to reduce the possibility of coring the stopper. The manufacturing process results in a residual vacuum in the vial; therefore, the use of automatic filling syringes is not recommended. Chymodiactin should be stored under refrigeration (2 to 8°C) until it is reconstituted with sterile water for injection, USP and used. The drug must be used within 2 hours of its reconstitution with sterile water for injection, USP. Unused drug must be promptly discarded and not stored for future use.

Each herniated disc should be treated with a single injection of chymopapain after needle tip placement has been verified by image intensifier. If a discogram is performed (see Warnings), at least 15 minutes must elapse between discogram and drug administration to allow for dispersion and absorption of the contrast media.

Chymopapain is limited to use under the professional supervision of a physician with the following considerations:

The appropriate use of chymopapain in chemonucleolysis, as pointed out in the Indications section, requires precise diagnosis and the ability to skillfully employ all acceptable diagnostic and treatment modalities as necessary, including surgical intervention other than chemonucleolysis, e.g., laminectomy, including all aspects of pre- and postoperative patient care.

The proper selection of patients for whom chemonucleolysis is applicable is of the utmost importance. There are circumstances in which nerve root compression resulting from conditions other than the herniated disc can produce similar signs and symptoms, therefore, extensive training and experience in the diagnosis and management of all spinal disorders and diseases is required.

Chymopapain should only be used by physicians who routinely care for patients with herniated lumbar intervertebral discs, who are qualified by training and experience to perform laminectomy, discectomy, or other spinal procedures, and who have received specialized training in chemonucleolysis.

Chymopapain should be used only in a hospital setting with the assistance of trained personnel, and in such a manner as to assure immediate and proper management of all potential complications, especially anaphylaxis.

Availability And Storage: Each glass vial of sterile and lyophilized powder contains: chymopapain 4 or 10 nKat units. Nonmedicinal ingredients: sodium L-cysteinate hydrochloride. Vials of 2 and 5 mL. Boxes of 1. Refrigerate at 2 to 8°C prior to reconstitution and use. Supplied to hospitals only.

CHYMODIACTIN® Knoll Chymopapain Proteolytic Enzyme

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