PubChem compound: 44384985
Collagenase interacts in the following cases:
The impact of treatment with collagenase on subsequent surgery, if needed, is not known.
Collagenase must be used with caution in patients with coagulation disorders or those taking anticoagulants. In the three double-blind, placebo-controlled phase 3 studies in Dupuytren’s contracture, 73% of collagenase-treated patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site. In the two double-blind, placebo-controlled phase 3 studies in Peyronie’s disease, 65.5% of collagenase-treated patients developed penile haematoma and 14.5% developed penile ecchymosis. The efficacy and safety of collagenase in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to collagenase administration is not known. Use of collagenase in patients who have received anticoagulants (with the exception of up to 150 mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of collagenase is not recommended.
For collagenase no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, or embryonal/foetal development. Parturition or postnatal development studies in animals were not conducted since human pharmacokinetic studies show that collagenase levels are not quantifiable in the systemic circulation following injection into a Dupuytren’s cord. Patients develop ADAs after repeated administration, the cross-reactivity of which versus endogenous MMPs involved in pregnancy and labour cannot be excluded. The potential risk for humans on parturition and postnatal development is unknown. Therefore, the use of collagenase is not recommended in pregnancy and treatment should be postponed until after pregnancy.
It is not known whether collagenase clostridium histolyticum is excreted in human milk. Caution should be exercised when Xiapex is administered to a breast-feeding woman.
Peyronie’s disease occurs exclusively in adult male patients and hence there is no relevant information for use in females. Low levels of collagenase clostridium histolyticum were quantifiable in the plasma of evaluable male patients for up to 30 minutes following administration of collagenase into the penile plaque of patients with Peyronie’s disease.
Collagenase may have a major influence on the ability to drive and use machines due to the swelling and pain which may impair the use of the treated hand in Dupuytren’s disease. Other minor influences on the ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache that have also been reported following injection of collagenase. Patients must be instructed to avoid potentially hazardous tasks such as driving or using machines until it is safe to do so or as advised by the physician.
The most frequently reported adverse reactions during the collagenase clinical studies (272 of 409 patients received up to three single injections of collagenase and 775 patients received two concurrent injections in the same hand) were local injection site reactions such as oedema peripheral (local to the injection site), contusion (including ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very common, occurring in the vast majority of patients, were mostly mild to moderate in severity and generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture (6 cases), tendonitis (1 case), other ligament injury (2 cases) and complex regional pain syndrome (1 case) related to the medicinal product were reported. Anaphylactic reaction was reported in a patient previously treated with collagenase (1 case).
Table 1 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100), and not known: cannot be estimated from the available data. Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme are those that occurred in the Phase 3 double blind placebo-controlled studies for the treatment of Dupuytren’s contracture in adult patients with a palpable cord (AUX-CC-857, AUX-CC-859) and the post-marketing clinical studies (AUX-CC-864, AUX-CC-867) for two concurrent injections in the same hand.
Table 1. Tabulated list of adverse reactions:
| System organ class | Very common | Common | Uncommon | Not known |
|---|---|---|---|---|
| Infections and infestations | Injection site cellulitis Lymphangitis | |||
| Blood and lymphatic system disorders | Lymphadenopathy | Lymph node pain | Thrombocytopenia Lymphadenitis | |
| Immune system disorders | Hypersensitivity Anaphylactic reaction | |||
| Psychiatric disorders | Disorientation Agitation Insomnia Irritability Restlessness | |||
| Nervous system disorders | Paresthesia Hypoesthesia Burning sensation Dizziness Headache | Complex regional pain syndrome Monoplegia Syncope vasovagal Tremor Hyperaesthesia | ||
| Eye disorders | Eyelid oedema | |||
| Vascular disorders | Haematoma Hypotension | |||
| Respiratory thoracic and mediastinal disorders | Dyspnoea Hyperventilation | |||
| Gastrointestinal disorders | Nausea | Diarrhoea Vomiting Abdominal pain upper | ||
| Skin and subcutaneous tissue disorders | Pruritus Ecchymosis | Blood blistera Blister Rash Erythema Hyperhidrosis | Erythematous or macular rash Eczema Swelling face Skin disorders, like exfoliation, lesions, pain, tightness, discoloration or scab | |
| Musculoskeletal and connective tissue disorders | Pain in extremity | Arthralgia Axillary mass Joint swelling Myalgia | Pain in chest wall, groin, neck or shoulder Musculoskeletal discomfort or stiffness, joint stiffness or crepitation Limb discomfort Tendonitis Muscle spasms or weakness | |
| Reproductive system and breast disorders | Breast tenderness Hypertrophy breast | |||
| General disorders and administration site conditions | Oedema peripheralc Injection site haemorrhage, pain or swelling Tenderness | Axillary pain Inflammation Injection site warmth, erythema, inflammation, vesicles or pruritus Swelling | Local swelling Pyrexia Pain Discomfort Fatigue Feeling hot Influenza like illness Injection site reaction, malaise, irritation, anaesthesia, desquamation, nodule or discoloration Cold intolerance of the treated fingers | |
| Investigations | Lymph node palpable Alanine aminotransferase increased Aspartate aminotransferase increased Body temperature increased | |||
| Injury, poisoning and procedural complications | Contusion | Skin lacerationa,b | Tendon rupture Ligament injury Limb injury Open wound Wound dehiscence | Digital necrosis Digital fracture |
a reported with a higher incidence (very common) in patients who received two concurrent injections of collagenase in the same hand compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren’s contracture.
b “skin laceration” includes “injection site laceration” and "laceration"
c “oedema peripheral” includes “injection site oedema” and "oedema"
The incidence of skin laceration (29.1%) was higher for subjects treated with two concurrent injections of collagenase in historically-controlled clinical study AUX-CC-867 compared with subjects treated with up to three single injections in the Phase 3 placebo-controlled pivotal studies in Dupuytren’s contracture (CORD I and CORD II) (8.8%). The majority of the skin lacerations occurred on the manipulation day. A higher incidence of skin laceration may be attributable to more vigorous finger extension procedures in patients after receiving anaesthesia to the hand. In Study AUX-CC-867, most (85%) subjects received local anaesthesia prior to the finger extension procedure. There were no other clinically relevant differences between two concurrent injections of collagenase in the same hand and up to three single injections of collagenase in the types of adverse events reported (i.e., most adverse events were local to the treated extremity and of mild or moderate intensity).
The overall safety profile was similar regardless of the timing of the post-injection finger extension procedure (i.e., 24 hours, 48 hours, and ≥72 hours after injection) among patients who received two concurrent injections of collagenase in Study AUX-CC-867.
The overall safety profile was similar in the two Phase 3 double-blind placebo-controlled studies (832 male patients, 551 patients received collagenase) and in an open-label Phase 3 study (189 male patients) of patients who had previously received placebo in the controlled studies. In the two Phase 3 double-blind placebo-controlled studies, most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered. The most frequently reported adverse drug reactions (≥25%) during the collagenase controlled clinical studies were penile haematoma, penile swelling and penile pain. Severe penile haematoma including severe injection site haematoma were reported with the frequency very common.
In the controlled and uncontrolled clinical studies of collagenase in Peyronie’s disease corporal rupture and other serious penile injury were reported uncommonly.
A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking” and sometimes accompanied by detumescence, haematoma and/or pain, were reported in 73/551 (13.2%) collagenase-treated patients and 1/281 (0.3%) placebo-treated patients, in Studies 1 and 2 combined.
Table 2 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and not known: cannot be estimated from the available data. Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme are those that occurred in the Phase 3 double-blind placebo-controlled studies.
Table 2. Tabulated list of adverse reactions:
| System organ class | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Fungal skin infection Infection Upper respiratory infection | ||
| Blood and lymphatic system disorders | Lymph node pain Eosinophilia Lymphadenopathy | ||
| Immune system disorders | Drug hypersensitivity Anaphylactic reaction* | ||
| Metabolism and nutrition disorders | Fluid retention | ||
| Psychiatric disorders | Abnormal dreams Depression Sexual inhibition | ||
| Nervous system disorders | Headache Dizziness Dysgeusia Paraesthesia Burning sensation Hyperaesthesia Hypoaesthesia | ||
| Ear and labyrinth disorders | Tinnitus | ||
| Cardiac disorders | Tachycardia | ||
| Vascular disorders | Haematoma Hypertension Haemorrhage Lymphangiopathy Thrombophlebitis superficial | ||
| Respiratory, thoracic and mediastinal disorders | Cough | ||
| Gastrointestinal disorders | Abdominal distension Constipation | ||
| Skin and subcutaneous tissue disorders | Blood blister Skin discolouration | Erythema Penile ulceration Rash erythematous Night sweats Skin disorder, nodule, granuloma, blister, irritation or oedema Pigmentation disorder Skin hyperpigmentaton | |
| Musculoskeletal and connective tissue disorders | Back, pubic or groin pain Ligament disorder Ligament pain Musculoskeletal discomfort | ||
| Renal and urinary disorders | Dysuria Micturition urgency | ||
| Reproductive system and breast disorders | Penile haematomaa, swellingb, painc or ecchymosisd | Penile blister Pruritus genital Painful erection Erectile dysfunction Dyspareunia Penile erythema | Penile adhesion Penis disorder Progression of Peyronie’s disease Sexual dysfunction Scrotal erythema Genital discomfort Genital haemorrhage Pelvic pain Penile size reduced Penile vein thrombosis Scrotal oedema Scrotal pain |
| General disorders and administration site conditions | Injection site vesicles or pruritus Localised oedema Nodule Suprapubic pain | Feeling hot Injection site reaction or discolouration Pyrexia Swelling Asthenia Chills Cyst Induration Influenza like illness Oedema Secretion discharge Tenderness | |
| Investigations | Blood glucose increased Blood pressure systolic increased Body temperature increased | ||
| Injury, poisoning and procedural complications | Procedural pain | Fracture of penis Skin laceration Open wound Scrotal haematoma Joint injury Penis injury |
a Includes: injection site haematoma and penile haematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of patients.
b Includes: injection site swelling, penile oedema, penile swelling, local swelling, scrotal swelling, and injection site oedema.
c Includes: injection site pain, penile pain, and injection site discomfort.
d Includes: contusion, ecchymosis, penile haemorrhage, and injection site haemorrhage.
∗ reported from a post-marketing clinical study in a patient who had previous exposure to collagenase for the treatment of Dupuytren’s contracture.
No allergic sensitivity or toxic reactions have been noted in clinical use when used as directed. However, one case of systemic manifestations of hypersensitivity to collagenase in a patient treated for more than one year with a combination of collagenase and cortisone has been reported.
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