Chemical formula: C₃₇H₅₉N₅O₉PdS Molecular mass: 840.26 g/mol
Padeliporfin interacts in the following cases:
In vitro studies predict that padeliporfin at therapeutic concentrations is unlikely to inhibit cytochrome P450 enzymes but could inhibit OATP1B1 and OATP1B3 transporters.
The magnitude of interaction has not been investigated clinically but a transient increase in the plasma concentration of co-administered substrates of OATP1B1 and OATP1B3 cannot be ruled out. The use of medicinal products that are substrates of OATP1B1 or OATP1B3 (repaglinide, atorvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, bosentan, glyburide) for which concentration-dependent serious adverse events have been observed should be avoided on the day of padeliporfin infusion and for at least 24 hours after administration. Co-administration should be done with caution and close monitoring is recommended.
Medicinal products which have potential photosensitising effects (such as tetracyclines, sulphonamides, quinolones, phenothiazines, sulfonylurea hypoglycaemic agents, thiazide diuretics, griseofulvin or amiodarone) should be stopped at least 10 days before the procedure with padeliporfin and for at least 3 days after the procedure or replaced by other treatments without photosensitizing properties. If it is not possible to stop a photosensitising medicinal product (such as amiodarone), the patient should be advised that increased sensitivity to sunlight may occur and they may need to protect themselves from direct light exposure for a longer period.
Padeliporfin should be used with caution in patients with severe hepatic impairment.
Anticoagulant medicinal products and those that decrease platelet aggregation (e.g. acetylsalicylic acid) should be stopped at least 10 days before the procedure with padeliporfin. Medicinal products that prevent or reduce platelet aggregation should not be started for at least 3 days after the procedure.
Patients with abnormal clotting may develop excessive bleeding due to the insertion of the needles required to position the light fibres. This may also cause bruising, haematuria and/or local pain. It is not expected that a delay in clotting will reduce the effectiveness of the padeliporfin-VTP treatment; however, it is recommended that drugs that affect clotting are stopped prior to and for the immediate period following the VTP procedure.
Patients with a history of urethral stricture or with urinary flow problems may be at increased risk of poor flow and urinary retention post the padeliporfin-VTP procedure. Urinary retention immediately post procedure has been attributed to transient prostatic oedema and generally only short term recatheterisation was required.
Although they were excluded from the clinical trials, there is a potential risk of increased stenosis post the padeliporfin-VTP procedure in patients with pre-existing stenosis.
Padeliporfin is not indicated for the treatment of women.
Padeliporfin is not indicated for the treatment of women.
If the patient is sexually active with women who are capable of getting pregnant, he and/or his partner should use an effective form of birth control to prevent getting pregnant during a period of 90 days after the VTP procedure.
Padeliporfin has not been tested for reproductive toxicity and fertility.
However, all stages of spermatogenesis have been observed in animal. Minimal seminiferous epithelial degeneration was also recorded in one high-dose male with vacuolation. All these changes were considered to be incidental and probably related to the intravenous administration procedure.
Padeliporfin has no influence on the ability to drive or use machines. However, as the procedure includes general anaesthesia, patients should not perform complex tasks like driving or using machines until 24 hours after a general anaesthetic is employed.
The most frequently reported adverse reactions in the Phase II and III clinical studies were urinary and reproductive system disorders: dysuria (25.1%), erectile dysfunction (21.1%), haematuria (19.6%), perineal pain/haematoma (15.3%), urinary retention (13.3%), micturition urgency (9.0%), pollakiuria (7.3%), urinary tract infection (5.5%), incontinence (5.3%) and ejaculation failure (5.0%).
Unspecific adverse events probably linked to the general anaesthesia were also observed: transient global amnesia, bradycardia, sinus arrhythmia, atrial fibrillation, hypotension, bronchospasm, pharyngeal inflammation, respiratory tract congestion, nausea, vomiting, constipation, pyrexia, procedural hypotension. Some cases of hepatotoxicity (1.5%), such as elevation of transaminases, were also reported. All of them were mild in intensity.
Adverse reactions reported are listed below by organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100).
Summary of adverse reactions considered related to TOOKAD and/or the study device and/or the study procedure in the pooled safety analysis (N=398):
Common: Genito-urinary tract infection1
Uncommon: Prostatic abscess
Uncommon: Libido decreased, Affective disorder, Encopresis
Uncommon: Headache, Dizziness, Sciatica, Sensory disturbance, Formication
Uncommon: Eye irritation, Photophobia
Common: Haematoma, Hypertension,
Uncommon: Exertional dyspnoea
Common: Haemorrhoids, Anorectal discomfort2, Abdominal pain, Rectal haemorrhage3
Uncommon: Abdominal discomfort, Abnormal faeces, Diarrhoea
Common: Hepatotoxicity4
Common: Ecchymosis
Uncommon: Rash, Erythema, Dry skin, Pruritus, Skin depigmentation, Skin reaction
Common: Back pain5
Uncommon: Groin pain, Muscle haemorrhage, Haemarthrosis, Musculoskeletal pain, Pain in extremity
Very common: Urinary retention, Haematuria, Dysuria6, Micturition disorders7
Common: Urethral stenosis Urinary incontinence8
Uncommon: Ureteric haemorrhage, Urethral haemorrhage, Urinary tract disorders
Very common: Perineal pain9, Male sexual dysfunction10
Common: Prostatitis, Genital pain11, Prostatic pain12, Haematospermia
Uncommon: Genital haemorrhage, Penile swelling13, Prostatic haemorrhage, Testicular swelling
Common: Fatigue
Uncommon: Asthenia, Catheter site pain, Laser device failure, Infusion site bruising, Nodule, Pain, Application site erythema
Common: Abnormal clotting14
Uncommon: Blood lactate dehydrogenase increased, Blood triglyceride increased, Gamma-glutamyltransferase increased, Blood cholesterol increased, Blood creatine phosphokinase increased, Blood potassium decreased, Low density lipoprotein increased, Neutrophil count increased, PSA increased, Weight decreased, White blood cell count increased
Common: Perineal injury15
Uncommon: Surgical procedure repeated, Contusion, Post-procedural urine leak, Procedural pain, Post-procedural discharge, Fall
The following terms represent a group of related events that describes a medical condition rather than a single event.
1 Genito-urinary tract infection (urinary tract infection, orchitis, epididymitis, cystitis).
2 Anorectal discomfort (proctalgia, rectal tenesmus).
3 Rectal haemorrhage (anal haemorrhage).
4 Hepatotoxicity (alanine aminotransferase increased, aspartate aminotransferase increased).
5 Back pain (intervertebral disc protrusion).
6 Dysuria (bladder pain, bladder spasm, hypertonic bladder, urethral spasm, urinary tract pain).
7 Micturition disorders (micturition urgency, pollakiuria, nocturia, urine flow decreased, urinary straining).
8 Urinary incontinence (urge incontinence, incontinence, stress urinary incontinence).
9 Perineal pain (pelvic pain).
10 Male sexual dysfunction (erectile dysfunction, ejaculation failure, dyspareunia, ejaculation disorder, hypospermia, painful ejaculation, retrograde ejaculation, sexual dysfunction, semen volume decreased).
11 Genital pain (penile pain, testicular pain, scrotal pain, non-infective orchitis, spermatic cord inflammation, genital contusion).
12 Prostatic pain (prostatism, prostatic disorders, prostatic fibrosis).
13 Penile swelling (balanoposthitis).
14 Abnormal clotting (fibrin D dimer increased, aPTT prolonged, INR increased).
15 Perineal injury (post-procedural haematoma, necrosis, perineal haematoma, pelvic haematoma).
In the Phase III European study, 60 (30.5%) of patients in the TOOKAD-VTP arm experienced erectile dysfunction and 16 (8.1%) experienced ejaculation failure. 53 (26.9%) patients experienced erectile dysfunction for more than 6 months, including 34 (17.3%) patients in whom the erectile dysfunction had not resolved at the end of the study. When the analysis was restricted to patients that underwent unilateral VTP, 33 (16.8%) patients experienced erectile dysfunction for more than 6 months, including 17 (8.6%) patients in whom the erectile dysfunction had not resolved at the end of the study.
In the Phase III European study, 30 (15.2%) patients experienced urinary retention. The median time to onset of urinary retention was 3 days (1-417). The median duration was 10 days (1-344).
The most common infections are orchitis, epididymitis and urinary tract infections including cystitis. In the Phase III European study, 20 (10.2%) patients in the TOOKAD-VTP arm experienced genito-urinary infection. In 5 (2.5%) patients, the infection was considered serious. The median time to onset of genito-urinary infections was 22.5 days (4-360). The median duration was 21 days (4-197).
In the Phase III European study, 25 (12.7%) patients experienced urinary incontinence (including incontinence, stress urinary incontinence and urge incontinence). The median time to onset of urinary incontinence was 4 days (1-142). In 18 patients the adverse event resolved with a median duration of 63.5 days (1-360), and the adverse event was still ongoing at the end of the study for 7 patients. Only 1 (0.5%) patient had a severe (Grade 3) urinary incontinence. None of these patients required an operation for incontinence.
Perineal injury and perineal pain occurred in 46 (23.4%) patients in the controlled Phase III European study. In some cases pain relief was required for perineal pain or anorectal discomfort. One patient had Grade 3 perineal pain that started 35 weeks after the VTP procedure, and lasted for about 35 weeks before resolving without sequelae.
Prostatitis occurred in 7 (3.6%) patients in the controlled Phase III European study. One patient had Grade 3 prostatitis considered as serious that started 4 days after the VTP procedure, and lasted for 31 days before resolving without sequelae.
In the pivotal Phase III European study, moderate or severe urethral stenosis developed in 2 (1.0%) patients 5 to 6 months post-procedure. This required urethral dilatation.
Two cases of excessive extraprostatic necrosis occurred due to incorrect laser calibration without clinical sequelae. One case of external urethral fistula occurred due to fibre misplacement.
In a patient treated at 2 mg/kg of TOOKAD, one case of Grade 3 ischaemic optic neuropathy was reported 33 days after the VTP procedure. This resolved with a small defect in the visual field.
One serious adverse event of prostatic abscess which was considered severe was reported in the study performed in Latin America in a patient who had a unilateral VTP procedure. The case resolved within three days.
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