Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Steba Biotech S.A., 7 Place du Théâtre, L-2613, Luxembourg, Luxembourg
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Any previous prostatic interventions where the internal urinary sphincter may have been damaged, including trans-urethral resection of the prostate (TURP) for benign prostatic hypertrophy.
Current or prior treatment for prostate cancer.
Patients who have been diagnosed with cholestasis.
Current exacerbation of rectal inflammatory bowel disease (see section 4.4).
Any medical condition that precludes the administration of a general anaesthetic or invasive procedures.
Before treatment, the tumour must be accurately located and confirmed as unilateral using high-resolution biopsy strategies based on current best practice, such as multi-parametric MRI-based strategies or template-based biopsy procedures.
Simultaneous treatment of both prostate lobes was associated with an inferior outcome in clinical trials and should not be performed. Insufficient patients underwent retreatment of the ipsilateral lobe or sequential treatment of the contralateral lobe to determine the efficacy and safety of a second TOOKAD-VTP procedure.
There is limited biopsy data beyond 2 years after TOOKAD treatment, so long-term efficacy has not been determined. Residual tumour has been found on follow-up biopsy of the treated lobe at 12 and 24 months, usually outside of the treated volume, but occasionally within the area of necrosis.
There is limited data on long-term outcomes and on potential consequences of post-TOOKAD local scarring in case of disease progression.
At present TOOKAD-VTP has been shown to defer the need for radical therapy and its associated toxicity. Longer follow-up will be required to determine whether TOOKAD-VTP will be curative in a proportion of patients.
Following TOOKAD VTP, patients should undergo digital rectal examination (DRE) and have their serum PSA monitored, including an assessment of PSA dynamics (PSA doubling time and PSA velocity). PSA should be tested every 3 months for first 2 years post VTP and every 6-months thereafter in order to assess PSA dynamics (PSA Doubling Time (DT), PSA velocity). Digital Rectal Examination (DRE) is recommended to be performed at least once a year and more often if clinically justified.Routine biopsy is recommended at 2-4 years and 7 years post VTP, with additional biopsies based on clinical/PSA assessment. mpMRI may be used to improve the decision making but not, at present, to replace biopsy. In case of positive biopsies, patients who exceed the threshold for low risk disease (i.e. have GS > 6, > 3 positive cores or any single core length > 5mm) should receive a treatment recommendation for radical therapy.
The safety and efficacy of subsequent radical therapy (surgery or radiotherapy) is uncertain. Limited information is available regarding the safety and efficacy of radical prostatectomy after TOOKAD-VTP. In small surgical series, there have been reports of T3 tumours, positive margins and impotence. In the 24 months of the pivotal European Phase III study, no patients underwent radical radiotherapy post TOOKAD-VTP.
There is a risk of skin and eye photosensitivity with exposure to light post TOOKAD-VTP.
It is important that all patients follow the light precautions below for 48 hours post-procedure to minimize the risk of damage to the skin and eyes.
Patients should avoid exposure to direct sunlight (including through windows) and all bright light sources, both indoors and outdoors. This includes sunbeds, bright computer monitor screens and medical examination lights, such as ophthalmoscopes, otoscopes and endoscopy equipment, for 48 hours following the VTP procedure.
Sunscreen creams do not protect against near infra-red light and, therefore, do not provide adequate protection.
If the patient reports discomfort to the skin or eyes during hospitalisation, reduce the level of lighting and take extra care to shield the patient from artificial and natural light.
The patient should wear protective goggles and be kept under medical surveillance for at least 6 hours in a room with dimmed light.
The patient may be discharged in the evening of the same day at the physician’s discretion.
The patient must stay in a dimmed light environment without any direct exposure of the skin and the eyes to daylight. The patient may only use incandescent light bulbs with a maximum power of 60 watts or equivalent (i.e. 6 watts for LED lights, 12 watts for fluorescent low-energy lights).
The patient may watch television from a distance of 2 metres and, from 6 hours onwards, may use electronic devices such as smartphones, tablets and computers. If the patient must go outdoors during daylight hours, he should wear protective clothes and high protection goggles to shield his skin and eyes.
The patient may go outdoors during daylight hours but only in shaded areas or when it is overcast. He should wear dark clothes and take care when exposing hands and face to the sun.
The patient can return to normal activity and tolerate direct sunlight 48 hours after the procedure.
No patients with photosensitive dermatitis, skin conditions such as porphyria or a history of sensitivity to sunlight have received TOOKAD in clinical studies. However, the short duration of action of TOOKAD means that the risk of enhanced phototoxicity is expected to be low provided these patients strictly follow the precautions against light exposure.
There could be an additional risk of eye photosensitivity in patients who have received intra-occular anti-VEGF therapy. Patients who have received prior VEGF therapy should take particular care to protect the eyes from light for 48 hours post TOOKAD injection. Concomitant use of systemic VEGF inhibitors is not recommended with TOOKAD.
See section 4.5 for interactions with photosensitizing medicinal products.
Erectile dysfunction may occur even if radical prostatectomy is avoided. Some degree of erectile dysfunction is possible soon after the procedure and may last for more than 6 months (see section 4.8).
There may be extraprostatic necrosis in the peri-prostatic fat not associated with clinical symptoms.
Excessive extraprostatic necrosis occurred as a result of incorrect calibration of the laser or placement of the light fibres (see section 4.8). In consequence there is a potential risk of damage to adjacent structures, such as the bladder and/or rectum, and development of a recto-urethral or external fistula. A urinary fistula has occurred in one case due to incorrect fibre placement.
The equipment should be carefully calibrated and use the treatment guidance software to reduce the risk of clinically significant extraprostatic necrosis.
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 TOOKAD-VTP procedure. Urinary retention immediately post procedure has been attributed to transient prostatic oedema and generally only short term recatheterisation was required.
Poor urinary flow due to urethral stricture developed some months post procedure. In certain cases, the bulbar location suggested that the stenosis was caused by urinary catheterisation. In other cases, urethral stenosis may have been a late consequence of TOOKAD-VTP induced necrosis.
Although they were excluded from the clinical trials, there is a potential risk of increased stenosis post the TOOKAD-VTP procedure in patients with pre-existing stenosis (see section 4.8).
The risk of sphincter damage can be minimised by careful planning of the fibre placement using the treatment guidance software. Severe long-term urinary incontinence was observed in a patient who underwent a previous transurethral prostatectomy (TURP). This event was not considered to be related to a faulty procedure but rather the pre-existing damage to the internal urethral sphincter from the TURP. The TOOKAD-VTP procedure is contraindicated in patients with any previous prostatic interventions where the internal urinary sphincter may have been damaged, including transurethral resection of the prostate (TURP) for benign prostatic hypertrophy (see section 4.3).
TOOKAD-VTP should only be administered after careful clinical evaluation, to patients with a history of active rectal inflammatory bowel disease or any condition that may increase the risk of recto-urethral fistula formation (see section 4.3).
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 TOOKAD-VTP treatment; however, it is recommended that drugs that affect clotting are stopped prior to and for the immediate period following the VTP procedure (see section 4.5).
This medicinal product contains potassium and in general the dose (3.66 mg/kg) will be less than 1 mmol (39 mg) i.e. essentially ‘potassium free’. However, this will be exceeded in patients heavier than 115 kg. This should be taken into consideration in patients with reduced kidney function or patients on a controlled potassium diet where a rise in serum potassium would be considered detrimental (see section 4.2).
In vitro studies predict that TOOKAD at therapeutic concentrations is unlikely to inhibit cytochrome P450 enzymes but could inhibit OATP1B1 and OATP1B3 transporters (see section 5.2).
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 TOOKAD 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 TOOKAD 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 (see section 4.2).
Anticoagulant medicinal products and those that decrease platelet aggregation (e.g. acetylsalicylic acid) should be stopped at least 10 days before the procedure with TOOKAD. Medicinal products that prevent or reduce platelet aggregation should not be started for at least 3 days after the procedure.
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.
TOOKAD is not indicated for the treatment of women.
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.
TOOKAD 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 in Table 1 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).
Table 1. 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 (see section 4.4).
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 (see section 4.4).
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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