Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 16 February 2017

Indication(s)

1 INDICATIONS AND USAGE PHOTOFRIN is a photodynamic therapy drug indicated for: Esophageal Cancer (1.1) Palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer who, in the opinion of their physician

can not be satisfactorily treated with Nd:YAG laser therapy Endobronchial Cancer (1.2) Treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated Reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC High-Grade Dysplasia in Barrett 's Esophagus (1.3) Ablation of high-grade dysplasia (HGD) in Barrett 's esophagus (BE) patients who do not undergo esophagectomy 1.1 Esophageal Cancer PHOTOFRIN® is indicated for the palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer who, in the opinion of their physician, can not be satisfactorily treated with Nd:YAG laser therapy.

1.2 Endobronchial Cancer PHOTOFRIN is indicated for the treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated.

PHOTOFRIN is indicated for the reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC. 1.3 High-Grade Dysplasia in Barrett 's Esophagus PHOTOFRIN is indicated for the ablation of high-grade dysplasia in Barrett 's esophagus patients who do not undergo esophagectomy.

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Advisory information

contraindications

4 CONTRAINDICATIONS PHOTOFRIN is contraindicated in patients with porphyria.

Photodynamic therapy (PDT) is contraindicated in patients with an existing tracheoesophageal or bronchoesophageal fistula.

PDT is contraindicated in patients with tumors eroding into a major blood vessel.

PDT is not suitable for emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection with PHOTOFRIN and laser light treatment.

PDT is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers >1 cm in diameter.

Porphyria (4) Existing tracheoesophageal or bronchoesophageal fistula (4, 5.1) Tumors eroding into a major blood vessel (4, 5.2) Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection of PHOTOFRIN and laser light treatment (4)

Esophageal or gastric varices or esophageal ulcers >1 cm in diameter (4)

Adverse reactions

6 ADVERSE REACTIONS Most common adverse reactions reported during clinical trials (>10 % of patients) are (6.2): Esophageal Cancer: Anemia, pleural effusion, pyrexia, constipation, nausea, chest pain, pain, abdominal pain, dyspnoea, photosensitivity reaction, pneumonia, vomiting, insomnia, back pain, pharyngitis Obstructing Endobronchial Cancer: Dyspnoea, photosensitivity reaction, hemoptysis, pyrexia, cough, pneumonia Superficial Endobronchial Tumors: Exudate, photosensitivity reaction, bronchial obstruction, edema, bronchostenosis High-Grade Dysplasia in Barrett 's Esophagus: Photosensitivity reaction, esophageal stenosis, vomiting, chest pain, nausea, pyrexia, constipation, dysphagia, abdominal pain, pleural effusion, dehydration To report SUSPECTED ADVERSE REACTIONS

contact Pinnacle Biologics, Inc. at 1-866-248-2039 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Overall Adverse Reaction Profile Systemically induced effects of photodynamic therapy (PDT) with PHOTOFRIN consist of photosensitivity and mild constipation.

All patients who receive PHOTOFRIN will be photosensitive and must observe precautions to avoid sunlight and bright indoor light [see Warnings and Precautions (5.4)].

Photosensitivity reactions occurred in approximately 20 % of cancer patients and in 69 % of high-grade dysplasia (HGD) in Barrett 's esophagus (BE) patients treated with PHOTOFRIN.

Typically these reactions were mostly mild to moderate erythema but they also included swelling, pruritus, burning sensation, feeling hot, or blisters.

In a single study of 24 healthy subjects, some evidence of photosensitivity reactions occurred in all subjects.

Other less common skin manifestations were also reported in areas where photosensitivity reactions had occurred, such as increased hair growth, skin discoloration, skin nodule, skin wrinkling and increased skin fragility.

These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria).

Most toxicities of this therapy are local effects seen in the region of illumination and occasionally in surrounding tissues.

The local adverse reactions are characteristic of an inflammatory response induced by the photodynamic effect.

A few cases of fluid imbalance have been reported in patients treated with PHOTOFRIN PDT for overtly disseminated intraperitoneal malignancies.

Fluid imbalance is an expected PDT-related event.

A case of cataracts has been reported in a 51 year-old obese man treated with PHOTOFRIN PDT for HGD in BE.

The patient suffered from a PDT response with development of a deep esophageal ulcer.

Within two months post PDT, the patient noted difficulty with his distant vision.

A thorough eye examination revealed a change in the refractive error that later progressed to cataracts in both eyes.

Both of his parents had a history of cataracts in their 70s.

Whether PHOTOFRIN directly caused or accelerated a familial underlying condition is unknown.

6.2 Adverse

Reactions in

Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Esophageal Carcinoma The following adverse reactions were reported over the entire follow-up period in at least 5 % of patients treated with PHOTOFRIN PDT, who had completely or partially obstructing esophageal cancer.

Table 6 presents data from 88 patients who received the currently marketed formulation.

The relationship of many of these adverse reactions to PDT with PHOTOFRIN is uncertain.

TABLE 6.

Adverse Reactions Reported in 5 % or More of PatientsBased on adverse reactions reported at any time during the entire period of follow-up.

with Obstructing Esophageal Cancer SYSTEM ORGAN CLASS/Adverse Reaction N=88 n (%) Patients with at Least One Adverse Reaction 84 (95) BLOOD and LYMPHATIC SYSTEM DISORDERS Anemia 28 (32) CARDIAC DISORDERS Atrial fibrillation 9 (10) Cardiac failure 6 (7) Tachycardia 5 (6) GASTROINTESTINAL DISORDERS Constipation 21 (24) Nausea 21 (24) Abdominal pain 18 (20) Vomiting 15 (17) Dysphagia 9 (10) Esophageal edema 7 (8) Hematemesis 7 (8) Dyspepsia 5 (6) Esophageal stenosis 5 (6) Diarrhea 4 (5) Esophagitis 4 (5) Eructation 4 (5) Melena 4 (5) GENERAL DISORDERS & ADMINISTRATION SITE CONDITIONS Pyrexia 27 (31) Chest pain 19 (22) Pain 19 (22) Edema peripheral 6 (7) Asthenia 5 (6) Chest pain (substernal) 4 (5) Edema generalized 4 (5) INFECTIONS and INFESTATIONS Candidiasis 8 (9) Urinary tract infection 6 (7) INJURY

POISONING and PROCEDURAL COMPLICATIONS Post procedural complication 4 (5) INVESTIGATIONS Weight decreased 8 (9) METABOLISM and NUTRITION DISORDERS Anorexia 7 (8) Dehydration 6 (7) MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS Back pain 10 (11) NEOPLASMS BENIGN, MALIGNANT and UNSPECIFIED Tumor hemorrhage 7 (8) PSYCHIATRIC DISORDERS Insomnia 12 (14) Confusional state 7 (8) Anxiety 6 (7) RESPIRATORY

THORACIC and MEDIASTINAL DISORDERS Pleural effusion 28 (32) Dyspnoea 18 (20) Pneumonia 16 (18) Pharyngitis 10 (11) Respiratory insufficiency 9 (10) Cough 6 (7) Tracheoesophageal fistula 5 (6) SKIN and SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction 17 (19) VASCULAR DISORDERS Hypotension 6 (7) Hypertension 5 (6) Location of the tumor was a prognostic factor for three adverse reactions: upper-third of the esophagus (esophageal edema), middle-third (atrial fibrillation), and lower-third, the most vascular region (anemia).

Also, patients with large tumors (>10 cm) were more likely to experience anemia.

Two of 17 patients with complete esophageal obstruction from tumor experienced esophageal perforations, which were considered to be possibly treatment-associated; these perforations occurred during subsequent endoscopies.

Serious and other notable adverse reactions observed in less than 5 % of PDT-treated patients with obstructing esophageal cancer in the clinical studies include the following; their relationship to therapy is uncertain.

In the gastrointestinal system, esophageal perforation, gastric ulcer, ileus, jaundice, and peritonitis have occurred.

Sepsis has been reported occasionally.

Cardiovascular reactions have included angina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventricular tachycardia.

Respiratory reactions of bronchitis, bronchospasm, laryngotracheal edema, pneumonitis, pulmonary hemorrhage, pulmonary edema, respiratory failure, and stridor have occurred.

The temporal relationship of some gastrointestinal, cardiovascular and respiratory reactions to the administration of light was suggestive of mediastinal inflammation in some patients.

Vision-related reactions of abnormal vision, diplopia, eye pain and photophobia have been reported.

Obstructing Endobronchial Cancer Table 7 presents adverse reactions that were reported over the entire follow-up period in at least 5 % of patients with obstructing endobronchial cancer treated with PHOTOFRIN PDT or Nd:YAG.

These data are based on the 86 patients who received the currently marketed formulation.

Since it seems likely that most adverse reactions caused by these acute acting therapies would occur within 30 days of treatment, Table 7 presents those reactions occurring within 30 days of a treatment procedure, as well as those occurring over the entire follow-up period.

It should be noted that follow-up was 33 % longer for the PDT group than for the Nd:YAG group, thereby introducing a bias against PDT when adverse reaction rates are compared for the entire follow-up period.

The extent of follow-up in the 30-day period following treatment was comparable between groups (only 9 % more for PDT).

Transient inflammatory reactions in PDT-treated patients occur in about 10 % of patients and manifest as pyrexia, bronchitis, chest pain, and dyspnoea.

The incidences of bronchitis and dyspnoea were higher with

PDT than with

Nd:YAG. Most cases of bronchitis occurred within 1 week of treatment and all but one were mild or moderate in intensity.

The reactions usually resolved within 10 days with antibiotic therapy.

Treatment-related worsening of dyspnoea is generally transient and self-limiting.

Debridement of the treated area is mandatory to remove exudate and necrotic tissue.

Life-threatening respiratory insufficiency likely due to therapy occurred in 3 % of PDT-treated patients and 2 % of Nd:YAG-treated patients [see Warnings and Precautions (5.8)].

There was a trend toward a higher rate of fatal massive hemoptysis (FMH) occurring on the PDT arm (10 %) versus the Nd:YAG arm (5 %), however, the rate of FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG (4 % total events, 3 % treatment-associated events).

Patients who have received radiation therapy have a higher incidence of FMH after treatment with PDT and after other forms of local therapy than patients who have not received radiation therapy, but analyses suggest that this increased risk may be due to associated prognostic factors such as having a centrally located tumor.

The incidence of FMH in patients previously treated with radiotherapy was 21 % (6/29) in the PDT group and 10 % (3/29) in the Nd:YAG group.

In patients with no prior radiotherapy, the overall incidence of FMH was less than 1 %.

Characteristics of patients at high risk for FMH are described in Contraindications (4) and Warnings and Precautions (5.2).

Other serious or notable adverse reactions were observed in less than 5 % of PDT-treated patients with endobronchial cancer; their relationship to therapy is uncertain.

In the respiratory system, pulmonary thrombosis, pulmonary embolism, and lung abscess have occurred.

Cardiac failure, sepsis, and possible cerebrovascular accident have also been reported in one patient each.

TABLE 7.

Adverse Reactions Reported in 5 % or More of Patients with Obstructing Endobronchial Cancer Number (%) of Patients SYSTEM

ORGAN CLASS/Within 30 Days of Treatment Entire Follow-up PeriodFollow-up was 33 % longer for the PDT group than for the Nd:YAG group, introducing a bias against PDT when adverse reactions are compared for the entire follow-up period.

Adverse Reaction PDT N=86 n (%) Nd:YAG N=86 n (%) PDT N=86 n (%) Nd:YAG N=86 n (%) Patients with at Least One Adverse Reaction 43 (50) 33 (38) 62 (72) 48 (56) GASTROINTESTINAL DISORDERS Dyspepsia 1 (1) 4 (5) 2 (2) 5 (6) Constipation 4 (5) 1 (1) 4 (5) 2 (2) GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONS Pyrexia 7 (8) 7 (8) 14 (16) 8 (9) Chest pain 6 (7) 6 (7) 7 (8) 8 (9) Pain 1 (1) 4 (5) 4 (5) 8 (9) Edema peripheral 3 (3) 3 (3) 4 (5) 3 (3) MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS Back pain 3 (3) 1 (1) 3 (3) 5 (6) NERVOUS SYSTEM DISORDERS Dysphonia 3 (3) 2 (2) 4 (5) 2 (2) PSYCHIATRIC DISORDERS Insomnia 4 (5) 2 (2) 4 (5) 3 (4) Anxiety 3 (3) 0 (0) 5 (6) 0 (0) RESPIRATORY

THORACIC and MEDIASTINAL DISORDERS Dyspnoea 15 (17) 7 (8) 26 (30) 13 (15) Cough 5 (6) 8 (9) 13 (15) 11 (13) Hemoptysis 6 (7) 5 (6) 14 (16) 7 (8) Pneumonia 5 (6) 4 (5) 10 (12) 5 (6) Bronchitis 9 (10) 2 (2) 9 (10) 2 (2) Productive cough 4 (5) 5 (6) 7 (8) 6 (7) Respiratory insufficiency 0 (0) 0 (0) 5 (6) 1 (1) Pleural effusion 0 (0) 0 (0) 4 (5) 1 (1) Pneumothorax 0 (0) 0 (0) 0 (0) 4 (5) SKIN and SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction 16 (19) 0 (0) 18 (21) 0 (0) Superficial Endobronchial Tumors The following adverse reactions were reported over the entire follow-up period in at least 5 % of patients with superficial tumors (microinvasive or carcinoma in_situ) who received the currently marketed formulation.

TABLE 8.

Adverse Reactions Reported in 5 % or More of PatientsBased on adverse reactions reported at any time during the entire period of follow-up.

with Superficial Endobronchial Tumors Adverse Reaction N=90 n (%) Patients with at Least One Adverse Reaction 44 (49) RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS Exudate 20 (22) Bronchial mucus plug or bronchial obstruction 19 (21) Edema 16 (18) Bronchostenosis 10 (11) Bronchial ulceration 8 (9) Cough 8 (9) Dyspnoea 6 (7) SKIN and SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction 20 (22) In patients with superficial endobronchial tumors, 44 of 90 patients (49 %) experienced an adverse reaction, two-thirds of which were related to the respiratory system.

The most common reaction to therapy was a mucositis reaction in one-fifth of the patients, which manifested as edema, exudate, and obstruction.

The obstruction (mucus plug) is easily removed with suction or forceps.

Mucositis can be minimized by avoiding exposure of normal tissue to excessive light [see Warnings and Precautions (5.8)].

Three patients experienced life-threatening dyspnoea: one was given a double dose of light, one was treated concurrently in both mainstem bronchi and the other had had prior pneumonectomy and was treated in the sole remaining main airway [see Warnings and Precautions (5.2)].

Stent placement was required in 3 % of the patients due to endobronchial stricture.

Fatal massive hemoptysis occurred within 30 days of treatment in one patient with superficial tumors (1 %).

High-Grade Dysplasia (HGD) in Barrett 's Esophagus (BE) Table 9 presents adverse reactions that were reported over the follow-up period in at least 5 % of patients with HGD in BE in either controlled or uncontrolled clinical trials.

In the PHOTOFRIN PDT + OM group severe adverse reactions included chest pain of non-cardiac origin, dysphagia, nausea, vomiting, regurgitation, and heartburn.

The severity of these symptoms decreased within 4 to 6 weeks following treatment.

The majority of the photosensitivity reactions occurred within 90 days following PHOTOFRIN injection and was of mild (68 %) or moderate (24 %) intensity.

Fourteen (10 %) patients reported severe reactions, all of which resolved.

The typical reaction was described as skin disorder, sunburn or rash, and affected mostly the face, hands, and neck.

Associated symptoms and signs were swelling, pruritis, erythema, blisters, burning sensation, and feeling of heat.

The majority of esophageal stenosis including strictures reported in the PHOTOFRIN PDT + OM group were of mild (57 %) or moderate (35 %) intensity, while approximately 8 % were of severe intensity.

The majority of esophageal strictures were reported during Course 2 of treatment.

All esophageal strictures were considered to be due to treatment.

Most esophageal strictures were manageable through dilations [see Warnings and Precautions (5.9)].

Table 9.

Adverse Reactions Reported in?5 % of Patients Treated with PHOTOFRIN PDT in the Clinical Trials on High-Grade Dysplasia in Barrett 's Esophagus Treatment Groups SYSTEM ORGAN CLASS/Adverse Reaction HGDIncludes all HGD patients in the Safety population from PHO BAR 02 (N=133), TCSC 93-07 (N=44), and TCSC 96-01 (N=42).

PHOPDT +OM HGDIncludes all HGD patients in the Safety population from PHO BAR 02 (N=69).

OM Only OtherIncludes patients with

Barrett 's metaplasia, indefinite dysplasia, LGD, and adenocarcinoma at baseline in the Safety population from TCSC 93-07 (N=55) and TCSC 96-01 (N=44).

PHOPDT +OM Total PHOPDT +OM N=219 n (%) N=69 n (%) N=99 n (%) N=318 n (%) Patients with at Least One Adverse Reaction 206 (94) 9 (13) 97 (98) 303 (95) GASTROINTESTINAL DISORDERS 163 (74) 6 (9) 83 (84) 246 (77) Nausea 57 (26) 1 (1) 61 (62) 118 (37) Vomiting 63 (29) 1 (1) 34 (34) 97 (31) Esophageal StrictureEsophageal stricture was defined as a dilated esophageal stenosis.

81 (37) 0 33 (33) 114 (36) Esophageal NarrowingEsophageal narrowing was defined as an undilated esophageal stenosis.

71 (32) 4 (6) 24 (24) 95 (30) Dysphagia 49 (22) 0 26 (26) 75 (24) Constipation 25 (11) 1 (1) 7 (7) 32 (10) Abdominal pain (Upper, lower, NOS) 11 (5) 1 (1) 6 (6) 17 (5) Esophageal pain 13 (6) 0 9 (9) 22 (7) Dyspepsia 10 (5) 0 4 (4) 14 (4) Hiccups 16 (7) 0 1 (1) 17 (5) Odynophagia 13 (6) 0 4 (4) 17 (5) GENERAL and ADMINISTRATION SITE CONDITIONS 110 (50) 0 62 (63) 172 (54) Chest pain 63 (29) 0 37 (37) 100 (31) Pyrexia 41 (19) 0 13 (13) 54 (17) Chest discomfort 13 (6) 0 19 (19) 32 (10) Pain 11 (5) 0 7 (7) 18 (6) INJURY, POISONING and PROCEDURAL COMPLICATIONS 24 (11) 0 19 (19) 43 (14) Post procedural pain 14 (6) 0 14 (14) 28 (9) INVESTIGATIONS 24 (11) 0 11 (11) 35 (11) Weight decreased 15 (7) 0 2 (2) 17 (5) METABOLISM and NUTRITION DISORDERS 28 (13) 0 16 (16) 44 (14) Dehydration 24 (11) 0 8 (8) 32 (10) RESPIRATORY

THORACIC and MEDIASTINAL DISORDERS 35 (16) 0 18 (18) 53 (17) Pleural effusion 22 (10) 0 15 (15) 37 (12) SKIN and SUBCUTANEOUS TISSUE DISORDERS 115 (53) 1 (1) 28 (28) 143 (45) Photosensitivity reaction 102 (47) 0 16 (16) 118 (37) PHO: PHOTOFRIN NOTE: Adverse reactions classified using MedDRA 5.0 dictionary with the exception of esophageal stricture and esophageal narrowing.

Laboratory Abnormalities In patients with esophageal cancer, PDT with PHOTOFRIN may result in anemia due to tumor bleeding.

No significant effects were observed for other parameters in patients with endobronchial carcinoma or with HGD in BE. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Photofrin with PDT.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infusion reactions: Infusion reactions including urticaria, bradycardia, hypotension, dizziness, and hypertension

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Photodynamic therapy (PDT) with PHOTOFRIN is a two - stage process requiring administration of both drug and light.

The first stage of PDT is the intravenous injection of PHOTOFRIN at 2 mg/kg.

Illumination with laser light 40-50 hours following injection with PHOTOFRIN constitutes the second stage of therapy.

A second laser light application may be given 96-120 hours after injection [see Dosage and Administration (2.2)].

In clinical studies on endobronchial cancer, debridement via endoscopy was required 2-3 days after the initial light application.

Standard endoscopic techniques are used for light administration and debridement.

Practitioners should be fully familiar with the patient 's condition and trained in the safe and efficacious treatment of esophageal or endobronchial cancer, or high-grade dysplasia (HGD) in Barrett 's esophagus (BE) using PDT with PHOTOFRIN and associated light delivery devices.

PDT with PHOTOFRIN should be applied only in those facilities properly equipped for the procedure.

The laser system must be approved for delivery of a stable power output at a wavelength of 630 ± 3 nm.

Light is delivered to the tumor by cylindrical OPTIGUIDE™ fiber optic diffusers passed through the operating channel of an endoscope/bronchoscope.

Instructions for use of the fiber optic and the selected laser system should be read carefully before use.

OPTIGUIDE™ cylindrical diffusers are available in several lengths.

The choice of diffuser tip length depends on the length of the tumor or Barrett 's mucosa to be treated.

Diffuser length should be sized to avoid exposure of nonmalignant tissue to light and to prevent overlapping of previously treated malignant tissue.

Refer to the OPTIGUIDE™ instructions for use for complete instructions concerning the fiber optic diffuser.

PHOTOFRIN (2.1) PHOTOFRIN administration: 2 mg/kg intravenous Photoactivation (2.2) Esophageal Cancer Laser light dose of 300 J/cm of fiber optic diffuser length 40-50 hours following injection with PHOTOFRIN; repeated, if needed, 96-120 hours after initial injection Endobronchial Cancer Laser light dose of 200 J/cm of fiber optic diffuser length 40-50 hours following injection with PHOTOFRIN; repeated, if needed, after gentle debridement of residual tumor 96-120 hours after initial injection High-Grade Dysplasia in Barrett 's Esophagus Laser light dose of 130 J/cm of fiber optic diffuser length 40-50 hours following injection with PHOTOFRIN

repeated, if needed, with a light dose of 50 J/cm of fiber optic diffuser length 96-120 hours after initial injection 2.1 PHOTOFRIN PHOTOFRIN should be administered as a single slow intravenous injection over 3 to 5 minutes at 2 mg/kg of body weight.

Reconstitute each vial of PHOTOFRIN with 31.8 mL of either 5 % Dextrose Injection (USP) or 0.9 % Sodium Chloride Injection (USP), resulting in a final concentration of 2.5 mg /mL. Shake well until dissolved.

Do not mix PHOTOFRIN with other drugs in the same solution.

PHOTOFRIN, reconstituted with 5 % Dextrose Injection (USP) or with 0.9 % Sodium Chloride Injection (USP), has a pH in the range of 7 to 8.

PHOTOFRIN has been formulated with an overage to deliver the 75 mg labeled quantity.

The reconstituted product should be protected from bright light and used immediately.

Reconstituted PHOTOFRIN is an opaque solution, in which detection of particulate matter by visual inspection is extremely difficult.

Reconstituted PHOTOFRIN, however, like all parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Precautions should be taken to prevent extravasation at the injection site.

If extravasation occurs, care must be taken to protect the area from light.

There is no known benefit from injecting the extravasation site with another substance.

2.2 Photoactivation Esophageal Cancer Initiate 630 nm wavelength laser light delivery to the patient 40-50 hours following injection with PHOTOFRIN.

A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection with PHOTOFRIN. No further injection of PHOTOFRIN should be given for such retreatment with laser light.

Before providing a second laser light treatment, the residual tumor may be debrided.

The debridement is optional since the residua will be removed naturally by peristaltic action of the esophagus.

Vigorous debridement may cause tumor bleeding.

Photoactivation of PHOTOFRIN is controlled by the total light dose delivered.

In the treatment of esophageal cancer, a light dose of 300 Joules/ cm (J/cm) of diffuser length should be delivered.

The total power output at the fiber tip is set to deliver the appropriate light dose using exposure times of 12 minutes and 30 seconds.

For the treatment of esophageal cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to three courses of

PDT (each separated by a minimum of 30 days) can be given.

Before each course of treatment, patients with esophageal cancer should be evaluated for the presence of a tracheoesophageal or bronchoesophageal fistula [see Contraindications (4)].

All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel [see Contraindications (4)].

Endobronchial Cancer Initiate 630 nm wavelength laser light delivery to the patient 40-50 hours following injection with PHOTOFRIN.

A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection with PHOTOFRIN. No further injection of PHOTOFRIN should be given for such retreatment with laser light.

Before providing a second laser light treatment, the residual tumor should be debrided.

Vigorous debridement may cause tumor bleeding.

For endobronchial tumors, debridement of necrotic tissue should be discontinued when the volume of bleeding increases, as this may indicate that debridement has gone beyond the zone of the PDT effect.

Photoactivation of PHOTOFRIN is controlled by the total light dose delivered.

In the treatment of endobronchial cancer, a light dose of 200 J/cm of diffuser length should be delivered.

The total power output at the fiber tip is set to deliver the appropriate light dose using exposure times of 8 minutes and 20 seconds.

For noncircumferential endobronchial tumors that are soft enough to penetrate, interstitial fiber placement is preferred to intraluminal activation, since this method produces better efficacy and results in less exposure of the normal bronchial mucosa to light.

It is important to perform a debridement 2 to 3 days after each light administration to minimize the potential for obstruction caused by necrotic debris [see Warnings and Precautions (5.8)].

For the treatment of endobronchial cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to three courses of PDT (each separated by a minimum of 30 days) can be given.

In patients with endobronchial lesions who have recently undergone radiotherapy, sufficient time (approximately 4 weeks) should be allowed between the therapies to ensure that the acute inflammation produced by radiotherapy has subsided prior to PDT [see Warnings and Precautions (5.6)].

All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel [see Contraindications (4)].

High-Grade Dysplasia (HGD) in Barrett 's Esophagus (BE) Prior to initiating treatment with PHOTOFRIN PDT, the diagnosis of HGD in BE should be confirmed by an expert GI pathologist.

Approximately 40-50 hours after PHOTOFRIN administration light should be delivered by a X-Cell Photodynamic Therapy (PDT) Balloon with Fiber Optic Diffuser.

The choice of fiber optic/balloon diffuser combination will depend on the length of Barrett 's mucosa to be treated (Table 1).

TABLE 1.

Fiber

Optic Diffuser/Balloon

CombinationWhenever possible, the BE segment selected for treatment should include normal tissue margins of a few millimeters at the proximal and distal ends.

Treated Barrett 's Mucosa Length (cm) Fiber Optic Diffuser Length (cm) Balloon Window Length (cm) 6-7 9 7 4-5 7 5 1-3 5 3 Photoactivation is controlled by the total light dose delivered.

The objective is to expose and treat all areas of HGD and the entire length of BE.

The light dose administered will be 130 J/cm of diffuser length using a centering balloon.

Based on the randomized clinical study, acceptable light intensity for the balloon/diffuser combinations range from 200-270 mW/cm of diffuser length.

To calculate the light dose, the following specific light dosimetry equation applies for all fiber optic diffusers: Light Dose (J/cm) = Power Output From Diffuser (W) x Treatment Time (s)/Diffuser Length (cm) Table 2 provides the settings that will be used to deliver the dose within the shortest time (light intensity of 270 mW/cm).

A second option (light intensity of 200 mW/cm) has also been included where necessary to accommodate lasers with a total capacity that does not exceed 2.5 W. TABLE 2.

Fiber Optic Power Outputs and Treatment Times Required to Deliver 130 J/cm of Diffuser Length Using the Centering Balloon Balloon Window Length (cm) Fiber Optic Diffuser Length (cm) Light Intensity (mW/cm) Required Power Output from DiffuserAs measured by immersing the diffuser into the cuvet in the power meter and slowly increasing the laser power.

Note:

No more than 1.5 times the required diffuser power output should be needed from the laser.

If more than this is required, the system should be checked.

(mW) Treatment Time (sec) (min:sec) 3 5 270 1 350 480 8:00 5 7 270 1 900 480 8:00 7 9 270 2 440 480 8:00 200 1 800 480 10:50 Short fiber diffusers (?

2.5 cm) are to be used to pretreat nodules with 50 J/cm of diffuser length prior to regular balloon treatment in the first laser light session or for the treatment of " skip " areas (i.e., an area that does not show sufficient mucosal response) after the first light session.

For this treatment, the fiber optic diffuser is used without a centering balloon, and a light intensity of 400 mW/cm should be used.

For nodule pretreatment and treatment of skipped areas, care should be taken to minimize exposure to normal tissue as it is also sensitized.

Table 3 lists appropriate fiber optic power outputs and treatment times using a light intensity of 400 mW/cm.

TABLE 3.

Short Fiber Optic Diffusers to be Used Without a Centering Balloon to Deliver 50 J/cm of Diffuser Length at a Light Intensity of 400 mW/cm Fiber Optic Diffuser Length (cm) Required Power Output From DiffuserAs measured by immersing the diffuser into the cuvet in the power meter and slowly increasing the laser power.

Note:

No more than 1.5 times the required diffuser power output should be needed from the laser.

If more than this is required, the system should be checked.

(mW) Treatment Time (sec) Treatment Time (min:sec) 1.0 400 125 2:05 1.5 600 125 2:05 2.0 800 125 2:05 2.5 1 000 125 2:05 A maximum of 7 cm of esophageal mucosa is treated at the first light session using an appropriate size of centering balloon and fiber optic diffuser (Table 1).

Whenever possible, the segment selected for the first light application should contain all the areas of HGD.

Also, whenever possible, the BE segment selected for the first light application should include normal tissue margin of a few millimeters at the proximal and distal ends.

Nodules are to be pretreated at a light dose of 50 J/cm of diffuser length with a short (?2.5 cm) fiber optic diffuser placed directly against the nodule followed by standard balloon application as described above.

Repeat Light Application A second laser light application may be given to a previously treated segment that shows a " skip " area, using a short,?

2.5 cm, fiber optic diffuser without centering balloon at the light dose of 50 J/cm of the diffuser length.

Patients with BE >7 cm, should have the remaining untreated length of Barrett 's epithelium treated with a second PDT course at least 90 days later.

The treatment regimen is summarized in Table 4.

TABLE 4.

High-Grade Dysplasia in Barrett 's Esophagus Procedure Study Day Light Delivery Devices Treatment Intent PHOTOFRIN Injection Day 1 NA Uptake of photosensitizer Laser Light Application Day 3Discrete nodules will receive an initial light application of 50 J/cm (using a short fiber optic diffuser without balloon) before the balloon light application.

NA: Not Applicable 3, 5 or 7 cm balloon (130 J/cm) Photoactivation Laser Light Application (Optional) Day 5 Short (?

2.5 cm) fiber optic diffuser (50 J/cm) Treatment of " skip " areas only For the ablation of HGD in BE, patients may receive an additional course of PDT at a minimum of 90 days after the initial therapy; up to three courses of PDT (each injection separated by a minimum of 90 days) can be given to a previously treated segment which still shows HGD, low-grade dysplasia, or Barrett 's metaplasia, or to a new segment if the initial Barrett 's segment was >7 cm in length.

Both residual and additional segments may be treated in the same light session(s) provided that the total length of the segments treated with the balloon/diffuser combination is not greater than 7 cm.

In the case of a previously treated esophageal segment, if it has not sufficiently healed and/or histological assessment of biopsies is not clear, the subsequent course of PDT may be delayed for an additional 1-2 months.

Use in special populations

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Porfimer sodium has been shown to have an embryocidal effect in rats and rabbits when given in doses 0.64 times the recommended human dose on a mg/ m2 basis.

Porfimer sodium given to rat dams during fetal organogenesis intravenously at 0.64 times the clinical dose on a mg/ m2 basis for 10 days caused no major malformations or developmental changes.

This dose caused maternal and fetal toxicity resulting in increased resorptions, decreased litter size, delayed ossification, and reduced fetal weight.

Porfimer sodium caused no major malformations when given to rabbits intravenously during organogenesis at 0.65 times the clinical dose on a mg/ m2 basis for 13 days.

This dose caused maternal toxicity resulting in increased resorptions, decreased litter size, and reduced fetal body weight.

Porfimer sodium given to rats during late pregnancy through lactation intravenously at 0.32 times the clinical dose on a mg/ m2 basis for at least 42 days caused a reversible decrease in growth of offspring.

Parturition was unaffected.

There are no adequate and well-controlled studies of PHOTOFRIN in pregnant women.

PHOTOFRIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether PHOTOFRIN is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PHOTOFRIN, a decision should be made whether not to treat or to discontinue breastfeeding, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in children have not been established.

8.5 Geriatric Use Approximately 70 % of the patients treated with PDT using PHOTOFRIN in clinical trials were over 60 years of age.

There was no apparent difference in effectiveness or safety in these patients compared to younger people.

Dose modification based upon age is not required.

Pregnancy and lactation
8.3 Nursing Mothers It is not known whether PHOTOFRIN is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PHOTOFRIN, a decision should be made whether not to treat or to discontinue breastfeeding, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS Other photosensitizing agents: May increase the risk of photosensitivity reaction (7.1) Concomitant therapy: May decrease the efficacy of PDT (7.2) 7.1 Other Photosensitizing Agents There have been no formal interaction studies of PHOTOFRIN and any other drugs.

However, it is possible that concomitant use of other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, and fluoroquinolones) could increase the risk of photosensitivity reaction.

7.2 Concomitant Therapy Photodynamic therapy (PDT) with PHOTOFRIN causes direct intracellular damage by initiating radical chain reactions that damage intracellular membranes and mitochondria.

Tissue damage also results from ischemia secondary to vasoconstriction, platelet activation and aggregation and clotting.

Research in animals and in cell culture has suggested that many drugs could influence the effects of PDT, possible examples of which are described below.

There are no human data that support or rebut these possibilities.

Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide,?-carotene, ethanol, formate and mannitol would be expected to decrease PDT activity.

Preclinical data also suggest that tissue ischemia, allopurinol, calcium channel blockers and some prostaglandin synthesis inhibitors could interfere with PHOTOFRIN PDT. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could decrease the efficacy of PDT. Glucocorticoid hormones given before or concomitant with PDT may decrease the efficacy of the treatment.

More information

Category Value
Authorisation number NDA020451
Orphan designation No
Product NDC 76128-155
Date Last Revised 31-03-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 242166
Marketing authorisation holder Pinnacle Biologics, Inc.