Photofrin Side Effects

Please note - some side effects for Photofrin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Photofrin - for the Consumer

Photofrin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Photofrin:

Anxiety; appetite loss; belching; confusion; constipation; diarrhea; fever; headache; hiccups; indigestion; nausea; oral infection; swelling of the hands and feet; trouble sleeping; vomiting; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Photofrin:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back pain; burns or blisters on the skin; changes in vision; chest pain; chills; coughing; dark, bloody stools; dehydration; depression; difficulty swallowing; fast heartbeat; irregular heartbeat; lightheadedness; pain, redness, or swelling at the injection site; pneumonia; shortness of breath; slow or difficult breathing; throat, stomach, or abdominal pain; tightness in the chest; weakness; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Photofrin Side Effects - for the Professional

Photofrin

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.

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 cannot 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 Patients* with Obstructing Esophageal Cancer

* Based on adverse reactions reported at any time during the entire period of follow-up.
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

* Follow-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.
	Number (%) of Patients
SYSTEM ORGAN CLASS/	Within 30 Days of Treatment					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 Patients* with Superficial Endobronchial Tumors

* Based on adverse reactions reported at any time during the entire period of follow-up.
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

* Includes all HGD patients in the Safety population from PHO BAR 02 (N=133), TCSC 93-07 (N=44), and TCSC 96-01 (N=42). † Includes all HGD patients in the Safety population from PHO BAR 02 (N=69). ‡ Includes 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). § Esophageal stricture was defined as a dilated esophageal stenosis. ¶ Esophageal narrowing was defined as an undilated esophageal stenosis.
		Treatment Groups
SYSTEM ORGAN CLASS/ Adverse Reaction		HGD* PHOPDT +OM	HGD†OM Only	Other‡ 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 Stricture§		81 (37)	0	33 (33)	114 (36)
Esophageal Narrowing¶		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.

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Side Effects by Body System - for Healthcare Professionals

General

General side effects have included fever (31%), pain (up to 22%), chest pain (up to 22%), back pain (up to 11%), weight decrease (9%), peripheral edema (up to 7%), dehydration (7%), asthenia (6%), generalized edema (5%), and surgical complication (5%). Patients with at least one adverse event have been as high as 95%.

Respiratory

Respiratory side effects including pleural effusion (32%), dyspnea (up to 30%), pneumonia (up to 18%), hemoptysis (16%), coughing (up to 15%), pharyngitis (11%), bronchitis (10%), respiratory insufficiency (up to 10%), increased sputum (8%), and tracheoesophageal fistula (6%) have been reported.

Cardiovascular

Cardiovascular side effects have included edema (18%), atrial fibrillation (10%), cardiac failure (7%), hypotension (7%), tachycardia (6%), and hypertension (6%).

Nervous system

Nervous system side effects have included dysphonia (5%).

Gastrointestinal

Gastrointestinal side effects have included constipation (up to 24%), nausea (24%), abdominal pain (20%), vomiting (17%), dysphagia (10%), esophageal edema (8%), esophageal tumor bleeding (8%), hematemesis (8%), dyspepsia (6%), esophageal stricture (6%), diarrhea (5%), eructation (5%), esophagitis (5%), and melena (5%).

Psychiatric

Psychiatric side effects have included insomnia (up to 14%), anorexia (8%), confusion (8%), and anxiety (up to 7%).

Hematologic

Hematologic side effects have included anemia (32%).

Immunologic

Immunologic side effects have included moniliasis (9%).

Dermatologic

Dermatologic side effects have included photosensitivity reaction (up to 22%).

Genitourinary

Genitourinary side effects have included urinary tract infection (7%).

Local

Local side effects have included exudate (22%), obstruction (19%), stricture (11%), and ulceration (9%).

Ocular

Ocular side effects have included ocular discomfort (commonly described as sensitivity to sun, bright lights, or car headlights).

A case of cataracts has been reported in a fifty-one year old obese man treated with porfimer. The patient suffered from a photodynamic therapy (PDT) response. 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 the parents of the patient with cataracts in both eyes had a history of cataracts in their seventies. Whether porfimer directly caused or accelerated a familial underlying condition is unknown.

Other

Other side effects including a few cases of fluid imbalance have been reported following the use of photodynamic therapy (PDT) with porfimer in patients with overtly disseminated intraperitoneal malignancies.

Fluid imbalance is an expected PDT treatment-related event.

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