Nanomedicinal products: a survey on specific toxicity and side effects

Figures & data

Table 1 Products resulting from the inventory of registered NMPs within the EU, ordered by the type of nanostructure or drug

Structure type	Type of drug	Number of products	Product brand namesa
Cytostatics
Liposomes		6	Caelyx, DepoCyt, DaunoXome,b Eloxatin,b Mepact, Myocet
Micelle		1	Taxotere
Protein		1	Alimta
Others		1	Abraxane
Formulations with nanocarriers
Liposomes	Antifungal agent	2	Abelcet,b AmBisome
	Ophthalmological	1	Visudyne
Polymer conjugates	Recombinant protein conjugated to PEG	3	Mircera, Pegasys, Pegintron
	Recombinant protein	2	Neulasta, Somavert
	Phosphate-binding agent	1	Renagel
	Oligonucleotide	1	Macugen
Polymeric NP	Antipsychotic	1	Risperdal consta
Formulations with nAPIs
Iron NPs	Imaging agent	2	Lumirem,b,c Endoremb,c
	Antianemic	2	Rienso, Venofer
Nanodispersions	Antiemetic	1	Emend
	Immunosuppressant	1	Rapamune
	Antipsychotic	1	Invega
Emulsion	Immunosuppressant	1	Neoral
Protein	Antifungal agent	1	Cancidas
Monoclonal antibody/recombinant enzyme and proteins
	Monoclonal antibody	13	Adcetris, Arzerra, Avastin, Erbitux, Vectibix, Herceptin, Lemtrada, Mabthera, Orencia, Remicade, Xolair, Yervoy, Zevalin
	Recombinant enzyme, protein, human protein	4	Aldurazyme, Avonex, Fasturtec, Nanocollb
Vaccines
	Emulsion	1	Pandemrix
	Polymeric NP	1	Focetria
	Others	2	Cervarix, Gardasil
Gene therapy
		1	Glyberab

Notes: During grouping, cytostatics, monoclonal antibodies/recombinant enzymes and proteins, vaccines, and gene therapy have been allocated to separate categories because of their specific registration requirements with respect to toxicology.

a The product brand names are registered trademarks.

b No data publically available for the product.

c Withdrawn from market.

Abbreviations: nAPI, nanosized active pharmaceutical ingredient; NMPs, nanomedicinal products; NP, nanoparticle; PEG, polyethylene glycol.

Table 2 Number of NMPs per structure type or group with positive (+), negative (−), or unknown (?) effects for a specific toxicological end point, based on publically available, preclinical information

Structure type	N	Acute toxicity			Subacute toxicity (repeated dose)			Genotoxicity			Carcinogenicity			Reproductive toxicity			Developmental toxicity			Immunotoxicity
		+	−	?a	+	−	?a	+	−	?a	+	−	?a	+	−	?a	+	−	?a	+	−	?a
Cytostatics	9	6	0	3	6	0	3	3	1	5	0	0	9	3	0	6	5	0	4	1	0	8
Liposomes	6	3	0	3	4	0	2	1	1	4	0	0	6	0	0	6	2	0	4	0	0	6
Micelle	1	1	0	0	0	0	1	1	0	0	0	0	1	1	0	0	1	0	0	0	0	1
Protein	1	1	0	0	1	0	0	1	0	0	0	0	1	1	0	0	1	0	0	0	0	1
Others	1	1	0	0	1	0	0	0	0	1	0	0	1	1	0	0	1	0	0	1	0	0
Formulations with nanocarriers	11	9	0	2	10	0	1	1	5	5	1	0	10	2	6	3	1	6	4	1	0	10
Liposomes	3	2	0	1	2	0	1	1	0	2	0	0	3	0	2	1	0	2	1	0	0	3
Polymer conjugates	7	7	0	0	7	0	0	0	5	2	0	0	7	1	4	2	1	3	3	1	0	6
Polymeric NP	1	0	0	1	1	0	0	0	0	1	1	0	0	1	0	0	0	1	0	0	0	1
Formulations with nAPIs	9	6	0	3	6	0	3	0	7	2	4	0	5	2	4	3	2	5	2	1	0	8
Iron NPs	4	2	0	2	2	0	2	0	2	2	0	0	4	1	1	2	1	1	2	1	0	3
Nanodispersions	3	3	0	0	3	0	0	0	3	0	3	0	0	1	2	0	1	2	0	0	0	3
Emulsion	1	0	0	1	0	0	1	0	1	0	1	0	0	0	0	1	0	1	0	0	0	1
Protein	1	1	0	0	1	0	0	0	1	0	0	0	1	0	1	0	0	1	0	0	0	1
Total	29	21	0	8	22	0	7	4	13	12	5	0	24	7	10	12	8	11	10	3	0	26

Note:

a Unknown (no data available, not reported [no information available], not performed, or not tested with the specific nanoformulation). Data per product are given in the Supplementary materials.

Abbreviations: nAPI, nanosized active pharmaceutical ingredient; NMPs, nanomedicinal products; NP, nanoparticle.

Table 3 Overview of the sets of drugs investigated for the comparison of the side effects

Active substance	Brand name (conventional drug)	Nanoformulation of active substance	Brand name (nanosized drug)	Application
Paclitaxel	Taxol^®	Nab-paclitaxel	Abraxane^®	Cancer treatment, chemotherapy
Amphotericin B	Fungizone^®	Liposomal amphotericin B	AmBisome^®	Infectious diseases, antifungal drug
Doxorubicin	Doxorubicin	Pegylated liposomal doxorubicin	Caelyx^®	Cancer treatment, chemotherapy
Daunorubicin	Cerubidine^®	Liposomal daunorubicin	DaunoXome^®	Cancer treatment, chemotherapy
Cytarabine	Cytarabine	Liposomal cytarabine	DepoCyt^®	Cancer treatment, chemotherapy

Table 4 Differences in type or frequency of the side effects of nab-paclitaxel as reported for the brand name Abraxane^® versus paclitaxel as reported for the brand name Taxol^®a

SOC	Abraxane^® (nab-paclitaxel)	Taxol^® (paclitaxel)
Infections and infestations
Very common		Infection mainly in the urinary tract and upper respiration tract
Common	Folliculitis candidiasis, sinusitis, infection, urinary tract infection
Uncommon	Oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, catheter-related infection, fungal infection, herpes zoster, injection site infection, neutropenic sepsis, pneumonia, sepsis	Septic shock
Rare		Peritonitis, pneumonia,b sepsisb
Neoplasms: benign, malignant, and unspecified (including cysts and polyps)
Uncommon	Metastatic pain, tumor necrosis
Blood and lymphatic system disorders
Very common	Lymphopenia	Bleeding
Common	Febrile neutropenia
Rare	Pancytopenia	Febrile neutropeniab
Very rare		Acute myeloid leukemia,b myelodysplastic syndrome
Immune system disorders
Rare		Anaphylactic reactionsb
Very rare		Anaphylactic shockb
Metabolism and nutrition disorders
Very common	Anorexia
Common	Dehydration, decreased appetite, hypokalemia
Uncommon	Hypophosphatemia, fluid retention, hypoalbuminemia, polydipsia, hyperglycemia, hypocalcemia, hypoglycemia, hyponatremia
Very rare		Anorexiab
Unknownc		Tumor lysis syndromeb
Psychiatric disorders
Common	Insomnia, depression, anxiety
Uncommon	Restlessness
Very rare		Confusional stateb
Nervous system disorders
Very common	Neuropathy, hypoesthesia, paresthesia
Common	Peripheral sensory neuropathy, dysgeusia, sensory disturbance, somnolence, headache, dizziness, peripheral motor neuropathy, ataxia
Uncommon	Polyneuropathy, areflexia, dyskinesia, hyporeflexia, neuralgia, sensory loss, syncope, postural dizziness, neuropathic pain, tremor
Rare		Motor neuropathy
Very rare		Grand mal seizures,b autonomic neuropathy, encephalopathy,b convulsions,b headache,b dizziness,b ataxiab
Eye disorders
Common	Increased lacrimation, blurred vision, dry eye, keratoconjunctivitis sicca, madarosis
Uncommon	Eye irritation, eye pain, abnormal vision, reduced visual acuity, conjunctivitis eye pruritus, keratitis, visual disturbance
Rare	Cystoid macular edema
Very rare		Optic nerve disturbances, visual disturbanceb
Unknownc		Macular edema, photopsia, vitreous floaters
Ear and labyrinth disorders
Common	Vertigo
Uncommon	Ear pain, tinnitus
Very rare		Hearing loss,b ototoxicity,b vertigo,b tinnitus
Cardiac disorders
Common	Tachycardia, arrhythmia, supraventricular tachycardia	Brachycardia
Uncommon		Myocardial infarction, syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrioventricular block
Rare	Cardiac arrest, left ventricular dysfunction, congestive heart failure, brachycardia, atrioventricular block	Cardiac failure
Very rare		Atrial fibrillation,b supraventricular tachycardiab
Vascular disorders
Very common		Hypotension
Common	Flushing, hot flushes, lymphedema, hypertension
Uncommon	Peripheral coldness, orthostatic hypotension, hypotension	Thrombophlebitis, thrombosis, hypertension
Very rare	Thrombosis	Shockb
Unknownc		Phlebitisb
Respiratory, thoracic and mediastinal disorders
Common	Epistaxis, pharyngolaryngeal pain, rhinitis, rhinorrhea, dyspnea, cough
Uncommon	Productive cough, exertional dyspnea, sinus congestion, decreased breath sounds, allergic rhinitis, hoarseness, nasal congestion, nasal dryness, wheezing, pulmonary thromboembolism, pleural effusion, pulmonary emboli, interstitial pneumonitis
Rare		Respiration failure,b lung fibrosis,b pulmonary emboli,b interstitial pneumonitis,b dyspneab
Very rare		Coughb
Gastrointestinal disorders
Very common	Stomatitis, constipation	Mucosal inflammation
Common	Abdominal pain, abdominal distension, upper abdominal pain, dyspepsia, gastroesophageal reflux disease, oral hypoesthesia
Uncommon	Dysphagia, flatulence, glossodynia, dry mouth, gingival pain, loose stools, lower abdominal pain, mouth ulceration, oral pain, rectal hemorrhage, esophagitis
Rare		Bowel obstruction,b bowel perforation,b ischemic colitis,b pancreatitisb
Very rare		Mesenteric thrombosis,b pseudomembranous colitis,b neutropenic colitis,b ascites,b constipation,b esophagitisb
Hepatobiliary disorders
Uncommon	Hepatomegaly
Very rare		Hepatic necrosis,b hepatic encephalopathyb
Skin and subcutaneous tissue disorders
Very common	Rash
Common	Nail disorder, pruritus, dry skin, nail pigmentation/discoloration, skin hyperpigmentation, erythema, onycholysis
Uncommon	Nail bed tenderness, skin pain, photosensitivity reaction, pigmentation disorder, pruritic rash, skin disorder, hyperhidrosis, onychomadesis, erythematous rash, generalized rash, dermatitis, night sweats, maculopapular rash, vitiligo, hypotrichosis, nail discomfort, generalized pruritus, macular rash, papular rash, skin lesion, swollen face, urticaria
Rare		Pruritus,b rash, erythemab
Very rare		Erythema multiforme,b exfoliative dermatitis,b urticarial,b onycholysisb
Unknownc		Sclerodermab
Musculoskeletal and connective tissue disorders
Common	Muscle cramps, limb pain
Uncommon	Chest wall pain, muscular weakness, neck pain, groin pain, muscle spasms, musculoskeletal pain, flank pain, limb discomfort, muscle weakness
Unknownc		Systemic lupus erythematosusb
Renal and urinary disorders
Uncommon	Dysuria, pollakiuria, hematuria, nocturia, polyuria, urinary incontinence
Reproductive system and breast disorders
Uncommon	Breast pain
Investigations
Common	Decreased weight, increased alanine aminotransferase, decreased hematocrit, decreased red blood cell count, increased body temperature, increased gamma-glutamyltransferase
Uncommon	Increased blood pressure, increased weight, increased blood lactate dehydrogenase, increased blood glucose, increased blood phosphorus, decreased blood potassium, increased blood creatinine
Rare		Increased blood creatinineb
Injury, poisoning, and procedural complications
Uncommon	Contusion
Rare	Radiation recall phenomenon, radiation pneumonitis
General disorders and administration site conditions
Common		Injection site reactions (including localized edema, pain, erythema, induration, on occasion extravasation resulting in cellulitis, skin fibrosis and skin necrosis)
Rare		Pyrexia,b dehydration,b asthenia,b edema,b malaise

Notes:

a Side effects that are described with the same frequency for both drugs are not included in the table. The same side effects for both drugs, but with a different frequency, are shown in bold.

b Side effects reported in postmarket surveillance.

c Unknown: frequency cannot be estimated from available data.

Abbreviation: SOC, system organ class.

Table 5 Differences in type or frequency of the side effects of liposomal amphotericin B as reported for the brand name AmBisome^® versus amphotericin B as reported for the brand name Fungizone^®a

SOC	AmBisome^® (liposomal amphotericin B)	Fungizone^® (amphotericin B)
Blood and lymphatic system disorders
Common		Anemia
Uncommon	Thrombocytopenia
Unknownb	Anemia	Thrombocytopenia, agranulocytosis, coagulopathy, eosinophilia, leukocytosis, leukopenia
Immune system disorders
Uncommon	Anaphylactoid reaction
Unknownb	Hypersensitivity	Anaphylactoid reaction
Metabolism and nutrition disorders
Very common	Hypokalemia
Common	Hyponatremia, hypocalcemia, hyperglycemia
Unknownb		Anorexia
Nervous system disorders
Common	Headache
Uncommon	Convulsions
Unknownb		Headache, convulsions, encephalopathy, neurologic symptoms, neuropathy peripheral
Cardiac disorders
Common	Tachycardia
Unknownb		Ventricular fibrillation, cardiac failure
Ear and labyrinth disorder
Unknown		Deafness, tinnitus, vertigo
Eye disorders
Unknown		Blurred vision, diplopia
Respiratory, thoracic, and mediastinal disorders
Very common		Dyspnea
Common	Dyspnea
Uncommon	Bronchospasm
Unknownb		Bronchospasm, alveolitis allergic, non-cardiogenic pulmonary edema
Gastrointestinal disorders
Common	Diarrhea, abdominal pain
Unknownb		Diarrhea, abdominal pain, dyspepsia, hemorrhagic gastroenteritis, melena
Hepatobiliary disorders
Common	Hyperbilirubinemia, alkaline phosphatase increased, abnormal liver function tests	Abnormal hepatic function
Unknownb		Liver function tests abnormal, acute liver failure, jaundice
Skin and subcutaneous tissue
Unknownb	Angioneurotic edema	Rash maculopapular, pruritus, skin exfoliation, toxic epidermal necrolysis, Stevens–Johnson syndrome
Vascular disorder
Very common		Hypotension
Common	Hypotension, vasodilatation, flushing
Unknownb		Hypertension, shock
Musculoskeletal and connective tissue disorders
Common	Back pain
Unknownb	Rhabdomyolysis	Myalgia
Renal and urinary disorders
Very common		Renal function test abnormalities: azotemia, hyposthenuria, renal tubular acidosis, nephrocalcinosis
Common	Increased creatinine, blood urea increased
Unknownb		Anuria, nephrogenic diabetes insipidus, oliguria, renal impairment
General disorders and administration site conditions
Common	Chest pain
Uncommon		Flushing
Unknownb		Pain, malaise, injection site pain with or without phlebitis or thrombophlebitis
Investigations
Very common		Hypokalemia, increased blood creatinine
Unknownb		Hyperkalemia, weight decreased

Notes:

a Side effects that are described with the same frequency for both drugs are not included in the table. The same side effects for both drugs, but with a different frequency, are shown in bold.

b Unknown: frequency cannot be estimated from the available data.

Abbreviation: SOC, system organ class.

Table 6 Differences in type or frequency of the side effects of pegylated liposomal doxorubicin as reported for the brand name Caelyx^® versus doxorubicina

SOC	Caelyx (pegylated liposomal doxorubicin)	Doxorubicin
Infections and infestations
Common	Pharyngitis, folliculitis, fungal infection, cold sores, upper respiratory tract infection, infection, oral moniliasis, herpes zoster, urinary tract infection	Sepsis, septicemia
Neoplasms: benign, malignant
Uncommon		Acute lymphocytic leukemia, acute myelogenous leukemia
Rare		Secondary leukemia, tumor lysis syndrome
Blood and lymphatic system disorders
Very common		Myelosuppression, anemia
Common	Anemia, hypochromic anemia
Immune system disorders
Common	Allergic reaction
Rare		Anaphylactic reactions
Metabolism and nutrition disorders
Very common	Anorexia
Common	Dehydration, cachexia
Nervous system disorders
Common	Paresthesia, peripheral neuropathy, somnolence, headache, dizziness, neuropathy, hypertonia
Endocrine disorders
Very rare		Hot flashes
Eye disorders
Common	Lacrimation, blurred vision, conjunctivitis
Rare		Conjunctivitis
Unknownb		Increased lachrymation
Cardiac disorders
Very common		Cardiotoxicity
Common	Ventricular arrhythmia, cardiovascular disorder	Life-threatening congestive cardiomyopathy, sinus tachycardia, ventricular tachycardia, tachyarrhythmia, supraventricular and ventricular extrasystoles, bradycardia, arrhythmia, asymptomatic reduction in the left ventricular ejection fraction
Very rare		Unspecific ECG changes, isolated cases of life-threatening arrhythmias, acute left ventricular failure, pericarditis–myocarditis syndrome, atria ventricular block, bundle branch block
Vascular disorders
Common	Vasodilatation	Hemorrhage
Uncommon		Phlebitis
Very rare		Thromboembolism
Gastrointestinal disorders
Very common	Constipation, nausea, stomatitis, vomiting	Gastrointestinal disturbance, mucositis
Common	Abdominal pain, dyspepsia, mouth ulceration, esophagitis, gastritis, dysphagia, dry mouth, flatulence, gingivitis, taste perversion	Anorexia
Uncommon		Gastrointestinal hemorrhage, pharynx and gastrointestinal tract ulceration, ulceration and necrosis colon (in particular cecum), mouth ulceration
Very rare		Hyperpigmentation of oral mucous membrane
Respiratory, thoracic, and mediastinal disorders
Common	Dyspnea, increased cough
Unknownb		Bronchospasm, radiation pneumonitis
Skin and subcutaneous tissue disorders
Very common	Palmar-plantar erythrodysesthesia, alopecia, rash	Reddening, photosensitization
Common	Dry skin, skin discoloration, pigmentation abnormal, erythema bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, maculopapular rash, sweating, acne, skin ulcer	Local hypersensitivity reactions in the field of radiation
Rare		Urticaria, exanthema, hyperpigmentation of skin and nails, onycholysis, extravasation
Very rare		Acral erythema, blistering, palmar-plantar erythrodysesthesia
Unknownb		Actinic keratosis
Musculoskeletal and connective tissue disorders
Common	Back pain, myalgia	Arthralgia
Renal and urinary disorders
Very common		Red coloration to the urine
Very rare		Acute renal failure, hyperuricemia and subsequent uric acid nephropathy as a consequence of massive tumor lysis
Reproductive system and breast disorders
Common	Vaginitis, breast pain
Very rare		Amenorrhea, oligospermia, azoospermia
General disorders and administration site conditions
Very common	Asthenia, fatigue, mucositis, mucous membrane disorder	Fever
Common	Pain, weakness, fever, chills, chest pain, malaise, edema, peripheral edema, leg edema
Uncommon		Dehydration
Rare		Shivering, dizziness, injection site reactions
Unknownb		Malaise/weakness
Hepatobiliary disorders
Unknownb		Hepatotoxicity, transient increase in liver enzymes
Surgical and medical procedure
Unknownb		Radiation damage that is already healing may reappear following doxorubicin administration
Investigations
Common	Weight loss

Notes:

a Side effects that are described with the same frequency for both drugs are not included in the table. The same side effects for both drugs, but with a different frequency, are shown in bold.

b Unknown: frequency cannot be estimated from the available data.

Abbreviations: ECG, electrocardiogram; SOC, system organ class.

Table 7 Differences in type or frequency of the side effects of liposomal daunorubicin as reported for the brand name DaunoXome^® versus daunorubicin as reported for the brand name Cerubidinea

SOC	DaunoXome (liposomal daunorubicin)	Cerubidine (daunorubicin)
Infections and infestations
Very common		Sepsis/septicemia
Uncommon	Sepsis, septic shock
Unknownb		Septic shock
Neoplasms: benign, malignant, and unspecified (including cysts and polyps)
Uncommon		Acute myeloid leukemia
Unknownb		Myelodysplastic syndrome
Blood and lymphatic system disorders
Very common	Bone marrow suppression, agranulocytosis, febrile neutropenia, pancytopenia	Bone marrow failure, granulocytopenia
Immune system disorders
Very common	Infusion-associated reactions (including back pain, flushing, chest tightness, dyspnea, allergic reactions)
Rare	Anaphylactic reaction
Unknownb		Anaphylactic reaction/anaphylactoid reaction
Metabolism and nutrition disorders
Common	Dehydration
Unknownb		Dehydration, acute hyperuricemia
Psychiatric disorders
Common	Depression
Nervous system disorders
Very common	Headache
Common	Dizziness
Cardiac disorders
Very common		Cardiomyopathy (clinically manifested by dyspnea, cyanosis, dependent edema, hepatomegaly, ascites, pleural effusion, and congestive cardiac failure)
Common	Decreased left ventricular ejection fraction
Uncommon	Congestive heart failure, cardiomyopathy	Myocardial infarction
Rare	Atrial fibrillation, myocardial infarction
Unknownb		Myocardial ischemia (angina pectoris), endomyocardial fibrosis, pericarditis/myocarditis, supraventricular tachyarrhythmias (such as sinus tachycardia, ventricular extrasystoles, and atrioventricular block)
Vascular disorders
Unknownb	Shock	Flushing, shock, thrombophlebitis, phlebosclerosis
Respiratory, thoracic, and mediastinal disorders
Very common	Dyspnea
Unknownb		Hypoxia
Gastrointestinal disorders
Very common	Abdominal pain
Common		Abdominal pain
Unknownb		Colitis
Hepatobiliary disorders
Unknownb	Transient elevations in serum bilirubin, AST and ALP concentrations, hepatitis, hepatic failure
Skin and subcutaneous tissue disorders
Very common		Erythema, rash
Rare	Palmar-plantar erythrodysesthesia syndrome
Unknownb		Dermatitis contact, recall phenomenon, pruritus, skin hyperpigmentation and nail pigmentation, urticaria
Investigations
Very common		Blood bilirubin increased, AST increased, blood ALP increased
Common		Electrocardiogram abnormal (electrocardiogram ST-T change, electrocardiogram QRS complex abnormal, electrocardiogram T wave abnormal)
General disorders and administration site conditions
Very common	Asthenia, fatigue, fever, chills	Pyrexia, pain
Common	Extravasation at the injection site may result in erythema, pain, and swelling	Infusion site phlebitis
Unknownb		Death, hyperpyrexia, infusion site extravasation, chills

Notes:

a Side effects that are described with the same frequency for both drugs are not included in the table. The same side effects for both drugs, but with a different frequency, are shown in bold.

b Unknown: frequency cannot be estimated from available data.

Abbreviations: ALT, alkaline phosphatase; AST, aspartate aminotransferase; SOC, system organ class.

Table 8 Differences in type or frequency of the side effects of liposomal cytarabine as reported for the brand name DepoCyt^® versus Cytarabine^®a

SOC	DepoCyt (liposomal cytarabine)	Cytarabine
Nervous system disorders
Very common	Confusion
Common		Confusion
General disorders and administration site conditions
Very common		Fatigue
Common	Fatigue

Notes:

a Side effects that are described with the same frequency for both drugs are not included in the table. The same side effects for both drugs, but with a different frequency, are shown in bold.

Abbreviation: SOC, system organ class.