Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Celgene Europe B.V., Winthontlaan 6 N, 3526 KV Utrecht, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Lactation (see section 4.6).
Patients who have baseline neutrophil counts <1500 cells/mm³.
Abraxane is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantially different pharmacological properties compared to other formulations of paclitaxel (see sections 5.1 and 5.2). It should not be substituted for or with other paclitaxel formulations.
Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactions with fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinal product should be discontinued immediately, symptomatic treatment should be initiated, and the patient should not be rechallenged with paclitaxel.
Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Abraxane therapy. Patients should not be retreated with subsequent cycles of Abraxane until neutrophils recover to >1500 cells/mm³ and platelets recover to >100,000 cells/mm³ (see section 4.2).
Sensory neuropathy occurs frequently with Abraxane, although development of severe symptoms is less common. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose reduction. When Abraxane is used as monotherapy, if Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 followed by a dose reduction for all subsequent courses of Abraxane is recommended (see section 4.2). For combination use of Abraxane and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine at the same dose. Resume Abraxane at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2). For combination use of Abraxane and carboplatin, if Grade 3 or higher peripheral neuropathy develops, treatment should be withheld until improvement to Grade 0 or 1 followed by a dose reduction for all subsequent courses of Abraxane and carboplatin (see section 4.2).
Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm³ , then resume treatment at reduced dose levels (see section 4.2).
Pneumonitis occurred in 1% of patients when Abraxane was used as monotherapy and in 4% of patients when Abraxane was used in combination with gemcitabine. Closely monitor all patients for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).
Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Abraxane in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.
Abraxane is not recommended in patients that have total bilirubin >5 x ULN or AST >10 x ULN. In addition, Abraxane is not recommended in patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN) (see section 5.2).
Rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving Abraxane. Most of the individuals were previously exposed to cardiotoxic medicinal products such as anthracyclines, or had underlying cardiac history. Thus patients receiving Abraxane should be vigilantly monitored by physicians for the occurrence of cardiac events.
The effectiveness and safety of Abraxane in patients with central nervous system (CNS) metastases has not been established. CNS metastases are generally not well controlled by systemic chemotherapy.
If patients experience nausea, vomiting and diarrhoea following the administration of Abraxane, they may be treated with commonly used anti-emetics and constipating agents.
For patients of 75 years and older, no benefit for the combination treatment of Abraxane and gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (≥75 years) who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy, decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed for their ability to tolerate Abraxane in combination with gemcitabine with special consideration to performance status, co-morbidities and increased risk of infections (see section 4.2 and 4.8).
Although limited data is available, no clear benefit in terms of prolonged overall survival has been demonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start of treatment with Abraxane and gemcitabine (see section 5.1).
Erlotinib should not be coadministered with Abraxane plus gemcitabine (see section 4.5).
When reconstituted, each ml of Abraxane concentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.
The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, in the absence of a PK drug-drug interaction study, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.
Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance is primarily determined by CYP2C8 and CYP3A4 mediated metabolism followed by biliary excretion, while gemcitabine is inactivated by cytidine deaminase followed by urinary excretion. Pharmacokinetic interactions between Abraxane and gemcitabine have not been evaluated in humans.
A pharmacokinetic study was conducted with Abraxane and carboplatin in non-small cell lung cancer patients. There were no clinically relevant pharmacokinetic interactions between Abraxane and carboplatin.
Abraxane is indicated as monotherapy for breast cancer, in combination with gemcitabine for pancreatic adenocarcinoma, or in combination with carboplatin for non-small cell lung cancer (see section 4.1). Abraxane should not be used in combination with other anticancer agents.
Women of childbearing potential should use effective contraception during treatment and up to 1 month after receiving treatment with Abraxane. Male patients treated with Abraxane are advised to use effective contraception and to avoid fathering a child during and up to six months after treatment.
There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected to cause serious birth defects when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Women of childbearing potential should have a pregnancy test prior to starting treatment with Abraxane. Abraxane should not be used in pregnancy, and in women of childbearing potential not using effective contraception, unless the clinical condition of the mother requires treatment with paclitaxel.
Paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see section 5.3). It is not known if paclitaxel is excreted in human milk. Because of potential serious adverse reactions in breast-feeding infants, Abraxane is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy.
Abraxane induced infertility in male rats (see section 5.3). Based on findings in animals, male and female fertility may be compromised. Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Abraxane.
Abraxane has minor or moderate influence on the ability to drive and use machines. Abraxane may cause adverse reactions such as tiredness (very common) and dizziness (common) that may affect the ability to drive and use machinery. Patients should be advised not to drive and use machines if they feel tired or dizzy.
The most common clinically significant adverse reactions associated with the use of Abraxane have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.
The frequencies of adverse reactions associated with the administration of Abraxane are listed in Table 6 (Abraxane as monotherapy) and Table 7 (Abraxane in combination with gemcitabine), and Table 9 (Abraxane in combination with carboplatin).
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Tabulated list of adverse reactions:
Table 6 lists adverse reactions associated with the administration of Abraxane to patients from studies in which Abraxane has been administered as monotherapy at any dose in any indication (N=789).
Table 6. Adverse reactions reported with Abraxane monotherapy at any dose in clinical studies:
Common: Infection, urinary tract infection, folliculitis, upper respiratory tract infection, candidiasis, sinusitis
Uncommon: Oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, pneumonia, catheter-related infection, fungal infection, herpes zoster, injection site infection, sepsis2, neutropenic sepsis2
Uncommon: Metastatic pain, tumour necrosis
Very common: Neutropenia, anaemia, leukopenia, thrombocytopenia, lymphopenia, bone marrow suppression
Common: Febrile neutropenia
Rare: Pancytopenia
Uncommon1: Hypersensitivity
Rare: Severe hypersensitivity
Very common: Anorexia
Common: Dehydration, decreased appetite, hypokalaemia
Uncommon: Hypophosphataemia, fluid retention, hypoalbuminaemia, polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia, hyponatraemia
Common: Insomnia, depression, anxiety
Uncommon: Restlessness
Very common: Peripheral neuropathy, neuropathy, hypoaesthesia, paraesthesia
Common: Peripheral sensory neuropathy, headache, dysgeusia, dizziness, peripheral motor neuropathy, ataxia, sensory disturbance, somnolence
Uncommon: Polyneuropathy, areflexia, dyskinesia, hyporeflexia, neuralgia, sensory loss, syncope, postural dizziness, neuropathic pain, tremor
Common: Increased lacrimation, blurred vision, dry eye, keratoconjunctivitis sicca, madarosis
Uncommon: Eye irritation, eye pain, abnormal vision, reduced visual acuity, conjunctivitis, visual disturbance, eye pruritus, keratitis
Rare: Cystoid macular oedema2
Common: Vertigo
Uncommon: Ear pain, tinnitus
Common: Tachycardia, arrhythmia, supraventricular tachycardia
Rare: bradycardia, cardiac arrest, left ventricular dysfunction, congestive heart failure, atrioventricular block2
Common: Flushing, hot flushes, hypertension, lymphoedema
Uncommon: Hypotension, peripheral coldness, orthostatic hypotension
Rare: Thrombosis
Common: Interstitial pneumonitis3, dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhoea
Uncommon: Productive cough, exertional dyspnoea, sinus congestion, decreased breath sounds, pleural effusion, allergic rhinitis, hoarseness, nasal congestion, nasal dryness, wheezing, pulmonary emboli, pulmonary thromboembolism
Very common: Nausea, diarrhoea, vomiting, constipation, stomatitis
Common: Abdominal pain, abdominal distension, upper abdominal pain, dyspepsia, gastrooesophageal reflux disease, oral hypoaesthesia
Uncommon: Dysphagia, flatulence, glossodynia, dry mouth, gingival pain, loose stools, oesophagitis, lower abdominal pain, mouth ulceration, oral pain, rectal haemorrhage
Uncommon: Hepatomegaly
Very common: Alopecia, rash
Common: Nail disorder, pruritus, dry skin, erythema, nail pigmentation/discolouration, skin hyperpigmentation, onycholysis, nail changes
Uncommon: Nail bed tenderness, urticaria, skin pain, photosensitivity reaction, pigmentation disorder, pruritic rash, skin disorder, hyperhidrosis, onychomadesis, erythematous rash, generalised rash, dermatitis, night sweats, maculo-papular rash, vitiligo, hypotrichosis, nail discomfort, generalized pruritus, macular rash, papular rash, skin lesion, swollen face
Very rare: Stevens-Johnson syndrome2, toxic epidermal necrolysis2
Very common: Arthralgia, myalgia.
Common: Pain in extremity, bone pain, back pain, muscle cramps, limb pain
Uncommon: Chest wall pain, muscular weakness, neck pain, groin pain, muscle spasms, musculoskeletal pain, flank pain, limb discomfort, muscle weakness
Uncommon: Dysuria, pollakiuria, haematuria, nocturia, polyuria, urinary incontinence
Uncommon: Breast pain
Very common: Fatigue, asthenia, pyrexia
Common: Peripheral oedema, mucosal inflammation, pain, rigors, oedema, weakness, decreased performance status, chest pain, influenza-like illness, malaise, lethargy, hyperpyrexia
Uncommon: Chest discomfort, abnormal gait, swelling, injection site reaction
Rare: Extravasation
Common: Decreased weight, increased alanine aminotransferase, increased aspartate aminotransferase, decreased haematocrit, decreased red blood cell count, increased body temperature, increased gamma-glutamyltransferase, increased blood alkaline phosphatase
Uncommon: Increased blood pressure, increased weight, increased blood lactate dehydrogenase, increased blood creatinine, increased blood glucose, increased blood phosphorus, decreased blood potassium, increased bilirubin
Uncommon: Contusion
Rare: Radiation recall phenomenon, radiation pneumonitis
MedDRA = Medical Dictionary for Regulatory Activities. SMQ = Standardized MedDRA Query; SMQ is a grouping of several MedDRA preferred terms to capture a medical concept.
1 The frequency of hypersensitivity reactions is calculated based on one definitely related case in a population of 789 patients.
2 As reported in the post-marketing surveillance of Abraxane.
3 The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Abraxane monotherapy for breast cancer and for other indications using MedDRA SMQ Interstitial lung disease. See section 4.4.
The following are the most common and clinically relevant adverse reactions related to 229 patients with metastatic breast cancer who were treated with 260 mg/m² Abraxane once every three weeks in the pivotal phase III clinical study.
Neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (<500 cells/mm³) occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb <10 g/dl) was observed in 46% of patients on Abraxane, and was severe (Hb <8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.
In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving Abraxane. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on Abraxane with 10% being Grade 3, and no cases of Grade 4.
Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients.
Alopecia was observed in >80% of the patients treated with Abraxane. The majority of alopecia events occurred less than one month after initiation of Abraxane. Pronounced hair loss ≥50% is expected for the majority of patients who experience alopecia.
Arthralgia occurred in 32% of patients on Abraxane and was severe in 6% of cases. Myalgia occurred in 24% of patients on Abraxane and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after Abraxane administration and resolved within a week.
Asthenia/Fatigue was reported in 40% of the patients.
Adverse reactions were assessed in 421 patients treated with Abraxane in combination with gemcitabine and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas in a phase III randomized, controlled, open-label trial. Table 7 lists adverse reactions assessed in patients with pancreatic adenocarcinoma treated with Abraxane in combination with gemcitabine.
Table 7. Adverse reactions reported with Abraxane in combination with gemcitabine (N=421):
Common: Sepsis, pneumonia, oral candidiasis
Very common: Neutropenia, anaemia, thrombocytopenia
Common: Pancytopenia
Uncommon: Thrombotic thrombocytopenic purpura
Very common: Dehydration, decreased appetite, hypokalaemia
Very common: Insomnia, depression
Common: Anxiety
Very common: Peripheral neuropathy1, dysgeusia, headache, dizziness
Uncommon: VIIth nerve paralysis
Common: Lacrimation increased
Uncommon: Cystoid macular oedema
Common: Cardiac failure congestive, tachycardia
Common: Hypotension, hypertension
Very common: Dyspnoea, epistaxis, cough
Common: Pneumonitis2, nasal congestion
Uncommon: Dry throat, nasal dryness
Very common: Nausea, diarrhoea, vomiting, constipation, abdominal pain, abdominal pain upper
Common: Stomatitis, intestinal obstruction, colitis, dry mouth
Common: Cholangitis
Very common: Alopecia, rash
Common: Pruritus, dry skin, nail disorder, flushing
Very common: Pain in extremity, arthralgia, myalgia
Common: Muscular weakness, bone pain
Common: Acute renal failure
Uncommon: Haemolytic uraemic syndrome
Very common: Fatigue, oedema peripheral, pyrexia, asthenia, chills
Common: Infusion site reaction
Very common: Weight decreased, alanine aminotransferase increased
Common: Aspartate aminotransferase increased, blood bilirubin increased, blood creatinine increased
MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept).
1 Peripheral neuropathy evaluated using the SMQ (broad scope).
2 Pneumonitis is evaluated using the SMQ interstitial lung disease (broad scope)
In this phase III randomized, controlled, open-label trial, adverse reactions resulting in death within 30 days of the last dose of study drug were reported for 4% of patients receiving Abraxane in combination with gemcitabine and for 4% of patients receiving gemcitabine monotherapy.
The following are the most common and important incidences of adverse reactions related to 421 patients with metastatic adenocarcinoma of the pancreas who were treated with 125 mg/m² Abraxane in combination with gemcitabine at a dose of 1000 mg/m² given on Days 1, 8 and 15 of each 28-day cycle in the phase III clinical study.
Table 8 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with Abraxane in combination with gemcitabine or with gemcitabine.
Table 8: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial
| Abraxane(125 mg/m2)/Gemcitabine | Gemcitabine | |||
|---|---|---|---|---|
| Grades 1-4(%) | Grade 3-4(%) | Grades 1-4(%) | Grade 3-4(%) | |
| Anaemiaa,b | 97 | 13 | 96 | 12 |
| Neutropeniaa,b | 73 | 38 | 58 | 27 |
| Thrombocytopeniab,c | 74 | 13 | 70 | 9 |
a 405 patients assessed in Abraxane/gemcitabine-treated group
b 388 patients assessed in gemcitabine-treated group
c 404 patients assessed in Abraxane/gemcitabine-treated group
For patients treated with Abraxane in combination with gemcitabine, the median time to first occurrence of Grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was 21 days, and the median time to improvement from Grade 3 peripheral neuropathy to Grade 0 or 1 was 29 days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were able to resume Abraxane at a reduced dose. No patients treated with Abraxane in combination with gemcitabine had Grade 4 peripheral neuropathy.
Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥1500 cells/mm³, then resume treatment at reduced dose levels (see section 4.2).
Pneumonitis has been reported at a rate of 4% with the use of Abraxane in combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with Abraxane in combination with gemcitabine, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).
Table 9 lists adverse reactions associated with the administration of Abraxane in combination with carboplatin.
Table 9: Adverse reactions reported with Abraxane in combination with carboplatin (N = 514)
Common: Pneumonia, bronchitis, upper respiratory tract infection, urinary tract infection
Uncommon: Sepsis, oral candidiasis
Very common: Neutropenia1 , thrombocytopenia1, anaemia1, leukopenia1
Common: Febrile neutropenia, lymphopenia
Uncommon: Pancytopenia
Uncommon: Drug hypersensitivity, hypersensitivity
Very common: Decreased appetite
Common: Dehydration
Common: Insomnia
Very common: Peripheral neuropathy2
Common: Dysgeusia, headache, dizziness
Common: Vision blurred
Common: Hypotension, hypertension
Uncommon: Flushing
__Very common: Dyspnoea
Common: Haemoptysis, epistaxis, cough
Uncommon: Pneumonitis3
Very common: Diarrhoea, vomiting, nausea, constipation
Common: Stomatitis, dyspepsia, abdominal pain, dysphagia
Common: Hyperbilirubinaemia
Very common: Rash, alopecia
Common: Pruritus, nail disorder
Uncommon: Skin exfoliation, dermatitis allergic, urticaria
Very common: Arthralgia, myalgia
Common: Back pain, pain in extremity, musculoskeletal pain
Very common: Fatigue, asthenia, oedema peripheral
Common: Pyrexia, chest pain
Uncommon: Mucosal inflammation, infusion site extravasation, infusion site inflammation, infusion site rash
Common: Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, weight decreased
MedDRA = Medical Dictionary for Regulatory Activities: SMQ = Standardized MedDRA Query
1 Based on laboratory assessments: maximal degree of myelosuppression (treated population)
2 Peripheral neuropathy is evaluated using the SMQ neuropathy (broad scope)
3 Pneumonitis is evaluated using the SMQ interstitial lung disease (broad scope)
For non-small cell lung cancer patients treated with Abraxane and carboplatin, the median time to first occurrence of Grade 3 treatment related peripheral neuropathy was 121 days, and the median time to improvement from Grade 3 treatment related peripheral neuropathy to Grade 1 was 38 days. No patients treated with Abraxane and carboplatin experienced Grade 4 peripheral neuropathy.
Anemia and thrombocytopenia were more commonly reported in the Abraxane arm than in the Taxol arm (54% versus 28% and 45% versus 27% respectively).
Patient-reported taxane toxicity was assessed using the 4 subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeated measure analysis, 3 of the 4 subscales (peripheral neuropathy, pain hands/feet, and hearing) favored Abraxane and carboplatin (p ≤ 0.002). For the other subscale (oedema), there was no difference in the treatment arms.
Cranial nerve palsies, vocal cord paresis, and rare reports of severe hypersensitivity reactions have been reported during post-marketing surveillance of Abraxane.
There have been rare reports of reduced visual acuity due to cystoid macular oedema during treatment with Abraxane. Upon diagnosis of cystoid macular oedema, treatment with Abraxane should be discontinued.
There have been reports of tumour lysis syndrome during treatment with Abraxane.
In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae have been reported as part of the continuing surveillance of Abraxane. Because these events have been reported voluntarily during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.
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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