Akynzeo
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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

  



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1. NAME OF THE MEDICINAL PRODUCT  
 

Akynzeo 300 mg/0.5 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 

Each hard capsule contains 300 mg of netupitant and palonosetron hydrochloride equivalent to 0.5 mg 

of palonosetron. 

Excipients with known effect: 

Each hard capsule contains 7 mg of sorbitol and 20 mg of sucrose.  

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM  
 

Hard capsule. 

Opaque gelatin capsule of size “0” (length 21.7 mm) with white body and caramel cap with “HE1” 

printed on the body. The hard capsule is filled with three tablets and one soft capsule. 

 

 

4. CLINICAL PARTICULARS  
 

4.1 Therapeutic indications  

 

Akynzeo is indicated in adults for the: 

- Prevention of acute and delayed nausea and vomiting associated with highly emetogenic 

cisplatin-based cancer chemotherapy. 

- Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic 

cancer chemotherapy. 

 

4.2  Posology and method of administration  

 

Posology  

 

One 300 mg/0.5 mg capsule should be administered approximately one hour prior to the start of each 

chemotherapy cycle.  

 

The recommended oral dexamethasone dose should be reduced by approximately 50 % when co-

administered with netupitant/palonosetron capsules (see section 4.5 and clinical studies administration 

schedule in section 5.1). 
 

Special populations 

 

Elderly people 

No dosage adjustment is necessary for elderly patients. Caution should be exercised when using this 

medicinal product in patients over 75 years, due to the long half-life of the active substances and the 

limited experience in this population. 

 

Renal impairment 

Dosage adjustment is not considered necessary in patients with mild to severe renal impairment. Renal 

excretion for netupitant is negligible. Mild to moderate renal impairment does not significantly affect 



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palonosetron pharmacokinetic parameters. Total systemic exposure to intravenous palonosetron 

increased by approximately 28% in severe renal impairment relative to healthy subjects. The 

pharmacokinetics of palonosetron or netupitant has not been studied in subjects with end-stage renal 

disease requiring hemodialysis and no data on the effectiveness or safety of netupitant/palonosetron 

capsules in these patients are available. Therefore, use in these patients should be avoided. 
 

Hepatic impairment 

No dosage adjustment is necessary for patients with mild or moderate hepatic impairment (Child-

Pugh score 5-8). Limited data exist in patients with severe hepatic impairment (Child Pugh score ≥ 

9). As use in patients with severe hepatic impairment may be associated with increased exposure of 

netupitant, this medicinal product should be used with caution in these patients (see sections 4.4 and 

5.2).  

 

Paediatric population  

The safety and efficacy of Akynzeo capsules in the paediatric population have not been established. 

No data are available.  

 

Method of administration 

 

For oral use.  

 

The hard capsule should be swallowed whole. 

It can be taken with or without food.  

 

4.3  Contraindications  

 

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 

 

Pregnancy (see section 4.6). 

 

4.4  Special warnings and precautions for use  

 

Constipation 

 

As palonosetron may increase large bowel transit time, patients with a history of constipation or 

signs of subacute intestinal obstruction should be monitored following administration (see section 

4.8).  

 

Serotonin syndrome  

 

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or in 

combination with other serotonergic medicinal products (including selective serotonin reuptake 

inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation 

of patients for serotonin syndrome-like symptoms is advised (see section 4.8). 

 

QT Prolongation 

 

An ECG study was conducted in adult male and female healthy volunteers with oral netupitant either 

200 or 600 mg administered in combination with oral palonosetron 0.5 or 1.5 mg, respectively. The 

study demonstrated no clinically important effects on ECG parameters: the largest point estimate of 

the placebo and baseline corrected QTc interval was 7.0 ms (one-sided upper 95% confidence limit 

8.8 ms), observed 16 hours after the administration of supratherapeutic doses (600 mg netupitant and 

1.5 mg palonosetron). Upper 95% confidence limit of the point estimates of placebo and baseline 

corrected QTcI was constantly within 10 ms at all time points over 2 days after study substance 

administration.  

 



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However, since netupitant/palonosetron capsules contains a 5-HT3 receptor antagonist, caution should 

be exercised in concomitant use with medicinal products that increase the QT interval or in patients 

who have or are likely to develop prolongation of the QT interval. These conditions include patients 

with a personal or family history of QT prolongation, electrolyte abnormalities, congestive heart 

failure, bradyarrhythmia, conduction disturbances and in patients taking anti-arrhythmic medicinal 

products or other medicinal products that lead to QT prolongation or electrolyte abnormalities. 

Hypokalaemia and hypomagnesaemia should be corrected prior to administration. 
 

Caution should be exercised in patients with severe hepatic impairment since limited data are 

available in these patients. 

 

This medicinal product should be used with caution in patients receiving concomitant orally 

administered active substances that are metabolised primarily through CYP3A4 and with a narrow 

therapeutic range (see section 4.5).  

 

Chemotherapeutic agents that are substrates for CYP3A4 

 

Netupitant is a moderate inhibitor of CYP3A4 and can increase the exposure of chemotherapeutic 

agents that are substrates for CYP3A4 e.g. docetaxel (see section 4.5). Therefore, patients should be 

monitored for increased toxicity of chemotherapeutic agents that are substrates for CYP3A4, 

including irinotecan. Furthermore, netupitant may also affect the efficacy of chemotherapeutic agents 

that need activation by CYP3A4 metabolism.  

 

Excipients 

 

This medicinal product contains 7 mg of sorbitol in each hard capsule.  

 

This medicinal product also contains 20 mg of sucrose in each capsule. Patients with rare hereditary 

problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency 

should not take this medicinal product.  

 

This medicinal product contains less than 1 mmol sodium per (23 mg) per hard capsule, that is to say 

essentially ‘sodium-free’. 

 

It may also contain a trace of lecithin derived from soya. Therefore, patients with known 

hypersensitivity to peanut or soya should be monitored closely for signs of an allergic reaction (see 

section 4.8). 

 

4.5  Interaction with other medicinal products and other forms of interaction  

 

When netupitant/palonosetron capsules are used concomitantly with another CYP3A4 inhibitor, 

netupitant plasma concentrations could be elevated. When this medicinal product is used 

concomitantly with medicinal products that induce CYP3A4 activity, netupitant plasma concentrations 

could be reduced and this may result in decreased efficacy. This medicinal product can increase 

plasma concentrations of concomitantly administered medicinal products that are metabolised via 

CYP3A4. 
In humans, netupitant is eliminated mainly by hepatic metabolism mediated by CYP3A4 with a 

marginal renal excretion. At a dose of 300 mg in humans, netupitant is a substrate and moderate 

inhibitor of CYP3A4. Palonosetron is eliminated from the body through both renal excretion and 

metabolic pathways, with the latter mediated via multiple CYP enzymes. Palonosetron is mainly 

metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based on 

in vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinically 

relevant concentrations. 

 

Interaction between oral netupitant and oral palonosetron: 

 

No clinically relevant pharmacokinetic interactions have been observed between oral netupitant and 



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oral palonosetron.  

 

Interaction with CYP3A4 substrates: 

 

Dexamethasone 

Co-administration of a single dose of 300 mg netupitant with a dexamethasone regimen (20 mg on 

Day 1, followed by 8 mg twice daily from Day 2 to Day 4) significantly increased the exposure to 

dexamethasone in a time and dose dependent manner. The AUC0-24 (Day 1), the AUC24-36 (Day 2) 

and the AUC84-108 and AUC84-∞ (Day 4) of dexamethasone increased 2.4-fold, with co-administration 

of 300 mg netupitant. The pharmacokinetic profile of netupitant was unchanged when administered 

in combination with dexamethasone.  

As such, the oral dexamethasone dose should be reduced by approximately 50% when co-administered 

with netupitant/palonosetron capsules (see section 4.2). 
 

Chemotherapeutic medicinal products (docetaxel, etoposide, cyclophosphamide) 

Exposure to docetaxel and etoposide was increased 37% and 21%, respectively, when co-administered 

with netupitant/palonosetron capsules. No consistent effect was seen with cyclophosphamide after 

netupitant co-administration.  
 

Oral contraceptives 

Netupitant/palonosetron capsules, when given with a single oral dose of 60 μg ethinylestradiol and 

300 μg levonorgestrel had no significant effect on the AUC of ethinylestradiol and increased the AUC 

of levonorgestrel by 1.4-fold; clinical effects on the efficacy of hormonal contraception are unlikely. 

No relevant changes of netupitant and palonosetron pharmacokinetics were observed.   
 

Erythromycin and Midazolam 

Exposure to erythromycin and midazolam was increased approximately 1.3 and 2.4 fold, respectively, 

when each was co-administered with netupitant. These effects were not considered clinically 

important. The pharmacokinetic profile of netupitant was unaffected by the concomitant 

administration of either midazolam or erythromycin. The potential effects of increased plasma 

concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, 

triazolam) should be considered when coadministering these active substances with 

netupitant/palonosetron capsules. 
 

Serotonergic medicinal products (e.g. SSRIs and SNRIs) 

 

There have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and 

other serotonergic medicinal products (including SSRIs such as fluoxetine, paroxetine, sertraline, 

fluvoxamine, citalopram or escitalopram and SNRIs such as venlafaxine or duloxetine) (see section 

4.4). 

 

Effect of other medicinal products on the pharmacokinetics of Akynzeo 

 

Netupitant is mainly metabolized by CYP3A4; therefore, co-administration with medicinal products 

that inhibit or induce CYP3A4 activity may influence plasma concentrations of netupitant. 

Consequently, concomitant administration with strong CYP3A4 inhibitors (e.g., ketoconazole) 

should be approached with caution and concomitant administration with strong CYP3A4 inducers 

(e.g., rifampicin) should be avoided. Moreover, this medicinal product should be used with caution in 

patients receiving concomitant orally administered active substances with a narrow therapeutic range 

that are primarily metabolized by CYP3A4, such as cyclosporine, tacrolimus, sirolimus, everolimus, 

alfentanil, diergotamine, ergotamine, fentanyl, and quinidine. 

 

Effect of ketoconazole and rifampicin 

 

Administration of the CYP3A4 inhibitor ketoconazole with netupitant/palonosetron capsules increased 

the AUC of netupitant 1.8 fold and Cmax 1.3 fold when compared to the administration of 



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netupitant/palonosetron capsules alone. Co-administration with ketoconazole did not affect the 

pharmacokinetics of palonosetron.  
Administration of the CYP3A4 inducer rifampicin with Akynzeo alone decreased the AUC of 

netupitant 5.2 fold and Cmax 2.6 fold. Co-administration of rifampicin did not affect the 

pharmacokinetics of palonosetron. Consequently, concomitant administration with strong CYP3A4 

inhibitors (e.g., ketoconazole) should be approached with caution and concomitant administration 

with strong CYP3A4 inducers (e.g. rifampicin) should be avoided. 

 

Additional interactions 

 

Netupitant/palonosetron capsules are unlikely to interact with medicinal products which are P-gp 

substrates. Netupitant is not a substrate for P-gp. When netupitant was administered on Day 8 of a 

12-day regimen of digoxin, no changes in digoxin pharmacokinetics were observed.  
Inhibition of the efflux transported BCRP and glucuronidation isozyme UGT2B7 by netupitant and 

its metabolites is unlikely and, if it occurs, of scarce clinical relevance. 

In vitro data shows that netupitant inhibits UGT2B7, the magnitude of such an effect in the clinical 

setting is not established. Caution is recommended when netupitant is combined with an oral 

substrate of this enzyme (e.g.zidovudine, valproic acid, morphine). 

In vitro data suggests that netupitant inhibits the efflux of transporter BCRP. The clinical relevance 

of this effect is not established. 

In vitro data show that netupitant is a P-gp inhibitor. In a study performed in healthy volunteers, 

netupitant does not affect the exposure of digoxin, a P-gp substrate, whereas it increases its Cmax by 

1.09 fold [90%CI 0.9-1.31]. It is not excluded that this effect may be more marked, and then clinically 

relevant, in cancer patients, notably those having abnormal renal function. Therefore, caution is 

recommended when netupitant is combined with digoxin or with other P-gp substrates such as 

dabigatran, or colchicine. 
 

4.6 Fertility, pregnancy and lactation  

 

Women of childbearing potential/ contraception in females 

 

Women of childbearing potential should not be pregnant or become pregnant while on treatment with 

netupitant/palonosetron capsules. A pregnancy test should be performed on all pre-menopausal women 

prior to treatment. Women of childbearing potential must use effective contraception during therapy 

and up to one month after treatment with this medicinal product.  
 

Pregnancy 

 

Netupitant 

There are no data about the use of netupitant in pregnant women.  Studies in animals have shown 

reproductive toxicity including teratogenic effects in rabbit without safety margin (see section 5.3).  

 

Palonosetron 

There are no data about the use of palonosetron in pregnant women. Animal data do not indicate 

direct or indirect harmful effects of palonosetron with the respect to reproductive toxicity (see section 

5.3).  

 

Netupitant/palonosetron capsules are contraindicated during pregnancy (see section 4.3).  
 

Breast-feeding 

 

It is unknown whether palonosetron or netupitant are excreted in human milk. A risk to the suckling 

child cannot be excluded. Netupitant/palonosetron capsules should not be used during breast-feeding. 

Breast-feeding should be discontinued during treatment with this medicinal product and for 1 month 

after the last dose. 
 

Fertility 



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Netupitant 

No effect on fertility has been observed in animal studies. 

 

Palonosetron  

Degeneration of seminiferous epithelium has been observed in rat study (see section 5.3). 

 

4.7 Effects on ability to drive and use machines  

 

Netupitant/palonosetron capsules have moderate influence on the ability to drive and use machines.  

Since it may induce dizziness, somnolence or fatigue, patients should be cautioned not to drive or use 

machines if such symptoms occur. 
 

4.8 Undesirable effects  

 

Summary of the safety profile 

 

Common adverse reactions reported with netupitant/palonosetron capsules were headache (3.6%), 

constipation (3.0%) and fatigue (1.2%).   
 

Tabulated list of adverse reactions 

 

Adverse reactions are listed below by MedDRA body system organ class and frequency. 

 

The following convention has been used for classification of frequency: 

Very common (≥1/10), 

Common (≥1/100 to <1/10), 

Uncommon (≥1/1,000 to <1/100), 

Rare (≥1/10,000 to <1/1,000), 

Very rare (<1/10,000),   

Not known (cannot be estimated from the available data). 

  



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Table1: Adverse reactions  

System organ class Common  Uncommon  Rare  

Infections and 

infestations 

  Cystitis 

Blood and lymphatic 

system disorders 

 Neutropenia Leukopenia 

 Leucocytosis Lymphocytosis 

Metabolism and 

nutrition disorders 

 Decreased appetite  Hypokalaemia 

Psychiatric disorders  Insomnia Acute psychosis 

  Mood altered 

  Sleep disorder 

Nervous system 

disorders 

Headache Dizziness Hypoaesthesia 

  Somnolence 

Eye disorders   Conjunctivitis 

   Vision blurred 

Ear and labyrinth 

disorders 

 Vertigo Tinnitus 

Cardiac disorders  Atrioventricular 

block first degree 

Arrhythmia 

 Cardiomyopathy Atrioventricular block second 

degree 

 Conduction disorder Bundle branch block left 

 Tachycardia Bundle branch block right 

  Mitral valve incompetence 

  Myocardial ischaemia 

  Ventricular extrasystoles 

Vascular disorders  Hypertension Flushing 

  Hypotension 

Respiratory, thoracic 

and mediastinal 

disorders 

 Hiccups  

Gastrointestinal 

disorders 

Constipation Abdominal 

distension 

Dry mouth 

 Abdominal pain Dysphagia 

 Diarrhoea Eructation 

 Dyspepsia Haemorrhoids 

 Flatulence Tongue coated 

 Nausea Vomiting 

Skin and subcutaneous 

tissue disorders 

 Alopecia Erythema 

 Urticaria Pruritus 

   Rash 

Musculoskeletal and 

connective tissue 

disorders 

  Back pain  

  Pain in extremities 

General disorders and 

administration site 

conditions 

Fatigue Asthenia Feeling hot 

  Non-cardiac chest pain 

  Product taste abnormal 

Investigations  Liver transaminases 

increased 

Blood bilirubin increased 

 Blood alkaline 

phosphatase 

increased 

Blood creatine phosphokinase 

increased 

 Blood creatinine Blood creatine phosphokinase 



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increased MB increased 

 Electrocardiogram 

QT prolonged 

Blood urea increased 

  Electrocardiogram ST segment 

depression 

  Electrocardiogram ST-T 

segment abnormal 

  Myoglobin blood increased 

  Neutrophil count increased 

  Troponin increased 

 

Post-marketing data indicates that the adverse reactions profile is generally similar to that seen in 

clinical trials. 

 

Description of selected adverse reactions 

 

Netupitant: 

 

No common adverse reactions are attributable to netupitant, the new component of the fixed 

combination. 

 

Palonosetron: 

Cases of constipation with faecal impaction requiring hospitalisation have been reported in 

association with palonosetron 0.75 mg. 

 

In addition, eye swelling, dyspnoea and myalgia as adverse reactions have been reported with oral 

palonosetron but not observed during the development of this medicinal product. All these reactions 

were uncommon. 
 

Very rare cases of anaphylaxis, anaphylactic/anaphylactoid reactions and shock have been reported 

from the post-marketing use of intravenous palonosetron. The signs may include hives, itch, 

angioedema, low blood pressure, throat tightness, chest tightness, dyspnoea, loss of consciousness. 

 

There have also been reports of serotonin syndrome. The signs may include tremor, agitation, 

sweating, myoclonic movements, hypertonia and fever. 

 

Netupitant and Palonosetron Combinate Capsule:  

 

This medicinal product may contain a trace of lecithin derived from soya. Therefore, patients with 

known hypersensitivity to peanut or soya should be monitored closely for signs of an allergic reaction. 

The signs may include hives, skin rash, itching, difficulty breathing or swallowing, swollen mouth, 

face, lips, tongue or throat and sometimes a drop-in blood pressure. 

 

 

Reporting of suspected adverse reactions 

 

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. 

 

4.9 Overdose  

 

Based on the experience with healthy subjects exposed to oral netupitant 600 mg in combination with 

palonosetron 1.50 mg the potential acute symptoms of overdose are headache, dizziness, 

constipation, anxiety, palpitations, euphoric mood and pain in the legs. In case of overdose, the 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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medicinal product should be discontinued and general supportive treatment and monitoring should be 

provided. Because of the antiemetic activity of netupitant and palonosetron, emesis induced by a 

medicinal product may not be effective. Dialysis studies have not been performed. However, due to 

the large volume of distribution of palonosetron and netupitant, dialysis is unlikely to be an effective 

treatment for overdose. 

 

 

5. PHARMACOLOGICAL PROPERTIES  
 

5.1 Pharmacodynamic properties  

 

Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5-HT3) antagonists; ATC 

code: A04AA55  

 

Mechanism of action 

 

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.  

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little 

or no affinity for other receptors. Chemotherapeutic substances produce nausea and vomiting by 

stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin 

then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.  

Delayed emesis has been associated with the activation of tachykinin family neurokinin 1 (NK1) 

receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As 

shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses. 

 

Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%, 

86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after 

administration of 300 mg netupitant. 

 

Clinical efficacy and safety 

 

Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acute 

and delayed nausea and vomiting associated with highly and moderately emetogenic cancer 

chemotherapy in two separate pivotal studies.  

 

Highly Emetogenic Chemotherapy (HEC) study  

In a multicenter, randomized, parallel, double-blind, controlled clinical study of 694 patients, the 

efficacy and safety of single doses of oral netupitant in combination with oral palonosetron was 

compared with a single oral dose of palonosetron in cancer patients receiving a chemotherapy 

regimen that included cisplatin (median dose = 75 mg/m2). The efficacy of Akynzeo was assessed in 

135 patients who received a single oral dose (netupitant 300 mg and palonosetron 0.5 mg) and 136 

patients who received oral palonosetron 0.5 mg alone.   

 

Treatment regimens for the Akynzeo and the palonosetron 0.5 mg arms are displayed in Table below. 

 

Table 2: Oral Antiemetic treatment regimen –– HEC study 

 

Treatment regimen  Day 1  Days 2 to 4  

Akynzeo  Akynzeo (Netupitant 300 mg + 

Palonosetron 0.5 mg)  

Dexamethasone 12 mg  

Dexamethasone 8 mg once 

a day  

Palonosetron  Palonosetron 0.5 mg  

Dexamethasone 20 mg 

Dexamethasone 8 mg twice 

a day 

 

The primary efficacy endpoint was complete response (CR) rate (defined as no emetic episodes, no 

rescue medication) within 120 hours (overall phase) after the start of the highly emetogenic 



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chemotherapy administration.  

A summary of the key results from this study is shown in Table 3 below.  

 

Table 3: Proportion of patients receiving cisplatin chemotherapy responding by treatment 

group and phase 

 

 Akynzeo 

Palonosetron 

0.5 mg   

 N=135 N=136  

 % % p-value 

Primary endpoint    

Complete response    

 Overall phase§ 89.6 76.5 0.004 

Major secondary endpoints    

Complete response    

 Acute phase‡ 98.5 89.7 0.007 

 Delayed phase† 90.4 80.1 0.018 

No emesis    

 Acute phase 98.5 89.7 0.007 

 Delayed phase 91.9 80.1 0.006 

 Overall phase 91.1 76.5 0.001 

No significant nausea    

 Acute phase 98.5 93.4 0.050 

 Delayed phase 90.4 80.9 0.004 

 Overall phase 89.6 79.4 0.021 
‡Acute phase: 0 to 24 hours post-cisplatin treatment. 
†Delayed phase: 25 to 120 hours post-cisplatin treatment. 
§Overall: 0 to 120 hours post-cisplatin treatment. 

 

Moderately Emetogenic Chemotherapy (MEC) study 

In a multicenter, randomized, parallel, double-blind, active-controlled, superiority study, the efficacy 

and safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron 

0.5 mg in cancer patients scheduled to receive the first cycle of an anthracycline and cyclophosphamide 

regimen for the treatment of a solid malignant tumor. At the time of the study, anthracycline-

cyclophosphamide containing chemotherapy regimens were considered to be moderately emetogenic. 

Recent guidance has updated these regimens to highly emetogenic.  

All patients received a single oral dose of dexamethasone.  

 

Table 4: Oral Antiemetic treatment regimen – MEC study 

 

Treatment 

regimen  

Day 1  Days 2 to 3  

Akynzeo  Akynzeo Netupitant 300 mg  

Palonosetron 0.5 mg  

Dexamethasone 12 mg  

No antiemetic treatment 

Palonosetron  Palonosetron 0.5 mg 

Dexamethasone 20 mg 

No antiemetic treatment 

 

After completion of cycle 1, patients had the option to participate in a multiple-cycle extension, 

receiving the same treatment as assigned in cycle 1.  There was no pre-specified limit of the number 



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of repeat consecutive cycles for any patient. A total of 1450 patients (Akynzeo n=725; Palonosetron 

n=725) received study medication. Of these, 1438 patients (98.8%) completed cycle 1 and 

1286 patients (88.4%) continued treatment in the multiple-cycle extension. A total of 907 patients 

(62.3%) completed the multiple-cycle extension up to a maximum of eight treatment cycles.  

A total of 724 patients (99.9%) were treated with cyclophosphamide. All patients were additionally 

treated with either doxorubicin (68.0%) or epirubicin (32.0%).  

 

The primary efficacy endpoint was the CR rate in the delayed phase, 25-120 hours after the start of 

the chemotherapy administration. 

 

A summary of the key results from this study is shown in Table below.  

 

Table 5: Proportion of patients receiving anthracycline and cyclophosphamide chemotherapy 

responding by treatment group and phase – cycle 1 

 

 Akynzeo Palonosetron 

0.5 mg 

 

 N=724 N=725  

 % % p-value* 

Primary endpoint    

Complete response    

 Delayed phase† 76.9 69.5 0.001 

Major secondary endpoints    

Complete response    

 Acute phase‡ 88.4 85.0 0.047 

 Overall phase§ 74.3 66.6 0.001 

No emesis    

 Acute phase 90.9 87.3 0.025 

 Delayed phase 81.8 75.6 0.004 

 Overall phase 79.8 72.1 <0.001 

No significant nausea    

 Acute phase 87.3 87.9 N.S. 

 Delayed phase 76.9 71.3 0.014 

 Overall phase 74.6 69.1 0.020 

* p-value from Cochran-Mantel-Haenszel test, stratified by age class and region. 
‡Acute phase: 0 to 24 hours after anthracycline and cyclophosphamide regimen 
†Delayed phase: 25 to 120 hours after anthracycline and cyclophosphamide regimen  
§Overall: 0 to 120 hours after anthracycline and cyclophosphamide regimen 

 

Patients continued into the Multiple-Cycle extension for up to 7 additional cycles of chemotherapy. 

Antiemetic activity of Akynzeo was maintained throughout repeat cycles for those patients 

continuing in each of the multiple cycles. 

The impact of nausea and vomiting on patients’ daily lives was assessed using the Functional Living 

Index–Emesis (FLIE). The proportion of patients with Overall no impact on daily life was 6.3% 

higher (p value =0.005) in the Akynzeo group (78.5%) than in the palonosetron group (72.1%).  

 

Multiple-cycle safety study in patients receiving either Highly Emetogenic Chemotherapy or 

Moderately Emetogenic Chemotherapy  

In a separate study, a total of 413 patients undergoing initial and repeat cycles of chemotherapy 

(including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens), were randomized to receive 



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either Akynzeo (n=309) or aprepitant and palonosetron (n=104). Safety and efficacy were maintained 

throughout all cycles. 

 

Paediatric population  

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Akynzeo in all subsets of the paediatric population in prevention of acute and delayed nausea and 

vomiting associated with highly emetogenic cisplatin-based and moderately emetogenic cancer 

chemotherapy (see section 4.2 for information on paediatric use).  
 

5.2 Pharmacokinetic properties  

 

Absorption 

 

Netupitant 

Absolute netupitant bioavailability data are not available in humans; based on data from two studies 

with intravenous netupitant, the bioavailability in humans is estimated to be greater than 60%.  

In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hours 

after dosing. Plasma concentrations followed a first order absorption process and reached Cmax in 

approximately 5 hours. There was a supra-proportional increase in Cmax and AUC parameters for 

doses from 10 mg to 300 mg.  

In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitant 

concentration (Cmax) was 486 ±268 ng/mL (mean ± SD) and median time to maximum concentration 

(Tmax) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. In a pooled analysis, females had a 

higher netupitant exposure compared to males; there was a 1.31-fold increase in Cmax, a 1.02 fold 

increase for AUC and a 1.36 fold increase in half-life.  

Netupitant AUC0-∞ and Cmax increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal.  

 

Palonosetron 

Following oral administration, palonosetron is well absorbed with its absolute bioavailability 

reaching 97%. After single oral doses using buffered solution mean maximum palonosetron 

concentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional 

over the dose range of 3.0 to 80 mcg/kg in healthy subjects. 

In 36 healthy male and female subjects given a single oral dose of 0.5 mg palonosetron, maximum 

plasma concentration (Cmax) was 0.81 ± 1.66 ng/mL (mean ± SD) and time to maximum 

concentration (Tmax) was 5.1 ± 1.7 hours. In female subjects (n=18), the mean AUC was 35% higher 

and the mean Cmax was 26% higher than in male subjects (n=18). In 12 cancer patients given a single 

oral dose of palonosetron 0.5 mg one hour prior to chemotherapy, Cmax was 0.93 ± 0.34 ng/mL and 

Tmax was 5.1 ± 5.9 hours.  The AUC was 30% higher in cancer patients than in healthy subjects. A 

high fat meal did not affect the Cmax and AUC of oral palonosetron. 

 

Distribution 

 

Netupitant 

After a single oral 300 mg dose administration in cancer patients, netupitant disposition was 

characterised by a two compartment model with an estimated median systemic clearance of 20.5 L/h 

and a large distribution volume in the central compartment (486 L). Human plasma protein binding 

of netupitant and its two major metabolites M1 and M3 is > 99% at concentrations ranging from 10 

to 1500 ng/mL. The third major metabolite, M2, is > 97% bound to plasma proteins. 

 

Palonosetron  

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of 

palonosetron is bound to plasma proteins. 

 

Biotransformation 

 

Netupitant 



14 

 

Three metabolites have been detected in human plasma at netupitant oral doses of 30 mg and higher 

(the desmethyl derivative, M1; the N-oxide derivative, M2; the OH-methyl derivative, M3). In vitro 

metabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are 

involved in the metabolism of netupitant. After administration of a single oral dose of 300 mg 

netupitant, mean plasma netupitant/plasma radioactivity ratios ranged from 0.13 to 0.49 over 96 h 

post-dose. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose, 

indicating that netupitant is being rapidly metabolized. Mean Cmax was approximately 11%, 47% and 

16% of the parent for M1, M2 and M3 respectively; M2 had the lowest AUC relative to the parent 

(14%) whereas M1 and M3 AUC were approximately 29% and 33% of the parent, respectively. M1, 

M2 and M3 metabolites were all shown to be pharmacologically active in an animal 

pharmacodynamic model, where M3 was most potent and M2 least active. 

 

Palonosetron  

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two 

primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each 

have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism 

studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in 

the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly 

different between poor and extensive metabolizers of CYP2D6 substrates. 

 

Elimination  

 

Netupitant 

Following administration of a single dose of Akynzeo, netupitant is eliminated from the body in a 

multi-exponential fashion, with an apparent mean elimination half-life of 88 hours in cancer patients.  

Renal clearance is not a significant elimination route for netupitant-related entities. The mean 

fraction of an oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95% 

and 70.7% of the radioactive dose was recovered in the urine and faeces, respectively.  

Approximately half the radioactivity administered orally as [14C]-netupitant was recovered from 

urine and faeces within 120 h of dosing. Elimination via both routes was estimated to be complete by 

Day 29-30 post-dose. 

 

Palonosetron  

Following administration of a single oral 0.75 mg dose of [14C]-palonosetron to six healthy subjects, 

85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in faeces. 

The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the 

administered dose.  In healthy subjects given palonosetron capsules 0.5 mg, the terminal elimination 

half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½ was 48 ± 

19 hours. After a single dose of approximately 0.75 mg intravenous palonosetron, the total body 

clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance 

was 66.5± 18.2 mL/h/kg. 

 

Special populations 

 

Hepatic Impairment 

 

Netupitant 

Maximum concentrations and total exposure of netupitant were increased in subjects with mild 

(n=8), moderate (n=8), and severe (n=2) hepatic impairment compared to matching healthy subjects, 

although there was pronounced individual variability in both hepatically-impaired and healthy 

subjects. Exposure to netupitant (Cmax, AUC0-t and AUC0-∞) compared to matching healthy subjects 

was 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically-

impaired subjects, respectively. As such, no dosage adjustment is necessary for patients with mild to 

moderate hepatic impairment. Limited data exist in patients with severe hepatic impairment (Child 

Pugh score ≥9). 

 

Palonosetron 



15 

 

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to 

the healthy subjects. While the terminal elimination half-life and mean systemic exposure of 

palonosetron is increased in the subjects with severe hepatic impairment, this does not warrant dose 

reduction. 

 

Renal impairment 

 

Netupitant 

No specific studies were performed to evaluate netupitant in patients with renal impairment. In the 

ADME trial, less than 5% of all netupitant-related material was excreted in urine and less than 1% of 

the netupitant dose was eliminated unchanged in the urine and therefore any accumulation of 

netupitant or metabolites after a single dose would be negligible. Furthermore, the population PK 

study showed no correlation between PK parameters of netupitant and markers of renal dysfunction. 

 

Palonosetron 

Mild to moderate renal impairment does not significantly affect palonosetron PK parameters. Total 

systemic exposure to intravenous palonosetron increased by approximately 28% in patients with 

severe impairment relative to healthy subjects. In a population PK study, patients with a reduced 

creatinine clearance (CLCR) also had a reduced palonosetron clearance, but this reduction would not 

result in a significant change in palonosetron exposure.  

 

Therefore, Akynzeo can be administered without dosage adjustment in patients with renal 

impairment.  

 

Neither netupitant nor palonosetron have been evaluated in patients with end-stage renal disease. 

 

5.3 Preclinical safety data  

 

Palonosetron  

 

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of 

the maximum human exposure, indicating little relevance to clinical use. Non-clinical studies 

indicate that palonosetron, only at very high concentrations, may block ion channels involved in 

ventricular de- and re-polarisation and prolong action potential duration. Degeneration of 

seminiferous epithelium was associated with palonosetron following a one month oral repeat dose 

toxicity study in rats.  Animal studies do not indicate direct or indirect harmful effects with respect to 

pregnancy, embryonal/foetal development, parturition or postnatal development. Only limited data 

from animal studies are available regarding the placental transfer (see section 4.6). Palonosetron is 

not mutagenic. High doses of palonosetron (each dose causing at least 15 times the human 

therapeutic exposure) applied daily for two years caused an increased rate of liver tumors, endocrine 

neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumors in rats but not in mice. 

The underlying mechanisms are not fully understood, but because of the high doses employed and 

since the medicinal product is intended for single application in humans, these findings are not 

considered relevant for clinical use. 

 

Netupitant and combination with palonosetron 

 

Effects in non-clinical studies based on safety pharmacology and single and repeated dose toxicity 

were observed only at exposures considered in excess of the maximum human exposure, indicating 

little relevance to clinical use. Phospholipidosis (foamy macrophages) has been observed with the 

administration of netupitant after repeated administration in rats and dogs. The effects were 

reversible or partially reversible after the recovery period. The significance of these findings in 

humans is unknown.  

 

Non-clinical studies indicate that netupitant and its metabolites and the combination with 

palonosetron only at very high concentrations may block ion channels involved in ventricular de- and 

re-polarisation and prolong action potential duration. Reproductive studies in animals with netupitant 



16 

 

do not indicate direct or indirect harmful effects with respect to fertility, parturition or postnatal 

development. An increased incidence of positional foetal abnormalities of the limbs and paws, fused 

sternebrae and agenesis of accessory lung lobe were observed following daily administration of 

netupitant in rabbits at 10 mg/kg/day and higher during the period of organogenesis. In a pilot dose 

range finding study in rabbits, cleft palate, microphtalmia and aphakia were observed in four foetuses 

from one litter in the 30 mg/kg/day group. The relevance of these findings in humans is unknown. No 

data from animal studies with netupitant are available regarding placental transfer and lactation. 

Netupitant is not mutagenic.  

 

 

6. PHARMACEUTICAL PARTICULARS 
 

6.1  List of excipients 

 

Hard capsule content: 

 

Netupitant tablets 

Microcrystalline cellulose (E460) 

Sucrose lauric acid esters 

Povidone K-30 

Croscarmellose sodium   

Colloidal hydrated silica 

Sodium stearyl fumarate      

Magnesium stearate  

 

Palonosetron soft capsule 

 

Capsule content 

Glycerol monocaprylocaproate (type I) 

Glycerol 

Polyglyceryl oleate 

Purified water 

Butylhydroxyanisole (E320) 

 

Capsule shell 

Gelatin 

Glycerol 

Sorbitol 

1,4 sorbitan 

Titanium dioxide (E171) 

 

Hard capsule shell: 

 

Gelatin 

Titanium dioxide (E171) 

Yellow iron oxide (E172) 

Red iron oxide (E172) 

 

Printing ink 

Shellac glaze (partially esterified) 

Black iron oxide (E172) 

Propylene glycol (E1520) 

 

6.2 Incompatibilities 

 

Not applicable. 

 



17 

 

6.3 Shelf life 

 

4 years. 

 

6.4 Special precautions for storage  

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container  

 

Alu/Alu blister. 

Pack size of one hard capsule or 4 x 1 hard capsules in perforated unit dose blisters.  

Not all pack sizes may be marketed.  

 

6.6 Special precautions for disposal  

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements.  

 

 

7. MARKETING AUTHORISATION HOLDER  
 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown 

Mulhuddart 

Dublin 15 

Ireland. 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  
 

EU/1/15/1001/001 

EU/1/15/1001/002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
 

Date of first authorisation: 27 May 2015 

Date of latest renewal: 9 January 2020 

 

 

10. DATE OF REVISION OF THE TEXT  
 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 

  

http://www.ema.europa.eu/
http://www.ema.europa.eu/


18 

 

 

 

1. NAME OF THE MEDICINAL PRODUCT  
 

Akynzeo 235 mg/0.25 mg powder for concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 

Each vial contains fosnetupitant chloride hydrochloride equivalent to 235 mg of fosnetupitant, which 

corresponds to 197.5 mg of netupitant and palonosetron hydrochloride equivalent to 0.25 mg of 

palonosetron.  

 

After reconstitution and dilution 1 ml of solution contains 4.7 mg fosnetupitant, which corresponds to 

3.95 mg of netupitant, and 0.005 mg palonosetron. 

 

Excipients with known effect 

 

Each vial contains approximately 24.8 mg of sodium. 

If reconstituted and diluted with sodium chloride 9 mg/ml (0.9%) solution for injection, the final 

solution contains approximately 202 mg of sodium. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM  
 

Powder for concentrate for solution for infusion. 

White to off-white amorphous powder. 

 

 

4. CLINICAL PARTICULARS  
 

4.1 Therapeutic indications  

 

Akynzeo is indicated in adults for the: 

- Prevention of acute and delayed nausea and vomiting associated with highly emetogenic 

cisplatin-based cancer chemotherapy. 

- Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic 

cancer chemotherapy. 

 

4.2 Posology and method of administration  

 

Posology  

 

The recommended dose is 235 mg/0.25 mg (the content of one vial of powder, reconstituted and 

diluted) administered as an infusion over 30 minutes, initiated approximately 30 minutes prior to the 

start of each chemotherapy cycle (see section 6.6).  

At the end of the infusion, the infusion line should be flushed with the same carrier solution to ensure 

complete medicinal product administration. 

 

The recommended oral dexamethasone dose should be reduced by approximately 50 % when co-

administered with fosnetupitant and palonosetron hydrochloride combination (see section 4.5 and 

clinical studies administration schedule in section 5.1). 

 

Special populations 

 



19 

 

Elderly people 

No dosage adjustment is necessary for elderly patients. Caution should be exercised when using this 
medicinal product in patients over 75 years, due to the long half-life of the active substances and the 

limited experience in this population. 

 

Renal impairment 

Dosage adjustment is not considered necessary in patients with mild to severe renal impairment. Renal 

excretion for netupitant is negligible. Mild to moderate renal impairment does not significantly affect 

palonosetron pharmacokinetic parameters. Total systemic exposure to intravenous palonosetron 

increased by approximately 28% in severe renal impairment relative to healthy subjects. The 

pharmacokinetics of palonosetron or netupitant have not been studied in subjects with end-stage renal 

disease requiring hemodialysis and no data on the effectiveness or safety of fosnetupitant and 

palonosetron hydrochloride combination in these patients are available. Therefore, the use in these 

patients should be avoided. 

 

Hepatic impairment 

No dosage adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh 

score 5-8). Limited data exist in patients with severe hepatic impairment (Child Pugh score ≥ 9). As 

use in patients with severe hepatic impairment may be associated with increased exposure of 

netupitant, this medicinal product should be used with caution in these patients (see sections 4.4 and 

5.2).  

 

Paediatric population  

The safety and efficacy of Akynzeo in children aged 1 month to less than 18 years have not yet been 

established. No data are available.  

 

Method of administration 

 

This medicinal product should be administered intravenously. Intravenous administration occurs 

preferably through a running intravenous infusion over 30 minutes (see section 6.6).  

 

For instructions on reconstitution and dilution of the medicinal product before administration, see 

section 6.6. 

 

4.3 Contraindications  

 

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 

Pregnancy (see section 4.6). 

4.4 Special warnings and precautions for use  

 

Constipation 

 

As palonosetron may increase large bowel transit time, patients with a history of constipation or signs 

of subacute intestinal obstruction should be monitored following administration (see section 4.8). 

 

Serotonin syndrome  

 

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or in 

combination with other serotonergic medicinal products (including selective serotonin reuptake 

inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation 

of patients for serotonin syndrome-like symptoms is advised (see section 4.8). 

 

QT Prolongation 

 



20 

 

An ECG study was conducted in adult male and female healthy volunteers with oral netupitant either 

200 mg or 600 mg administered in combination with oral palonosetron 0.5 mg or 1.5 mg, respectively. 

The study demonstrated no clinically important effects on ECG parameters: the largest point estimate 

of the placebo and baseline corrected QTc interval was 7.0 ms (one-sided upper 95% confidence limit 

8.8 ms), observed 16 hours after the administration of supratherapeutic doses (600 mg netupitant and 
1.5 mg palonosetron). The upper 95% confidence limit of the point estimates of placebo and baseline 

corrected QTcI was constantly within 10 ms at all time points over 2 days after study administration of 

the medicinal product.  

 

However, since netupitant and palonosetron hydrochloride combination contains a 5-HT3 receptor 

antagonist, caution should be exercised in concomitant use with medicinal products that increase the 

QT interval or in patients who have or are likely to develop prolongation of the QT interval. These 

conditions include patients with a personal or family history of QT prolongation, electrolyte 

abnormalities, congestive heart failure, bradyarrhythmia, conduction disturbances and in patients 

taking anti-arrhythmic medicinal products or other medicinal products that lead to QT prolongation or 

electrolyte abnormalities. Hypokalaemia and hypomagnesaemia should be corrected prior to 

administration. 

 

This product should not be used to prevent nausea and vomiting in the days following chemotherapy if 

not associated with another chemotherapy administration. 

 

It should not be used to treat nausea and vomiting following chemotherapy.  

 

Caution should be exercised in patients with severe hepatic impairment since limited data are available 

in these patients. 

 

This medicinal product should be used with caution in patients receiving concomitant orally 

administered active substances that are metabolised primarily through CYP3A4 and with a narrow 

therapeutic range (see section 4.5).  

 

Chemotherapeutic agents that are substrates for CYP3A4 

 

Netupitant is a moderate inhibitor of CYP3A4 and can increase the exposure of chemotherapeutic 

agents that are substrates for CYP3A4, e.g. docetaxel (see section 4.5). Therefore, patients should be 

monitored for increased toxicity of chemotherapeutic agents that are substrates for CYP3A4, including 

irinotecan. Furthermore, netupitant may also affect the efficacy of chemotherapeutic agents that need 

activation by CYP3A4 metabolism.  

 

Excipients 

 

This medicinal product contains approximately 24.8 mg of sodium per vial, equivalent to 1.24% of the 

WHO recommended maximum daily intake of 2 g sodium for an adult. 

If reconstituted and diluted with sodium chloride 9 mg/ml (0.9%) solution for injection, the final 

solution contains approximately 202 mg of sodium per dose, equivalent to 10.1% of the WHO 

recommended maximum daily intake of 2 g sodium for an adult. 

 
4.5 Interaction with other medicinal products and other forms of interaction  

 

Pharmacokinetic interactions 

 

When administered intravenously fosnetupitant is rapidly converted to netupitant. 

Interactions with other medicinal products following administration of intravenous fosnetupitant are 

likely to occur with active substances that interact with oral netupitant. The following information 

was derived from studies conducted with oral netupitant and studies conducted with intravenous 

fosnetupitant.  

 



21 

 

In humans, netupitant is eliminated mainly by hepatic metabolism mediated by CYP3A4 with a 

marginal renal excretion. At a dose of 300 mg in humans, netupitant is a substrate and moderate 

inhibitor of CYP3A4. Palonosetron is eliminated from the body through both renal excretion and 

metabolic pathways, with the latter mediated via multiple CYP enzymes. Palonosetron is mainly 

metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based on in 

vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinically 

relevant concentrations. 

 

Interaction between oral netupitant and oral palonosetron 

 

No clinically relevant pharmacokinetic interactions have been observed between oral netupitant and 

oral palonosetron.  

 

Interaction with CYP3A4 substrates 

 

Dexamethasone 

Co-administration of a single oral dose of 300 mg netupitant or a single intravenous dose of 235 mg 

fosnetupitant with a dexamethasone regimen (20 mg on Day 1, followed by 8 mg twice daily from 

Day 2 to Day 4) significantly increased the exposure to dexamethasone in a time and dose dependent 

manner. The AUC84-∞ (Day 4) of dexamethasone increased 2.4-fold with co-administration of 300 mg 

netupitant or 235 mg fosnetupitant. The pharmacokinetic profile of netupitant was unchanged when 

administered in combination with dexamethasone.  

As such, the oral dexamethasone dose should be reduced by approximately 50% when co-administered 

with fosnetupitant and palonosetron hydrochloride combination (see section 4.2). 

 

Chemotherapeutic medicinal products (docetaxel, etoposide, cyclophosphamide) 

Exposure to docetaxel and etoposide was increased 37% and 21%, respectively, when co-administered 

with netupitant/palonosetron capsules. No consistent effect was seen with cyclophosphamide after 

netupitant co-administration.  

 

Oral contraceptives 

Netupitant/palonosetron capsules, when given with a single oral dose of 60 μg ethinylestradiol and 

300 μg levonorgestrel had no significant effect on the AUC of ethinylestradiol and increased the AUC 

of levonorgestrel by 1.4-fold; clinical effects on the efficacy of hormonal contraception are unlikely. 

No relevant changes of netupitant and palonosetron pharmacokinetics were observed.   

 

Erythromycin and Midazolam 

Exposure to erythromycin and midazolam was increased approximately 1.3 and 2.4 fold, respectively, 

when each was co-administered with netupitant administered orally. These effects were not considered 

clinically important. The pharmacokinetic profile of netupitant was unaffected by the concomitant 

administration of either midazolam or erythromycin. The potential effects of increased plasma 

concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, 

triazolam) should be considered when coadministering these active substances with netupitant and 

palonosetron hydrochloride combination. 

 

Serotonergic medicinal products (e.g. SSRIs and SNRIs) 

 

There have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and 

other serotonergic medicinal products (including SSRIs such as fluoxetine, paroxetine, sertraline, 

fluvoxamine, citalopram or escitalopram and SNRIs such as venlafaxine or duloxetine) (see section 

4.4). 

 

Effect of other medicinal products on the pharmacokinetics of Akynzeo 

 

Netupitant is mainly metabolized by CYP3A4; therefore, co-administration with medicinal products 

that inhibit or induce CYP3A4 activity may influence plasma concentrations of netupitant. 

Consequently, concomitant administration with strong CYP3A4 inhibitors (e.g., ketoconazole) should 



22 

 

be approached with caution and concomitant administration with strong CYP3A4 inducers (e.g., 

rifampicin) should be avoided. Moreover, this medicinal product should be used with caution in 

patients receiving concomitant orally administered active substances with a narrow therapeutic range 

that are primarily metabolized by CYP3A4, such as cyclosporine, tacrolimus, sirolimus, everolimus, 

alfentanil, diergotamine, ergotamine, fentanyl, and quinidine. 

 

Effect of ketoconazole and rifampicin 

 

Administration of the CYP3A4 inhibitor ketoconazole with netupitant/palonosetron capsules 

administered orally increased the AUC of netupitant 1.8 fold and Cmax 1.3 fold when compared to the 

administration of Akynzeo alone. Co-administration with ketoconazole did not affect the 

pharmacokinetics of palonosetron.  

Administration of the CYP3A4 inducer rifampicin with Akynzeo administered orally alone decreased 

the AUC of netupitant 5.2 fold and Cmax 2.6 fold. Co-administration of rifampicin did not affect the 

pharmacokinetics of palonosetron. Consequently, concomitant administration with strong CYP3A4 

inhibitors (e.g., ketoconazole) should be approached with caution and concomitant administration with 

strong CYP3A4 inducers (e.g. rifampicin) should be avoided. 

 

Additional interactions 

Fosnetupitant/palonosetron powder for concentrate for solution for infusion is unlikely to interact with 

medicinal products which are P-gp substrates. Netupitant is not a substrate for P-gp. When netupitant 

was administered on Day 8 of a 12-day regimen of digoxin, no changes in digoxin pharmacokinetics 

were observed.  

Inhibition of the efflux transporter BCRP and glucuronidation isozyme UGT2B7 by netupitant and its 
metabolites is unlikely and, if it occurs, of scarce clinical relevance. 

In vitro data shows that netupitant inhibits UGT2B7, the magnitude of such an effect in the clinical 

setting is not established. Caution is recommended when netupitant is combined with an oral substrate 

of this enzyme (e.g. zidovudine, valproic acid, morphine). 

In vitro data suggests that netupitant inhibits the efflux of transporter BCRP. The clinical relevance of 

this effect is not established. 

In vitro data show that netupitant is a P-gp inhibitor. In a study performed in healthy volunteers, 

netupitant does not affect the exposure of digoxin, a P-gp substrate, whereas it increases its Cmax by 

1.09 fold [90%CI 0.9-1.31]. It is not excluded that this effect may be more marked, and then clinically 

relevant, in cancer patients, notably those having abnormal renal function. Therefore, caution is 

recommended when netupitant is combined with digoxin or with other P-gp substrates such as 

dabigatran, or colchicine. 

 

Pharmacodynamic interactions 

 

Akynzeo contains a 5-HT3 receptor antagonist, palonosetron that may increase QT interval 

prolongation. Therefore, caution should be exercised in concomitant use with medicinal products that 

increase the QT interval, including but not limited to: levofloxacine, amytriptyline, alfuzosin, 

azythromicin, arsenic trioxide (see section 4.4). 

Furthermore, caution is advised in case of fosnetupitant/palonosetron concomitantly with medicinal 

products known to induce hypokalaemia, such as ampicillin, albuterol, terbutaline, furosemide, 

thiazides, or bradycardia, such as beta blockers, verapamil, diltiazem, digitalis, antiarrhythmic drugs. 

 

4.6 Fertility, pregnancy and lactation  

 

Women of childbearing potential/contraception in females 

 

Women of childbearing potential should not be pregnant or become pregnant while on treatment with 

fosnetupitant/ palonosetron powder for concentrate for solution for infusion. A pregnancy test should 

be performed on all pre-menopausal women prior to treatment. Women of childbearing potential must 

use effective contraception during therapy and up to one month after treatment with this medicinal 

product.  

 



23 

 

Pregnancy 

 

Fosnetupitant 

There are no data about the use of fosnetupitant or netupitant in pregnant women. Studies in animals 

have shown reproductive toxicity including teratogenic effects in rabbit without safety margin (see 

section 5.3).  

 

Palonosetron 

There are no data about the use of palonosetron in pregnant women. Animal data do not indicate direct 

or indirect harmful effects of palonosetron with the respect to reproductive toxicity (see section 5.3).  

 

Akynzeo is contraindicated during pregnancy (see section 4.3).  

 

Breast-feeding 

 

It is unknown whether palonosetron or netupitant are excreted in human milk. A risk to the 

newborns/infants cannot be excluded. Akynzeo should not be used during breast-feeding. Breast-

feeding should be discontinued during treatment with this medicinal product and for 1 month after the 

last dose. 

 

Fertility 

 

Fosnetupitant 

No effect on fertility has been observed in animal studies. 

 

Palonosetron  

Degeneration of seminiferous epithelium has been observed in rat study (see section 5.3). 

 

4.7 Effects on ability to drive and use machines  

 

Akynzeo has moderate influence on the ability to drive and use machines. Since it may induce 

dizziness, somnolence or fatigue, patients should be cautioned not to drive or use machines if such 

symptoms occur. 

 

4.8 Undesirable effects  

 

Summary of the safety profile 

 

Common adverse reactions reported with Akynzeo were headache (3.6%), constipation (3.0%) and 

fatigue (1.2%).  None of these events was serious.  

 

Tabulated list of adverse reactions 

 

Adverse reactions are listed below by MedDRA body system organ class and frequency. 

 

The following convention has been used for classification of frequency: 

Very common (≥1/10),  

Common (≥1/100 to <1/10),  

Uncommon (≥1/1,000 to <1/100),  

Rare (≥1/10,000 to <1/1,000),  

Very rare (<1/10,000),   

Not known (cannot be estimated from the available data). 

 

  



24 

 

Table 1: Adverse reactions  

System organ class Common  Uncommon  Rare  

Infections and 

infestations 
  Cystitis 

Blood and lymphatic 

system disorders 
 Neutropenia Leukopenia 

 Leucocytosis Lymphocytosis 

Metabolism and 

nutrition disorders 
 Decreased appetite  Hypokalaemia 

Psychiatric disorders  Insomnia Acute psychosis 

  Mood altered 

  Sleep disorder 

Nervous system 

disorders 
Headache Dizziness Hypoaesthesia 
  Somnolence 

Eye disorders   Conjunctivitis 

   Vision blurred 

Ear and labyrinth 

disorders 
 Vertigo Tinnitus 

Cardiac disorders  Atrioventricular block 
first degree 

Arrhythmia 

 Cardiomyopathy Atrioventricular block second degree 

 Conduction disorder Bundle branch block left 

 Tachycardia Bundle branch block right 

  Mitral valve incompetence 

  Myocardial ischaemia 

  Ventricular extrasystoles 

Vascular disorders  Hypertension Flushing 

  Hypotension 

Respiratory, thoracic 

and mediastinal 

disorders 

 Hiccups  

Gastrointestinal 

disorders 
Constipation Abdominal distension   Dry mouth 
 Abdominal pain Dysphagia 

 Diarrhoea Eructation 

 Dyspepsia Haemorrhoids 

 Flatulence Tongue coated 

 Nausea Vomiting 

Skin and subcutaneous 

tissue disorders 
 Alopecia Erythema 

 Urticaria Pruritus 

  Rash 

Musculoskeletal and 

connective tissue 

disorders 

  Back pain  

  Pain in extremities 

General disorders and 

administration site 

conditions 

Fatigue Asthenia Feeling hot 

  Non-cardiac chest pain 

  Product taste abnormal 

Investigations  Liver transaminases 
increased 

Blood bilirubin increased 

 Blood alkaline 
phosphatase increased 

Blood creatine phosphokinase 

increased 

 Blood creatinine 
increased 

Blood creatine Phosphokinase MB 

increased 

  



25 

 

  Electrocardiogram QT 
prolonged 

Blood urea increased 

  Electrocardiogram ST segment 
depression 

  Electrocardiogram ST-T segment 
abnormal 

  Myoglobin blood increased 

  Neutrophil count increased 

  Troponin increased 

 

Post-marketing data indicates that the adverse reactions profile is generally similar to that seen in 

clinical trials. 

 

Description of selected adverse reactions 

 

Netupitant: 

 

No common adverse reactions are attributable to netupitant, the new component of the fixed 

combination.  

 

Palonosetron: 

 

Cases of constipation with faecal impaction requiring hospitalisation have been reported in association 

with palonosetron 0.75 mg. 

 

In addition, eye swelling, dyspnoea and myalgia have been reported as adverse reactions with oral 

palonosetron but not observed during the development of netupitant and palonosetron hydrochloride 

combination. All these reactions were uncommon. 

 

Very rare cases of anaphylaxis, anaphylactic/anaphylactoid reactions and shock have been reported 

from the post-marketing use of intravenous palonosetron. The signs may include hives, itch, 

angioedema, low blood pressure, throat tightness, chest tightness, dyspnoea, loss of consciousness. 

 

Cases of serotonin syndrome have reported with palonosetron alone. The signs may include tremor, 

agitation, sweating, myoclonic movements, hypertonia and fever. 

 

The safety profile of Akynzeo 235 mg/0.25 mg powder for concentrate for solution for infusion was 

similar to that seen with Akynzeo 300 mg/0.5 mg hard capsules. 

 

Reporting of suspected adverse reactions 

 

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. 

 

4.9 Overdose  

 

Based on the experience with healthy subjects exposed to oral netupitant 600 mg in combination with 

palonosetron 1.50 mg the potential acute symptoms of overdose are headache, dizziness, constipation, 

anxiety, palpitations, euphoric mood and pain in the legs. In case of overdose, the medicinal product 

should be discontinued and general supportive treatment and monitoring should be provided. Because 

of the antiemetic activity of netupitant and palonosetron, emesis induced by a medicinal product may 

not be effective. Dialysis studies have not been performed. However, due to the large volume of 

distribution of palonosetron and netupitant, dialysis is unlikely to be an effective treatment for 

overdose. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

 

 

 

5. PHARMACOLOGICAL PROPERTIES  
 

5.1 Pharmacodynamic properties  

 

Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5-HT3) antagonists; ATC code: 

A04AA55  

 

Mechanism of action 

 

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.  

Fosnetupitant is the prodrug of netupitant and when administered intravenously is converted rapidly to 

netupitant (see section 5.2). 

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or 

no affinity for other receptors. Chemotherapeutic substances produce nausea and vomiting by 

stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin 

then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.  

Delayed emesis has been associated with the activation of tachykinin family neurokinin 1 (NK1) 

receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown 

in in vitro and in vivo studies, netupitant inhibits substance P mediated responses. 

 

Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%, 

86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after 

administration of 300 mg netupitant. 

 

Clinical efficacy and safety 

 

Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acute 

and delayed nausea and vomiting associated with highly and moderately emetogenic cancer 

chemotherapy in two separate pivotal studies.  

 

Highly Emetogenic Chemotherapy (HEC) study  

In a multicenter, randomized, parallel, double-blind, controlled clinical study of 694 patients, the 

efficacy and safety of single doses of oral netupitant in combination with oral palonosetron was 

compared with a single oral dose of palonosetron in cancer patients receiving a chemotherapy regimen 

that included cisplatin (median dose = 75 mg/m2). The efficacy of Akynzeo was assessed in 135 

patients who received a single oral dose (netupitant 300 mg and palonosetron 0.5 mg) and 136 patients 

who received oral palonosetron 0.5 mg alone.   

 

Treatment regimens for the Akynzeo and the palonosetron 0.5 mg arms are displayed in Table 2 

below. 

 

Table 2: Oral Antiemetic treatment regimen –– HEC study 

Treatment regimen  Day 1  Days 2 to 4  
Akynzeo  Akynzeo (Netupitant 300 mg + 

Palonosetron 0.5 mg)  
Dexamethasone 12 mg  

Dexamethasone 8 mg once a 

day  

Palonosetron  Palonosetron 0.5 mg  
Dexamethasone 20 mg 

Dexamethasone 8 mg twice a 

day 
 

The primary efficacy endpoint was complete response (CR) rate (defined as no emetic episodes, no 

rescue medication) within 120 hours (overall phase) after the start of the highly emetogenic 

chemotherapy administration.  

A summary of the key results from this study is shown in Table 3 below.  



27 

 

 

Table 3: Proportion of patients receiving cisplatin chemotherapy responding by treatment group 

and phase 

 Akynzeo 
Palonosetron 

0.5 mg   

 N=135 N=136  

 % % p-value 

Primary endpoint    

Complete response    

 Overall phase§ 89.6 76.5 0.004 

Major secondary endpoints    

Complete response    
 Acute phase‡ 98.5 89.7 0.007 

 Delayed phase† 90.4 80.1 0.018 

No emesis    

 Acute phase 98.5 89.7 0.007 

 Delayed phase 91.9 80.1 0.006 

 Overall phase 91.1 76.5 0.001 

No significant nausea    

 Acute phase 98.5 93.4 0.050 

 Delayed phase 90.4 80.9 0.004 

 Overall phase 89.6 79.4 0.021 
‡Acute phase: 0 to 24 hours post-cisplatin treatment. 
†Delayed phase: 25 to 120 hours post-cisplatin treatment. 
§Overall: 0 to 120 hours post-cisplatin treatment. 

 

Moderately Emetogenic Chemotherapy (MEC) study 

In a multicenter, randomized, parallel, double-blind, active-controlled, superiority study, the efficacy 

and safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron 

0.5 mg in cancer patients scheduled to receive the first cycle of an anthracycline and 

cyclophosphamide regimen for the treatment of a solid malignant tumour. At the time of the study, 

anthracycline-cyclophosphamide containing chemotherapy regimens were considered to be 

moderately emetogenic. Recent guidance has updated these regimens to highly emetogenic.  

All patients received a single oral dose of dexamethasone.  

 

Table 4: Oral Antiemetic treatment regimen – MEC study 

Treatment 

regimen  
Day 1  Days 2 to 3  

Akynzeo  Akynzeo (Netupitant 300 mg + 
Palonosetron 0.5 mg)  
Dexamethasone 12 mg  

No antiemetic treatment 

Palonosetron  Palonosetron 0.5 mg 
Dexamethasone 20 mg 

No antiemetic treatment 

 
After completion of cycle 1, patients had the option to participate in a multiple-cycle extension, 

receiving the same treatment as assigned in cycle 1.  There was no pre-specified limit of the number of 

repeat consecutive cycles for any patient. A total of 1450 patients (Akynzeo n=725; Palonosetron 

n=725) received study medication. Of these, 1438 patients (98.8%) completed cycle 1 and 



28 

 

1286 patients (88.4%) continued treatment in the multiple-cycle extension. A total of 907 patients 

(62.3%) completed the multiple-cycle extension up to a maximum of eight treatment cycles.  

A total of 724 patients (99.9%) were treated with cyclophosphamide. All patients were additionally 

treated with either doxorubicin (68.0%) or epirubicin (32.0%).  

 

The primary efficacy endpoint was the CR rate in the delayed phase, 25-120 hours after the start of the 

chemotherapy administration. 

 

A summary of the key results from this study is shown in the table 5 below.  

 

Table 5: Proportion of patients receiving anthracycline and cyclophosphamide chemotherapy 

responding by treatment group and phase – cycle 1 

 Akynzeo Palonosetron 
0.5 mg 

 

 N=724 N=725  

 % % p-value* 

Primary endpoint    

Complete response    

 Delayed phase† 76.9 69.5 0.001 

Major secondary endpoints    

Complete response    

 Acute phase‡ 88.4 85.0 0.047 

 Overall phase§ 74.3 66.6 0.001 

No emesis    

 Acute phase 90.9 87.3 0.025 

 Delayed phase 81.8 75.6 0.004 

 Overall phase 79.8 72.1 <0.001 

No significant nausea    

 Acute phase 87.3 87.9 N.S. 

 Delayed phase 76.9 71.3 0.014 

 Overall phase 74.6 69.1 0.020 

* p-value from Cochran-Mantel-Haenszel test, stratified by age class and region. 
‡Acute phase: 0 to 24 hours after anthracycline and cyclophosphamide regimen 
†Delayed phase: 25 to 120 hours after anthracycline and cyclophosphamide regimen  
§Overall: 0 to 120 hours after anthracycline and cyclophosphamide regimen 

 

Patients continued into the Multiple-Cycle extension for up to 7 additional cycles of chemotherapy. 

Antiemetic activity of Akynzeo was maintained throughout repeat cycles for those patients continuing 

in each of the multiple cycles. 

The impact of nausea and vomiting on patients’ daily lives was assessed using the Functional Living 

Index–Emesis (FLIE). The proportion of patients with Overall no impact on daily life was 6.3% higher 

(p value =0.005) in the Akynzeo group (78.5%) than in the palonosetron group (72.1%).  

 

Multiple-cycle safety study in patients receiving either Highly Emetogenic Chemotherapy or 

Moderately Emetogenic Chemotherapy  

In a separate study, a total of 413 patients undergoing initial and repeat cycles of chemotherapy 

(including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens), were randomized to receive 

either Akynzeo (n=309) or aprepitant and palonosetron (n=104). Safety and efficacy were maintained 

throughout all cycles. 

 



29 

 

Paediatric population  

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Akynzeo in one or more subsets of the paediatric population in prevention of chemotherapy-induced 

nausea and vomiting, as per PIP decision in the granted indication. See 4.2 for information on 

paediatric use. 

 

5.2 Pharmacokinetic properties  

 

Absorption 

 

Netupitant 

Absolute netupitant bioavailability data are not available in humans; based on data from two studies 

with intravenous netupitant, the bioavailability in humans is estimated to be greater than 60%.  

In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hours after 

dosing. Plasma concentrations followed a first order absorption process and reached Cmax in 

approximately 5 hours. There was a supra-proportional increase in Cmax and AUC parameters for doses 

from 10 mg to 300 mg.  

In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitant 

concentration (Cmax) was 486 ±268 ng/mL (mean ± SD) and median time to maximum concentration 

(Tmax) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. In a pooled analysis, females had a 
higher netupitant exposure compared to males; there was a 1.31-fold increase in Cmax, a 1.02 fold 

increase for AUC and a 1.36 fold increase in half-life.  

Netupitant AUC0-∞ and Cmax increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal.  

 

Fosnetupitant 

After single dose administration of Akynzeo, administered as a 30-minute infusion to healthy subjects 

and cancer patients, fosnetupitant achieved Cmax at the end of the infusion with an apparent terminal 

half-life less than 1 hour. Within 30 minutes of completion of the infusion, the concentration of 

fosnetupitant decreased to less than 1% of the Cmax. The pharmacokinetic parameters of netupitant and 

palonosetron were similar to those observed after Akynzeo 300 mg/0.5 mg hard capsules.  

 

Table 6: PK Parameters (mean and CV%) After Single Dose Administration Akynzeo Powder 

for Concentrate for Solution for Infusion in Healthy Volunteers (HVs) and Cancer Patients 

  Fosnetupitant Netupitant Palonosetron2 

Cmax (ng/mL) 
HVs 6431 (14) 841 (21) 2.1 (61) 

Patients 3478 (45) 590 (28) 0.8 (35) 

tmax1 (h) 
HVs 0.5 (0.25 – 0.5) 0.5 (0.5 – 0.4) 0.55 

Patients 0.5 (0.5 – 0.6) 0.6 (0.5 – 4) 0.6 (0.5 – 6) 

AUC (ng*h/mL) 
HVs 2938 (12) 13854 (21) 35 (33) 

Patients 1401 (46) 15588 (32) 36 (30) 

t1/2 (h) 
HVs 0.96 (57) 36.1 (19) 43 (32) 

Patients 0.75 (54) 144 (50) 58 (47) 
1 median (min-max); 2 IV bolus in HVs 

Fosnetupitant Cmax and AUC were lower in patients than in healthy subjects, although the systemic 

exposures to netupitant were comparable. 

In healthy subjects, there was a dose-proportional increase in the systemic exposure of fosnetupitant 

with the dose increase of fosnetupitant from 17.6 to 353 mg 

 

Palonosetron 

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 

97%. After single oral doses using buffered solution mean maximum palonosetron concentrations 

(Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose 

range of 3.0 to 80 mcg/kg in healthy subjects. 

In 36 healthy male and female subjects given a single oral dose of 0.5 mg palonosetron, maximum 

plasma concentration (Cmax) was 0.81 ± 1.66 ng/mL (mean ± SD) and time to maximum concentration 



30 

 

(Tmax) was 5.1 ± 1.7 hours. In female subjects (n=18), the mean AUC was 35% higher and the mean 

Cmax was 26% higher than in male subjects (n=18). In 12 cancer patients given a single oral dose of 

palonosetron 0.5 mg one hour prior to chemotherapy, Cmax was 0.93 ± 0.34 ng/mL and Tmax was 5.1 ± 

5.9 hours.  The AUC was 30% higher in cancer patients than in healthy subjects. A high fat meal did 

not affect the Cmax and AUC of oral palonosetron. 

 

Distribution 

 

Netupitant 

After a single oral 300 mg dose administration in cancer patients, netupitant disposition was 

characterised by a two compartment model with an estimated median systemic clearance of 20.5 L/h 

and a large distribution volume in the central compartment (486 L). Human plasma protein binding of 

netupitant and its two major metabolites M1 and M3 is > 99% at concentrations ranging from 10 to 

1500 ng/mL. The third major metabolite, M2, is > 97% bound to plasma proteins. 

 

Fosnetupitant 

The mean  SD volume of distribution (Vz) of fosnetupitant in healthy subjects and in patients was 

124  76 L and 296 535 L, respectively. The human plasma protein binding of fosnetupitant was 

92% at 1 micromolar and 95% at 10 micromolar. The free fraction was in the range 5 to 8%. 

 

Palonosetron  

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of 

palonosetron is bound to plasma proteins. 

 

Biotransformation 

 

Netupitant 

Three metabolites have been detected in human plasma at netupitant oral doses of 30 mg and higher 

(the desmethyl derivative, M1; the N-oxide derivative, M2; the OH-methyl derivative, M3). In vitro 

metabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are 

involved in the metabolism of netupitant. After administration of a single oral dose of 300 mg 

netupitant, mean plasma netupitant/plasma radioactivity ratios ranged from 0.13 to 0.49 over 96 h 

post-dose. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose, 

indicating that netupitant is being rapidly metabolized. Mean Cmax was approximately 11%, 47% and 

16% of the parent for M1, M2 and M3 respectively; M2 had the lowest AUC relative to the parent 

(14%) whereas M1 and M3 AUC were approximately 29% and 33% of the parent, respectively. M1, 

M2 and M3 metabolites were all shown to be pharmacologically active in an animal 

pharmacodynamic model, where M3 was most potent and M2 least active. 

 

Fosnetupitant 

Fosnetupitant is rapidly converted in vivo to netupitant by metabolic hydrolysis. In patients receiving 

Akynzeo 235 mg/0.25 mg powder concentrate for solution for infusion intravenously, netupitant 

exposure was 17-fold fosnetupitant exposure, as determined by their AUC ratio. Netupitant 

metabolites M1, M2 and M3 were rapidly generated from the released netupitant. In patients, 

metabolite M1, M2 and M3 exposures were 32%, 21% and 28% of netupitant exposure, as determined 

by their AUC ratio. The median tmax for M1, M2, and M3 were 12, 2 and 12 hours, respectively. 

 

Palonosetron  

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two 

primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each 

have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism 

studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the 

metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly 

different between poor and extensive metabolizers of CYP2D6 substrates. 

 

Elimination  



31 

 

 

Netupitant 

Following administration of a single dose of Akynzeo, netupitant is eliminated from the body in a 

multi-exponential fashion, with an apparent mean elimination half-life of 88 hours in cancer patients.  

Renal clearance is not a significant elimination route for netupitant-related entities. The mean fraction 

of an oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95% and 70.7% 

of the radioactive dose was recovered in the urine and faeces, respectively.  

Approximately half the radioactivity administered orally as [14C]-netupitant was recovered from urine 

and faeces within 120 h of dosing. Elimination via both routes was estimated to be complete by Day 

29-30 post-dose. 

 

Fosnetupitant 

After intravenous Akynzeo 235 mg/0.25 mg powder concentrate for solution for infusion 
administration, fosnetupitant plasma concentrations declined according to a biexponential profile. 

Thirty minutes after the end of the infusion, the mean plasma concentration of fosnetupitant was less 

than 1% of Cmax. 
 

Palonosetron  

Following administration of a single oral 0.75 mg dose of [14C]-palonosetron to six healthy subjects, 

85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in faeces. 

The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the 

administered dose.  In healthy subjects given palonosetron capsules 0.5 mg, the terminal elimination 

half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½ was 48 ± 

19 hours. After a single dose of approximately 0.75 mg intravenous palonosetron, the total body 

clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance 

was 66.5± 18.2 mL/h/kg. 

 

Special populations 

 

Hepatic Impairment 

 

Netupitant 

Maximum concentrations and total exposure of netupitant were increased in subjects with mild (n=8), 

moderate (n=8), and severe (n=2) hepatic impairment compared to matching healthy subjects, 

although there was pronounced individual variability in both hepatically-impaired and healthy 

subjects. Exposure to netupitant (Cmax, AUC0-t and AUC0-∞) compared to matching healthy subjects 

was 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically-

impaired subjects, respectively. As such, no dosage adjustment is necessary for patients with mild to 

moderate hepatic impairment. Limited data exist in patients with severe hepatic impairment (Child 

Pugh score ≥9). 

 

Palonosetron 

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the 

healthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetron 

is increased in the subjects with severe hepatic impairment, this does not warrant dose reduction. 

 

Renal impairment 

 

Netupitant 

No specific studies were performed to evaluate netupitant in patients with renal impairment. In the 

ADME trial, less than 5% of all netupitant-related material was excreted in urine and less than 1% of 

the netupitant dose was eliminated unchanged in the urine and therefore any accumulation of 

netupitant or metabolites after a single dose would be negligible. Furthermore, the population PK 

study showed no correlation between PK parameters of netupitant and markers of renal dysfunction. 

 

Palonosetron 



32 

 

Mild to moderate renal impairment does not significantly affect palonosetron PK parameters. Total 

systemic exposure to intravenous palonosetron increased by approximately 28% in patients with 

severe impairment relative to healthy subjects. In a population PK study, patients with a reduced 

creatinine clearance (CLCR) also had a reduced palonosetron clearance, but this reduction would not 

result in a significant change in palonosetron exposure.  

 

Therefore, Akynzeo can be administered without dosage adjustment in patients with renal impairment.  

 

Neither netupitant nor palonosetron have been evaluated in patients with end-stage renal disease. 

 

5.3 Preclinical safety data  

 

Palonosetron  

 

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the 

maximum human exposure, indicating little relevance to clinical use. Non-clinical studies indicate that 

palonosetron, only at very high concentrations, may block ion channels involved in ventricular de- and 

re-polarisation and prolong action potential duration. Degeneration of seminiferous epithelium was 

associated with palonosetron following a one month oral repeat dose toxicity study in rats.  Animal 

studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal 

development, parturition or postnatal development. Only limited data from animal studies are 

available regarding the placental transfer (see section 4.6). Palonosetron is not mutagenic. High doses 

of palonosetron (each dose causing at least 15 times the human therapeutic exposure) applied daily for 

two years caused an increased rate of liver tumours, endocrine neoplasms (in thyroid, pituitary, 

pancreas, adrenal medulla) and skin tumours in rats but not in mice. The underlying mechanisms are 

not fully understood, but because of the high doses employed and since the medicinal product is 

intended for single application in humans, these findings are not considered relevant for clinical use. 

 

Netupitant and combination with palonosetron 

 

Effects in non-clinical studies based on safety pharmacology and single and repeated dose toxicity 

were observed only at exposures considered in excess of the maximum human exposure, indicating 

little relevance to clinical use. Phospholipidosis (foamy macrophages) has been observed with the 

administration of netupitant after repeated administration in rats and dogs. The effects were reversible 

or partially reversible after the recovery period. The significance of these findings in humans is 

unknown.  

 

Non-clinical studies indicate that netupitant and its metabolites and the combination with palonosetron 

only at very high concentrations may block ion channels involved in ventricular de- and re-

polarisation and prolong action potential duration. Reproductive studies in animals with netupitant do 

not indicate direct or indirect harmful effects with respect to fertility, parturition or postnatal 

development. An increased incidence of positional foetal abnormalities of the limbs and paws, fused 

sternebrae and agenesis of accessory lung lobe were observed following daily administration of 

netupitant in rabbits at 10 mg/kg/day and higher during the period of organogenesis. In a pilot dose 

range finding study in rabbits, cleft palate, microphtalmia and aphakia were observed in four foetuses 

from one litter in the 30 mg/kg/day group. The relevance of these findings in humans is unknown. No 

data from animal studies with netupitant are available regarding placental transfer and lactation. 

Netupitant is not mutagenic.  

 

Fosnetupitant 

 

Daily intravenous administration of fosnetupitant in rats (at 3 times the human AUC for netupitant at 

the recommended single dose to be given with each cycle of chemotherapy) during the period of 

organogenesis produced delayed ossification of pubis.  No effects on embryo-fetal development were 

observed with daily administration of up to 13 mg/kg fosnetupitant in rats (2 times the human AUC 

for netupitant at the recommended single dose to be given with each cycle of chemotherapy). Due to 

the limited systemic exposure to fosnetupitant in pregnant rats, it is not possible to provide an AUC-



33 

 

based comparison of fosnetupitant exposure in rats and humans. An increase in resorptions was 

observed with daily intravenous administration of fosnetupitant at 6 mg/kg/day and higher in rabbits 

(9 times the human AUC for fosnetupitant and 0.4 times the human AUC for netupitant at the 

recommended single dose to be given with each cycle of chemotherapy) during the period of 

organogenesis. No effects were observed in rabbits at 3 mg/kg/day (5.4 times the human AUC for 

fosnetupitant and 0.4 times the human AUC for netupitant at the recommended single dose to be given 

with each cycle of chemotherapy).  Daily intravenous administration of 39 mg/kg fosnetupitant in rats 

(3 times the AUC for netupitant at the recommended single dose to be given with each cycle of 

chemotherapy) during organogenesis through lactation produced lower bodyweight in offspring at 

birth through maturation, and delayed physical development (pinna detachment, eye opening, and 

preputial separation). These effects were associated with maternal toxicity (reduced weight gain and 

food consumption). No effects occurred in offspring or dams at 13 mg/kg/day (2 times the human 

AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy). 

 

Fosnetupitant–palonosetron combination  

 

Intravenous and Intra-arterial administration in rabbits: for the clinical signs very slight to mild 

erythema were observed. No changes were noted at microscopic examination. 

Paravenous administration (a non-intended clinical route/misapplication) in rabbits: for the clinical 
signs very slight to mild erythema and very slight oedema were observed. At microscopic examination 

chronic inflammation (from mild to moderate), epidermal hyperplasia (from minimal to mild) of 

dermis were reported. 

 

 

6. PHARMACEUTICAL PARTICULARS 
 

6.1 List of excipients 

 

Mannitol 

Disodium edetate (E386)  

Sodium hydroxide (E524) (for pH adjustment) 

Hydrochloric acid (E507) (for pH adjustment) 

 

6.2 Incompatibilities 

 

Akynzeo powder for concentrate for solution for infusion is incompatible with any solutions 

containing divalent cations (e.g., Ca2+, Mg2+), including Hartman’s and lactated Ringer’s solutions.  

 

Akynzeo powder for concentrate for solution for infusion should not be infused simultaneously or 

mixed with other intravenous substances, additives or medicinal products unless compatibility has 

been demonstrated. If the same intravenous line is used for sequential infusion of several different 

medicinal products, the line should be flushed before and after infusion of Akynzeo with sodium 

chloride 9 mg/ml (0.9%) solution for injection. 

 

6.3 Shelf life 

 

4 years. 

 

Store the reconstituted and diluted solution below 25°C. 

 

The product should be diluted immediately after reconstitution. Chemical, physical and 

microbiological in-use stability after reconstitution and dilution has been demonstrated for 24 hours at 

25°C.  

 

6.4 Special precautions for storage  

 

Store in a refrigerator (2C – 8C).  



34 

 

Keep the vial in the outer carton in order to protect from light.  

For storage conditions after reconstitution of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container  

 

Single-dose 50 mL flint glass vials with 20 mm rubber stoppers and 20 mm aluminium cap seals.  

Pack of 1 vial. 

 

6.6 Special precautions for disposal and other handling 

 

Akynzeo must be reconstituted and then diluted prior to administration. 

 

Preparation of Akynzeo  

Step 1 Aseptically inject 20 mL 5% dextrose injection or sodium chloride 9 mg/ml (0.9%) 

solution for injection, into the vial. Ensure the solvent is added to the vial along the vial 

wall and not jetted in order to prevent foaming. Swirl the vial gently for 3 minutes. The 

powder should be dissolved before the solution is diluted in the infusion bag. 

Step 2 Aseptically prepare an infusion vial or bag filled with 30 mL of 5% dextrose injection, or 

sodium chloride 9 mg/ml (0.9%) solution for injection. 

Step 3 Dilution should occur immediately after reconstitution (according to Step 1). Aseptically 

withdraw the entire volume of reconstituted solution from the AKYNZEO vial and transfer 

it into the infusion vial or bag containing 30 mL of 5% dextrose injection or sodium 

chloride 9 mg/ml (0.9%) solution for injection to yield a total volume of 50 mL. 

Step 4 Gently invert the vial or bag until complete dissolution. 

Step 5 Before administration, inspect the final diluted solution for particulate matter and 

discolouration. Discard the vial or bag if particulates and/or discolouration are observed. 

 

Akynzeo must not be reconstituted or mixed with solutions for which physical and chemical 

compatibility has not been established (see section 6.2). 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements.  

 

 

7. MARKETING AUTHORISATION HOLDER  
 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown 

Mulhuddart 

Dublin 15 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  
 

EU/1/15/1001/003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
 

Date of first authorisation: 27 May 2015 

Date of latest renewal: 9 January 2020 



35 

 

 

 

10. DATE OF REVISION OF THE TEXT  
 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu.  

http://www.ema.europa.eu/
http://www.ema.europa.eu/
http://www.ema.europa.eu/


36 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



37 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown, 

Mulhuddart 

Dublin 15 

Ireland 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 

and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result 

of an important (pharmacovigilance or risk minimisation) milestone being reached.  

 

 

 

 

 

 

 

 

 

 

 

 

 

 



38 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



39 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
 



40 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Akynzeo 300 mg/0.5 mg hard capsules  

netupitant/palonosetron 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 300 milligrams of netupitant and 0.5 milligrams of palonosetron (as 

hydrochloride). 

 

 

3. LIST OF EXCIPIENTS 

 

Contains sucrose and sorbitol. See package leaflet for further information.  

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

1  hard capsule 

4x1 hard capsules  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



41 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown, Mulhuddart 

Dublin 15,  

Ireland  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1001/001 1 hard capsule 

EU/1/15/1001/002 4x1 hard capsules  

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

akynzeo  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



42 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Akynzeo 300 mg/0.5 mg hard capsules  

netupitant/palonosetron 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Helsinn  

 

 

3. EXPIRY DATE 

  

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 



43 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Akynzeo 235 mg/0.25 mg powder for concentrate for solution for infusion  

fosnetupitant/palonosetron 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each vial contains fosnetupitant chloride hydrochloride equivalent to 235 mg of fosnetupitant, which 

corresponds to 197.5 mg of netupitant, and palonosetron hydrochloride equivalent to 0.25 mg of 

palonosetron.  

 

After reconstitution and dilution, 1 ml of solution contains 4.7 mg fosnetupitant, which corresponds to 

3.95 mg of netupitant, and 0.005 mg palonosetron. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains mannitol, disodium edetate, sodium hydroxide and hydrochloric acid.  

See package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for concentrate for solution for infusion 

1 vial 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Intravenous use after reconstitution and dilution. 

Single use only. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 



44 

 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. Keep the vial in the outer carton in order to protect from light.  
After reconstitution and dilution: 24 hours below 25°C. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown 

Mulhuddart 

Dublin 15 

Ireland  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1001/003  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 



45 

 

PC: 

SN: 

NN: 

  



46 

 

PARTICULARS TO APPEAR THE IMMEDIATE PACKAGING 

VIAL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Akynzeo 235 mg/0.25 mg powder for concentrate for solution for infusion  

fosnetupitant/palonosetron 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each vial contains fosnetupitant chloride hydrochloride equivalent to 235 mg of fosnetupitant, which 

corresponds to 197.5 mg of netupitant, and palonosetron hydrochloride equivalent to 0.25 mg of 

palonosetron.  

 

After reconstitution and dilution, 1 ml of solution contains 4.7 mg fosnetupitant, which corresponds to 

3.95 mg of netupitant, and 0.005 mg palonosetron. 

 

 

3. LIST OF EXCIPIENTS 

  

Also contains mannitol, disodium edetate, sodium hydroxide and hydrochloric acid. 

See package leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for concentrate for solution for infusion 

1 vial 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

IV use after reconstitution and dilution 

Single use only. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE 

STORED OUT OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



47 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. Keep the vial in the outer carton in order to protect from light.  
After reconstitution and dilution: 24 hours below 25°C 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown 

Mulhuddart 

Dublin 15 

Ireland  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/15/1001/003     

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

  



48 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



49 

 

Package Leaflet: Information for the patient 

 

Akynzeo 300 mg/0.5 mg hard capsules 

netupitant/palonosetron 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

 

• Keep this leaflet. You may need to read it again. 

• If you have any further questions, ask your doctor, pharmacist or nurse. 

• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
even if their signs of illness are the same as yours. 

• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4.  

 

What is in this leaflet 

 

1.  What Akynzeo is and what it is used for 

2.  What you need to know before you take Akynzeo 

3.  How to take Akynzeo 

4.  Possible side effects 

5.  How to store Akynzeo 

6.  Contents of the pack and other information  

 

 

1. What Akynzeo is and what it is used for  

 

What Akynzeo is  

Akynzeo contains two medicines (‘active substances’) called: 

• netupitant 

• palonosetron. 
 

What Akynzeo is used for 

Akynzeo is used to help prevent adults with cancer feeling sick (nausea) or being sick (vomiting) 

while having cancer treatment called ‘chemotherapy’. 

 

How Akynzeo works 

Chemotherapy medicines can cause the body to release substances called serotonin and substance P. 

This stimulates the vomiting centre in the brain, making you feel or be sick.  The medicines in 

Akynzeo attach to the receptors in the nervous system through which serotonin and substance P work: 

netupitant (an NK1 receptor antagonist) blocks the receptors for substance P, and palonosetron (a 5-

HT3 receptor antagonist) blocks certain receptors for serotonin. By blocking the actions of substance P 

and serotonin in this way, the medicines help prevent the stimulation of the vomiting centre and the 

resulting sickness. 

 

 

2. What you need to know before you take Akynzeo 

 

Do not take Akynzeo if: 

 

• you are allergic to netupitant or palonosetron, or any of the other ingredients of this medicine 
(listed in section 6). If you are not sure, talk to your doctor, pharmacist or nurse before taking 

this medicine. 

• you are pregnant. 
 



50 

 

Warnings and precautions 

 

Talk to your doctor, pharmacist or nurse before taking Akynzeo if: 

• you have liver problems 

• you have a blockage in your gut, or you have had constipation in the past 

• you or one of your close relatives has ever had a heart problem called ‘QT interval 
prolongation’ 

• you have any other heart problems 

• you have been told you have an imbalance of minerals in your blood such as potassium and 
magnesium that has not been corrected. 

 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 

taking Akynzeo. 

 

Children and adolescents 

 

Akynzeo should not be taken by children and adolescents under 18 years. 

 

Other medicines and Akynzeo 

 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. 

 

In particular tell your doctor, pharmacist or nurse if you are taking any of the following medicines: 

• medicines for depression or anxiety called SSRIs (selective serotonin re-uptake inhibitors) - 
such as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram or escitalopram  

• medicines for depression or anxiety called SNRIs (serotonin noradrenaline re-uptake inhibitors) 
- such as venlafaxine or duloxetine. 

 

Also tell your doctor, pharmacist or nurse if you are taking any of the following medicines as your 

doctor may need to change the dose of these other medicines: 

• medicines that might cause abnormal heartbeat such as amiodarone, nicardipine, quinidine, 
moxifloxacin, haloperidol, chlorpromazine, quetiapine, thioridazine or domperidone 

• medicines with a narrow therapeutic range that are primarily metabolized by CYP3A4, such as 
cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, 

or quinidine 

• some chemotherapy medicines - such as docetaxel or etoposide  

• erythromycin - to treat bacterial infections 

• midazolam - a sedative used to treat anxiety 

• dexamethasone - can be used to treat feeling and being sick 

• ketoconazole - to treat Cushing's syndrome 

• rifampicin - to treat tuberculosis (TB) and other infections.  
 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 

taking Akynzeo. 

 

Pregnancy and breast-feeding  

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before taking this medicine. 

 
Do not take Akynzeo if you are pregnant or if you are a woman of childbearing potential not using 

contraception. 

 

Do not breast-feed if you are taking Akynzeo. This is because it is not known whether the medicine 

passes into breast milk. 



51 

 

 

Driving and using machines 

You may feel dizzy or tired after taking Akynzeo. If this happens, do not drive or use any tools or 

machines. 

 

Akynzeo contains sucrose, sorbitol, sodium and may contain traces of soya.  

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 

before taking this medicine. 

 

This medicine contains 7 mg of sorbitol in each hard capsule.  

 

This medicine contains less than 1 mmol sodium per (23 mg) per hard capsule, that is to say 

essentially ‘sodium-free’. 

 

It may contain traces of lecithin - which comes from soya. If you are allergic to peanut or soya, see 

your doctor straight away if you notice any signs of an allergic reaction.  The signs may include hives, 

skin rash, itching, difficulty breathing or swallowing, swollen mouth, face, lips, tongue or throat and 

sometimes a drop in blood pressure. 

 

 

3. How to take Akynzeo 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor, pharmacist or 

nurse if you are not sure.  

 

How much to take 

• The recommended dose is one capsule (each capsule contains 300 mg of netupitant and 0.5 mg 
of palonosetron). 

• Take the capsule about 1 hour before you start your chemotherapy cycle.  

• You can take Akynzeo with or without food. 
 

Akynzeo is taken before the chemotherapy to prevent sickness and feelings of sickness from 

developing. Do not take Akynzeo in the days after you have chemotherapy - unless you are about to 

have another chemotherapy cycle. 

 

If you take more Akynzeo than you should 

 

The usual dose is 1 capsule. If you think you may have taken more than you should, tell your doctor 

straight away. The symptoms of overdose may include headache, dizziness, constipation, anxiety, 

palpitations, euphoric mood and pain in the legs.  

 

If you forget to take Akynzeo 

 

If you think you have forgotten to take your dose, tell your doctor straight away.   

 

If you stop taking Akynzeo  

 

Akynzeo is taken to help prevent you feeling and being sick when you are having chemotherapy. If 

you do not want to take Akynzeo, discuss this with your doctor. If you decide not to take Akynzeo (or 

another similar medicine), your chemotherapy is likely to make you feel sick and be sick. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 



52 

 

 

Serious side effects  

Stop taking Akynzeo and tell your doctor straight away if you notice the following serious side effect - 

you may need urgent medical treatment: 

 

Very rare: may affect up to 1 in 10,000 people 

• severe allergic reaction signs include hives, skin rash, itching, difficulty breathing or swallowing, 
swollen mouth, face, lips, tongue or throat and sometimes a drop in blood pressure. 

 

Other side effects 

Tell your doctor, pharmacist or nurse if you notice any of the following side effects: 

 

Common: (may affect up to 1 in 10 people) 

• headache 

• constipation 

• feeling tired. 
 

Uncommon: (may affect up to 1 in 100 people) 

• hair loss 

• lack of energy (feeling weak) 

• decreased appetite 

• high blood pressure 

• raised, itchy rash on the skin (hives) 

• problems with the muscles in your heart (cardiomyopathy) 

• spinning sensation (vertigo), feeling dizzy or trouble sleeping (insomnia) 

• stomach problems including stomach discomfort, feeling bloated, nausea, pain, indigestion, 
hiccups, wind or diarrhoea 

• high levels of certain enzymes, including blood alkaline phosphatase and liver transaminases 
(shown in blood tests) 

• high levels of creatinine - which measures kidney function (shown in blood tests) 

• ECG (electrocardiogram) problems (called ‘QT and PR interval prolongation’, ‘conduction 
disorder’, ‘tachycardia’ and ‘atrioventricular block first degree’) 

• low levels of ‘neutrophils’ - a kind of white blood cell which fight infections (shown in blood 
tests) 

• high level of white blood cells (shown in blood tests). 
 

Rare: (may affect up to 1 in 1,000 people) 

• back pain, joint pain 

• feeling hot, reddening of the face or other areas of the skin (feeling flushed) 

• itchy skin rash 

• feeling drowsy 

• sleep problems 

• ring in the ear 

• vomiting 

• low blood pressure 

• chest pain (not related to the heart) 

• numbness, blurred vision 

• sudden nervous breakdown, change in mood 

• infection and inflammation in the bladder (cystitis) 

• haemorrhoids 

• conjunctivitis (a type of eye inflammation) 

• low level of potassium (shown in blood tests) 

• modifications (or disturbances) in heart rhythm  

• heart valve disorder (mitral valve incompetence) 



53 

 

• coating of the tongue, difficulty swallowing, dry mouth, belching, abnormal taste after medicine 
intake 

• decreased blood flow to the heart muscle (myocardial ischemia) 

• high levels of creatine phosphokinase/ creatine phosphokinase MB - which indicates sudden 
decreased blood flow to the heart muscle (shown in blood tests) 

• high levels of troponin - which indicates heart muscle dysfunction (shown in blood tests) 

• high levels of the pigment bilirubin - which indicates liver dysfunction (shown in blood tests) 

• high levels of myoglobin – which indicates muscle injury (shown in blood tests) 

• high levels of blood urea – which indicates kidney dysfunction (shown in blood tests) 

• high level of ‘lymphocytes’– type of white blood cell which help the body fight disease (shown 
in blood tests) 

• low level of white blood cells (shown in blood tests) 

• ECG (electrocardiogram) problems (called ‘ST segment depression’, ‘ST-T segment abnormal’ 
‘bundle branch block right/left’, and ‘atrioventricular block second degree’) 

 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V By reporting side effects, you can help provide more information on the 

safety of this medicine.  

 

 

5. How to store Akynzeo 

 

• Keep this medicine out of the sight and reach of children.  

• Do not use this medicine after the expiry date which is stated on the carton and blister after 
‘EXP’. The expiry date refers to the last day of that month. 

• This medicine does not require any special storage conditions. 

• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 
how to throw away medicines you no longer use. These measures will help protect the 

environment. 

 

 

6. Contents of the pack and other information 

 

What Akynzeo contains 

• The active substances are palonosetron and netupitant. Each hard capsule contains three tablets 
(300 mg of netupitant), and one soft capsule (palonosetron hydrochloride equivalent to 

0.5 milligrams of palonosetron). 

• The other ingredients are microcrystalline cellulose (E460), sucrose lauric acid esters, povidone 
K-30, croscarmellose sodium, colloidal hydrated silica, sodium stearyl fumarate, magnesium 

stearate, glycerol monocaprylocaproate (type I), glycerol, polyglyceryl oleate, purified water, 

butylhydroxyanisole (E320), gelatin, sorbitol, 1,4 sorbitan, titanium dioxide (E171), shellac 

glaze (partially esterified), yellow, red and black iron oxide (E172), propylene glycol (E1520).  

 

This medicine contains sucrose, sorbitol, sodium and may contain soya - see section 2 for more 

information. 

 

What Akynzeo looks like and contents of the pack 

 

The hard capsules are opaque with a white body and a caramel cap with ‘HE1’ printed on the body. 

Pack size containing 1 capsule in an aluminium blister or 4 x 1 hard capsules in aluminium perforated 

unit dose blisters. Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder and Manufacturer: 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


54 

 

 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown 

Mulhuddart 

Dublin 15 

Ireland 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Vifor Pharma 

Tél/Tel: +32(0)32 182070 

 

Lietuva 

PharmaSwiss 

Tel: +370 5 279 07 62 

 

България 

Angelini Pharma Bulgaria EOOD 

Teл.: +359 2 975 13 95 

 

Luxembourg/Luxemburg 

Vifor Pharma 

Tél/Tel: +32(0)32 182070 

Česká republika 

Angelini Pharma Česká republika s.r.o. 

Tel: (+420) 546 123 111 

Magyarország 

Angelini Pharma Magyarország Kft 

Tel.: + 36 1 336 1614 

Danmark 

Swedish Orphan Biovitrum A/S 

Tlf: + 45 32 96 68 69 

 

Malta 

Helsinn Birex Pharmaceuticals Ltd.  

Tel.: + 353 1 822 5404 

Deutschland 

RIEMSER Pharma GmbH 

Tel: + 49 30 338427-0 

 

Nederland 

Vifor Pharma 

Tel: +31(0)88 8484300 

 

Eesti 

PharmaSwiss 

Tel: +372 6827 400 

 

Norge 

Swedish Orphan Biovitrum AS 

Tlf: +47 66 82 34 00 

 

Ελλάδα 

Galenica A.E. 

Τηλ: +30 210 52 81 700 

 

Österreich 

Angelini Pharma Österreich GmbH 

Tel: +43-5-9-606-0 

 

España 

Vifor Pharma España, S.L. 

Tel: +34 902 121 111 

 

Polska 

Angelini Pharma Polska Sp. z o.o. 

Tel: +48 22 70 28 200 

France 

Vifor France 

Tél: +33 (0)1 41 06 58 90 

 

Portugal 

OM Pharma 

Tel: +351 21 470 85 00 

 

Hrvatska 

PharmaSwiss 

Tel: +385 1 6311 833 

România 

Angelini Pharmaceuticals Romania Srl 

Tel: +40 21 331 67 67 

Ireland 

Chugai Pharma France 

Tel: +33 1 79 36 36 18 

Slovenija 

PharmaSwiss 

Tel: +386 1 2364 700 

Ísland 

Swedish Orphan Biovitrum A/S 

Tlf: + 45 32 96 68 69 

Slovenská republika 

Angelini Pharma Slovenská republika s.r.o. 

Tel: +421 2 5920 7320 



55 

 

 

Italia 

Italfarmaco 

Tel: + 39 02 64431 

 

Suomi/Finland 

Oy Swedish Orphan Biovitrum Ab 

Puh./Tel: +358 201 558 840 

 

Κύπρος 

Galenica A.E. 

Τηλ: +30 210 52 81 700 

 

Sverige 

Swedish Orphan Biovitrum AB (publ) 

Tel: +46 8 697 20 00 

 

Latvija 

PharmaSwiss 

Tel: +371 6750 2185 

United Kingdom 

Chugai 

Tel: +44 1748 827 276 

 

 

This leaflet was last revised in  

 

Detailed information on this medicine is available on the European Medicines Agency website 

http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/
http://www.ema.europa.eu/


56 

 

 

 

Package Leaflet: Information for the patient 

 

Akynzeo 235 mg/0.25 mg powder for concentrate for solution for infusion 

fosnetupitant/palonosetron 

 

Read all of this leaflet carefully before you are given this medicine because it contains important 

information for you. 

 

• Keep this leaflet. You may need to read it again. 

• If you have any further questions, ask your doctor, pharmacist or nurse. 

• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4.  

 

What is in this leaflet 

 

1.  What Akynzeo is and what it is used for 

2.  What you need to know before you are given Akynzeo 

3.  How Akynzeo is given 

4.  Possible side effects 

5.  How Akynzeo is stored 

6.  Contents of the pack and other information  

 

 

1. What Akynzeo is and what it is used for  

 

What Akynzeo is  

Akynzeo contains two medicines (‘active substances’) called: 

• fosnetupitant 

• palonosetron. 
 

What Akynzeo is used for 

Akynzeo is used to help prevent adults with cancer feeling sick (nausea) or being sick (vomiting) 

while having cancer treatment called ‘chemotherapy’. 

 

How Akynzeo works 

Chemotherapy medicines can cause the body to release substances called serotonin and substance P. 

This stimulates the vomiting centre in the brain, making you feel or be sick.  The medicines in 

Akynzeo attach to the receptors in the nervous system through which serotonin and substance P work: 

fosnetupitant which is converted to netupitant (an NK1 receptor antagonist) in your body blocks the 

receptors for substance P, and palonosetron (a 5-HT3 receptor antagonist) blocks certain receptors for 

serotonin. By blocking the actions of substance P and serotonin in this way, the medicines help 

prevent the stimulation of the vomiting centre and the resulting sickness. 

 

 

2. What you need to know before you are given Akynzeo 

 

You should not be given Akynzeo if: 

 

• you are allergic to fosnetupitant, netupitant or palonosetron, or any of the other ingredients of 
this medicine (listed in section 6). If you are not sure, talk to your doctor, pharmacist or nurse 

before you are given this medicine. 

• you are pregnant. 
 

Warnings and precautions 

 



57 

 

Talk to your doctor, pharmacist or nurse before being given Akynzeo if: 

• you have liver problems 

• you have a blockage in your gut or you have had constipation in the past 

• you or one of your close relatives has ever had a heart problem called ‘QT interval 
prolongation’ 

• you have any other heart problems 

• you have been told you have an imbalance of minerals in your blood such as potassium and 
magnesium that has not been corrected. 

 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 

being given Akynzeo. 

 

Children and adolescents 

 

Akynzeo should not be given to children and adolescents under 18 years. 

 

Other medicines and Akynzeo 

 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. 

 

In particular tell your doctor, pharmacist or nurse if you are taking any of the following medicines: 

• medicines for depression or anxiety called SSRIs (selective serotonin re-uptake inhibitors) - 
such as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram or escitalopram  

• medicines for depression or anxiety called SNRIs (serotonin noradrenaline re-uptake inhibitors) 
- such as venlafaxine or duloxetine. 

 

Also tell your doctor, pharmacist or nurse if you are taking any of the following medicines as your 

doctor may need to change the dose of these other medicines: 

• medicines that might cause abnormal heartbeat such as amiodarone, nicardipine, quinidine, 
moxifloxacin, haloperidol, chlorpromazine, quetiapine, thioridazine or domperidone 

• medicines with a narrow therapeutic range that are primarily metabolized by CYP3A4, such as 
cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, 

or quinidine 
• some chemotherapy medicines - such as docetaxel or etoposide  

• erythromycin - to treat bacterial infections 

• midazolam - a sedative used to treat anxiety 

• dexamethasone - can be used to treat feeling and being sick 

• ketoconazole - to treat Cushing's syndrome 

• rifampicin - to treat tuberculosis (TB) and other infections.  
 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 

being given Akynzeo. 

 

Pregnancy and breast-feeding  

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before being given this medicine. 

 
You should not be given Akynzeo if you are pregnant or if you are a woman of childbearing potential 

not using contraception. 

 

Do not breast-feed if you are being given Akynzeo. This is because it is not known whether the 

medicine passes into breast milk. 

 



58 

 

Driving and using machines 

 

You may feel dizzy or tired after being given Akynzeo. If this happens, do not drive or use any tools 

or machines. 

 

This medicine contains 24.8 mg sodium (main component of cooking/table salt) in each vial. This is 

equivalent to 1.24% of the recommended maximum daily dietary intake of sodium for an adult. 

If reconstituted and diluted with sodium chloride 9 mg/ml (0.9%) solution for injection, the final 

solution contains approximately 202 mg of sodium per dose. This is equivalent to 10.1% of the 

recommended maximum daily dietary intake of sodium for an adult. 

 

 

3. How Akynzeo is given 

 

The recommended dose of Akynzeo is one vial (each vial contains 235 mg of fosnetupitant and 

0.25 mg of palonosetron) on Day 1 of your chemotherapy. 

• The powder is reconstituted and diluted before use. 

• Akynzeo is given to you by a doctor or nurse 

• Akynzeo is given as a drip into a vein (intravenous infusion) about 30 minutes before you start 
your chemotherapy treatment. 

 

Your doctor will ask you to take other medicines including a corticosteroid (such as dexamethasone) 

to prevent you feeling and being sick. Check with your doctor or nurse if you are not sure.  

 

If you stop being given Akynzeo  

 

Akynzeo is given to help prevent you feeling and being sick when you are having chemotherapy. If 

you do not want to be given Akynzeo, discuss this with your doctor. If you decide not to be given 

Akynzeo (or another similar medicine), your chemotherapy is likely to make you feel and be sick. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Serious side effects  

Stop being given Akynzeo and tell your doctor straight away if you notice the following serious side 

effect - you may need urgent medical treatment: 

 

Very rare (may affect up to 1 in 10,000 people) 

• severe allergic reaction – signs include hives, skin rash, itching, difficulty breathing or 
swallowing, swollen mouth, face, lips, tongue or throat and sometimes a drop in blood pressure. 

 

Other side effects 

Tell your doctor, pharmacist or nurse if you notice any of the following side effects: 

 

Common (may affect up to 1 in 10 people) 

• headache 

• constipation 

• feeling tired. 
 

Uncommon (may affect up to 1 in 100 people) 

• hair loss 

• lack of energy (feeling weak) 



59 

 

• decreased appetite 

• high blood pressure 

• raised, itchy rash on the skin (hives) 

• problems with the muscles in your heart (cardiomyopathy) 

• spinning sensation (vertigo), feeling dizzy or trouble sleeping (insomnia) 

• stomach problems including stomach discomfort, feeling bloated, nausea, pain, indigestion, 
hiccups, wind or diarrhoea 

• high levels of certain enzymes, including blood alkaline phosphatase and liver transaminases 
(shown in blood tests) 

• high levels of creatinine - which measures kidney function (shown in blood tests) 

• ECG (electrocardiogram) problems (called ‘QT and PR interval prolongation’, ‘conduction 
disorder’, ‘tachycardia’ and ‘atrioventricular block first degree’) 

• low levels of ‘neutrophils’ - a kind of white blood cell which fight infections (shown in blood 
tests) 

• high level of white blood cells (shown in blood tests). 
 

Rare (may affect up to 1 in 1,000 people) 

• back pain, joint pain 

• feeling hot, reddening of the face or other areas of the skin (feeling flushed) 

• itchy skin rash 

• feeling drowsy 

• sleep problems 

• ring in the ear 

• vomiting 

• low blood pressure 

• chest pain (not related to the heart) 

• numbness, blurred vision 

• sudden nervous breakdown, change in mood 

• infection and inflammation in the bladder (cystitis) 

• haemorrhoids 

• conjunctivitis (a type of eye inflammation) 

• low level of potassium (shown in blood tests) 

• modifications (or disturbances) in heart rhythm  

• heart valve disorder (mitral valve incompetence) 

• coating of the tongue, difficulty swallowing, dry mouth, belching, abnormal taste after medicine 
intake 

• decreased blood flow to the heart muscle (myocardial ischemia) 

• high levels of creatine phosphokinase//creatine phosphokinase MB - which indicates sudden 
decreased blood flow to the heart muscle (shown in blood tests) 

• high levels of troponin - which indicates heart muscle dysfunction (shown in blood tests) 

• high levels of the pigment bilirubin - which indicates liver dysfunction (shown in blood tests) 

• high levels of myoglobin – which indicates muscle injury (shown in blood tests) 

• high levels of blood urea – which indicates kidney dysfunction (shown in blood tests) 

• high level of ‘lymphocytes’– type of white blood cell which help the body fight disease (shown 
in blood tests) 

• low level of white blood cells (shown in blood tests) 

• ECG (electrocardiogram) problems (called ‘ST segment depression’, ‘ST-T segment 
abnormal’ ‘bundle branch block right/left’, and ‘atrioventricular block second degree’) 

 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects, you can help provide more information on the 

safety of this medicine.  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


60 

 

 

 

5. How to store Akynzeo 

 

• Keep this medicine out of the sight and reach of children.  

• Do not use this medicine after the expiry date which is stated on the carton and vial after ‘EXP’. 
The expiry date refers to the last day of that month. 

• Store in a refrigerator (2C – 8C). 

• Keep the vial in the outer carton in order to protect from light. 

• The total time from reconstitution to the start of the infusion should not exceed 24 hours. Store 
the reconstituted solution and the final diluted solution below 25°C. 

• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 
how to throw away medicines you no longer use. These measures will help protect the 

environment. 

 

 

6. Contents of the pack and other information 

 

What Akynzeo contains 

• The active substances are fosnetupitant and palonosetron. Each vial contains 235 mg of 
fosnetupitant and 0.25 milligrams of palonosetron. 

• The other ingredients are mannitol, disodium edetate (E386), sodium hydroxide (E524), 
hydrochloric acid diluted (E507) (for pH adjustment). 

 

What Akynzeo looks like and contents of the pack 

 

Akynzeo powder for concentrate for solution for infusion is a sterile, white to off-white lyophilized 

powder and is supplied in a pack of one Type I glass vial with chlorobutyl siliconised rubber stopper 

and aluminium cap. Each vial contains one dose.  

 

Pack of 1 vial. 

 

Marketing Authorisation Holder and Manufacturer: 

 

Helsinn Birex Pharmaceuticals Ltd. 

Damastown 

Mulhuddart 

Dublin 15 

Ireland 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Vifor Pharma 

Tél/Tel: +32(0)32 182070 

 

Lietuva 

PharmaSwiss 

Tel: +370 5 279 07 62 

 

България 

Angelini Pharma Bulgaria EOOD 

Teл.: +359 2 975 13 95 

 

Luxembourg/Luxemburg 

Vifor Pharma 

Tél/Tel: +32(0)32 182070 

Česká republika 

Angelini Pharma Česká republika s.r.o. 

Tel: (+420) 546 123 111 

Magyarország 

Angelini Pharma Magyarország Kft 

Tel.: + 36 1 336 1614 

Danmark Malta 



61 

 

Swedish Orphan Biovitrum A/S 

Tlf: + 45 32 96 68 69 

 

Helsinn Birex Pharmaceuticals Ltd.  

Tel.: + 353 1 822 5404 

Deutschland 

RIEMSER Pharma GmbH 

Tel: + 49 30 338427-0 

 

Nederland 

Vifor Pharma 

Tel: +31(0)88 8484300 

 

Eesti 

PharmaSwiss 

Tel: +372 6827 400 

 

Norge 

Swedish Orphan Biovitrum AS 

Tlf: +47 66 82 34 00 

 

Ελλάδα 

Galenica A.E. 

Τηλ: +30 210 52 81 700 

 

Österreich 

Angelini Pharma Österreich GmbH 

Tel: +43-5-9-606-0 

 

España 

Vifor Pharma España, S.L. 

Tel: +34 902 121 111 

 

Polska 

Angelini Pharma Polska Sp. z o.o. 

Tel: +48 22 70 28 200 

France 

Vifor France 

Tél: +33 (0)1 41 06 58 90 

 

Portugal 

OM Pharma 

Tel: +351 21 470 85 00 

 

Hrvatska 

PharmaSwiss 

Tel: +385 1 6311 833 

România 

Angelini Pharmaceuticals Romania Srl 

Tel: +40 21 331 67 67 

Ireland 

Chugai Pharma France 

Tel: +33 1 79 36 36 18 

Slovenija 

PharmaSwiss 

Tel: +386 1 2364 700 

Ísland 

Swedish Orphan Biovitrum A/S 

Tlf: + 45 32 96 68 69 

 

Slovenská republika 

Angelini Pharma Slovenská republika s.r.o. 

Tel: +421 2 5920 7320 

Italia 

Italfarmaco 

Tel: + 39 02 64431 

 

Suomi/Finland 

Oy Swedish Orphan Biovitrum Ab 

Puh./Tel: +358 201 558 840 

 

Κύπρος 

Galenica A.E. 

Τηλ: +30 210 52 81 700 

 

Sverige 

Swedish Orphan Biovitrum AB (publ) 

Tel: +46 8 697 20 00 

 

Latvija 

PharmaSwiss 

Tel: +371 6750 2185 

United Kingdom 

Chugai 

Tel: +44 1748 827 276 

 

 

 

This leaflet was last revised in  

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency website 

http://www.ema.europa.eu.  

 

 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


62 

 

The following information is intended for medical or healthcare professionals only: 

Instructions of how to reconstitute and dilute AKYNZEO 235 mg/0.25 mg 

 Preparation of Akynzeo  

Step 1 Aseptically inject 20 mL 5% dextrose injection or sodium chloride 9 mg/ml (0.9%) 

solution for injection, into the vial. Ensure the solvent is added to the vial along the vial 

wall and not jetted in order to prevent foaming. Swirl the vial gently for 3 minutes. The 

powder should be dissolved before the solution is diluted in the infusion bag. 

Step 2 Aseptically prepare an infusion vial or bag filled with 30 mL of 5% dextrose injection, or 

sodium chloride 9 mg/ml (0.9%) solution for injection. 

Step 3 Dilution should occur immediately after reconstitution (according to Step 1). Aseptically 

withdraw the entire volume of reconstituted solution from the AKYNZEO vial and transfer 

it into the infusion vial or bag containing 30 mL of 5% dextrose injection or sodium 

chloride 9 mg/ml (0.9%) solution for injection to yield a total volume of 50 mL. 

Step 4 Gently invert the vial or bag until complete dissolution. 

Step 5 Before administration, inspect the final diluted solution for particulate matter and 

discolouration. Discard the vial or bag if particulates and/or discolouration are observed. 

 

The reconstituted and diluted final solution is stable for 24 hours at 25°C. 

Parenteral medicines should be inspected visually for particulate matter and discoloration before 

administration whenever solution and container permit. 

The appearance of the reconstituted solution is the same as the appearance of the diluent. 

Discard any remaining solution and waste material. Any unused medicinal product or waste material 

should be disposed of in accordance with local requirements. 

The medicinal product must not be reconstituted or mixed with solutions for which physical and 

chemical compatibility has not been established (see Summary of Product Characteristic (SmPC), 

section 6.2). 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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years. other medicines and akynzeo tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. in particular tell your doctor, pharmacist or nurse if you are taking any of the following medicines: medicines for depression or anxiety called ssris (selective serotonin re-uptake inhibitors) - such as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram or escitalopram medicines for depression or anxiety called snris (serotonin noradrenaline re-uptake inhibitors) - such as venlafaxine or duloxetine. also tell your doctor, pharmacist or nurse if you are taking any of the following medicines as your doctor may need to change the dose of these other medicines: medicines that might cause abnormal heartbeat such as amiodarone, nicardipine, quinidine, moxifloxacin, haloperidol, chlorpromazine, quetiapine, thioridazine or domperidone medicines with a narrow therapeutic range that are primarily metabolized by cyp3a4, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, or quinidine some chemotherapy medicines - such as docetaxel or etoposide erythromycin - to treat bacterial infections midazolam - a sedative used to treat anxiety dexamethasone - can be used to treat feeling and being sick ketoconazole - to treat cushing's syndrome rifampicin - to treat tuberculosis (tb) and other infections. if any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking akynzeo. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. do not take akynzeo if you are pregnant or if you are a woman of childbearing potential not using contraception. do not breast-feed if you are taking akynzeo. this is because it is not known whether the medicine passes into breast milk. driving and using machines you may feel dizzy or tired after taking akynzeo. if this happens, do not drive or use any tools or machines. akynzeo contains sucrose, sorbitol, sodium and may contain traces of soya. if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. this medicine contains 7 mg of sorbitol in each hard capsule. this medicine contains less than 1 mmol sodium per (23 mg) per hard capsule, that is to say essentially 'sodium-free'. it may contain traces of lecithin - which comes from soya. if you are allergic to peanut or soya, see your doctor straight away if you notice any signs of an allergic reaction. the signs may include hives, skin rash, itching, difficulty breathing or swallowing, swollen mouth, face, lips, tongue or throat and sometimes a drop in blood pressure.", 'Entity_Recognition': [{'Text': 'akynzeo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 12, 'EndOffset': 19, 'Score': 0.9362275004386902, 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{'Title': '3. how to take akynzeo', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor, pharmacist or nurse if you are not sure. how much to take the recommended dose is one capsule (each capsule contains 300 mg of netupitant and 0.5 mg of palonosetron). take the capsule about 1 hour before you start your chemotherapy cycle. you can take akynzeo with or without food. akynzeo is taken before the chemotherapy to prevent sickness and feelings of sickness from developing. do not take akynzeo in the days after you have chemotherapy - unless you are about to have another chemotherapy cycle. if you take more akynzeo than you should the usual dose is 1 capsule. if you think you may have taken more than you should, tell your doctor straight away. the symptoms of overdose may include headache, dizziness, constipation, anxiety, palpitations, euphoric mood and pain in the legs. if you forget to take akynzeo if you think you have forgotten to take your dose, tell your doctor straight away. if you stop taking akynzeo akynzeo is taken to help prevent you feeling and being sick when you are having chemotherapy. if you do not want to take akynzeo, discuss this with your doctor. if you decide not to take akynzeo (or another similar medicine), your chemotherapy is likely to make you feel sick and be sick. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'akynzeo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '300', 'Type': 'NUMBER', 'BeginOffset': 204, 'EndOffset': 207}, {'Id': 4, 'BeginOffset': 214, 'EndOffset': 224, 'Score': 0.866145670413971, 'Text': 'netupitant', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.957254946231842, 'RelationshipScore': 0.9999983310699463, 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{'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects stop taking akynzeo and tell your doctor straight away if you notice the following serious side effect - you may need urgent medical treatment: very rare: may affect up to 1 in 10,000 people severe allergic reaction signs include hives, skin rash, itching, difficulty breathing or swallowing, swollen mouth, face, lips, tongue or throat and sometimes a drop in blood pressure. other side effects tell your doctor, pharmacist or nurse if you notice any of the following side effects: common: (may affect up to 1 in 10 people) headache constipation feeling tired. uncommon: (may affect up to 1 in 100 people) hair loss lack of energy (feeling weak) decreased appetite high blood pressure raised, itchy rash on the skin (hives) problems with the muscles in your heart (cardiomyopathy) spinning sensation (vertigo), feeling dizzy or trouble sleeping (insomnia) stomach problems including stomach discomfort, feeling bloated, nausea, pain, indigestion, hiccups, wind or diarrhoea high levels of certain enzymes, including blood alkaline phosphatase and liver transaminases (shown in blood tests) high levels of creatinine - which measures kidney function (shown in blood tests) ecg (electrocardiogram) problems (called 'qt and pr interval prolongation', 'conduction disorder', 'tachycardia' and 'atrioventricular block first degree') low levels of 'neutrophils' - a kind of white blood cell which fight infections (shown in blood tests) high level of white blood cells (shown in blood tests). rare: (may affect up to 1 in 1,000 people) back pain, joint pain feeling hot, reddening of the face or other areas of the skin (feeling flushed) itchy skin rash feeling drowsy sleep problems ring in the ear vomiting low blood pressure chest pain (not related to the heart) numbness, blurred vision sudden nervous breakdown, change in mood infection and inflammation in the bladder (cystitis) haemorrhoids conjunctivitis (a type of eye inflammation) low level of potassium (shown in blood tests) modifications (or disturbances) in heart rhythm heart valve disorder (mitral valve incompetence) 53 coating of the tongue, difficulty swallowing, dry mouth, belching, abnormal taste after medicine intake decreased blood flow to the heart muscle (myocardial ischemia) high levels of creatine phosphokinase/ creatine phosphokinase mb - which indicates sudden decreased blood flow to the heart muscle (shown in blood tests) high levels of troponin - which indicates heart muscle dysfunction (shown in blood tests) high levels of the pigment bilirubin - which indicates liver dysfunction (shown in blood tests) high levels of myoglobin which indicates muscle injury (shown in blood tests) high levels of blood urea which indicates kidney dysfunction (shown in blood tests) high level of 'lymphocytes' type of white blood cell which help the body fight disease (shown in blood tests) low level of white blood cells (shown in blood tests) ecg (electrocardiogram) problems (called 'st segment depression', 'st-t segment abnormal' 'bundle branch block right/left', and 'atrioventricular block second degree') reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v by reporting side effects, you can help provide more information on the safety of this medicine.", 'Entity_Recognition': [{'Text': 'akynzeo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 23, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9670403599739075, 'Text': 'side effects', 'Category': 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{'Title': '5. how to store akynzeo', 'Section_Content': " keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blister after 'exp'. the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.", 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': "what akynzeo contains the active substances are palonosetron and netupitant. each hard capsule contains three tablets (300 mg of netupitant), and one soft capsule (palonosetron hydrochloride equivalent to 0.5 milligrams of palonosetron). the other ingredients are microcrystalline cellulose (e460), sucrose lauric acid esters, povidone k-30, croscarmellose sodium, colloidal hydrated silica, sodium stearyl fumarate, magnesium stearate, glycerol monocaprylocaproate (type i), glycerol, polyglyceryl oleate, purified water, butylhydroxyanisole (e320), gelatin, sorbitol, 1,4 sorbitan, titanium dioxide (e171), shellac glaze (partially esterified), yellow, red and black iron oxide (e172), propylene glycol (e1520). this medicine contains sucrose, sorbitol, sodium and may contain soya - see section 2 for more information. what akynzeo looks like and contents of the pack the hard capsules are opaque with a white body and a caramel cap with 'he1' printed on the body. pack size containing 1 capsule in an aluminium blister or 4 x 1 hard capsules in aluminium perforated unit dose blisters. not all pack sizes may be marketed.", 'Entity_Recognition': [{'Text': 'akynzeo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 12, 'Score': 0.32915395498275757, 'Text': 'akynzeo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 48, 'EndOffset': 60, 'Score': 0.9917819499969482, 'Text': 'palonosetron', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9296382069587708, 'RelationshipScore': 0.9452845454216003, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 104, 'EndOffset': 117, 'Text': 'three tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8069469928741455, 'RelationshipScore': 0.9081029295921326, 'RelationshipType': 'DOSAGE', 'Id': 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