Alpivab - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Alpivab 200 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 20 mL vial of concentrate contains 200 mg peramivir.

• 1 mL concentrate for solution for infusion contains 10 mg peramivir (anhydrous base).

Excipients with known effect

Each mL of concentrate contains 0.154 millimole (mmol) sodium, which is 3.54 mg of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless, solution.

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4. CLINICAL PARTICULARS4.1 Therapeutic indications

Alpivab is indicated for the treatment of uncomplicated influenza in adults and children from the age of 2 years (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Posology

Alpivab should be administered as a single intravenous dose within 48 hours of the onset of symptoms of influenza.

The recommended single intravenous dose of peramivir depends on age and body weight as shown in

Table 1.

Table 1: Peramivir dose based on age and body weight _____________­_________________________

Age and body weight	Recommended single dose
Children aged from 2 years and <50 kg	12 mg/kg
Children aged from 2 years and >50 kg body weight	600 mg
Adults and adolescents (13 years and older)	600 mg

Elderly

No dose adjustment is required based on age (see sections 4.4 and 5.2).

Renal impairment

The dose should be reduced for adults and adolescents (13 years and older) with absolute glomerular filtration rate (GFR) below 50 mL/min as shown in Table 2 (see sections 4.4 and 5.2).

Table 2: Peramivir dose for adults and adolescents (from 13 years and 50 kg) based on absolute

GFR

Absolute Glomerular Filtration Rate (GFR)*	Recommended single dose
>50	600 mg
30 to 49	300 mg
10 to 29	200 mg

*Absolute GFR not adjusted for body surface area

In adults and adolescents (from 13 years and 50 kg) with chronic renal impairment maintained on haemodialysis, peramivir should be administered after dialysis at a dose adjusted for renal function (Table 2).

There are insufficient clinical data available in children and adolescents aged less than 13 years or with body weight less than 50 kg with renal impairment to be able to make any dosing recommendation.

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

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Paediatric population

The safety and efficacy of peramivir in children aged under 2 years has not yet been established. No data are available.

Method of administration

Alpivab is administered via intravenous infusion for 15 to 30 minutes.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Serious hypersensitivity reactions

Anaphylactic reactions and serious skin reactions (including erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported with peramivir (see section 4.8). If any hypersensitivity reaction occurs during infusion of peramivir, the infusion must be stopped immediately and appropriate management should be instituted.

Neuropsychiatrie events

Delirium, hallucinations and abnormal behaviour have been reported in patients with influenza who were receiving peramivir. These events were reported primarily among paediatric patients and often had an abrupt onset and rapid resolution. The contribution of peramivir to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behaviour.

Reduced renal function

Acute renal failure, renal failure, pre-renal failure, renal disorder, anuria, nephritis, and increased blood creatinine have been reported in patients with influenza who were receiving peramivir. Most of the cases occurred in elderly patients with comorbidities and multiple concomitant medicinal products. The contribution of peramivir to these events has not been established. Patients with influenza and already existing diseases should be closely monitored for renal function.

Limitations of the clinical data

The efficacy of peramivir as a single dose treatment for uncomplicated influenza was demonstrated in a single placebo-controlled study conducted in 300 adult patients in Japan during the 2007/2008 influenza season. The recommended 600 mg single intravenous dose resulted in shortening of the median time to alleviation of symptoms by 21 hours (see section 5.1).

Available data do not support a conclusion that peramivir is effective in patients with influenza B or in patients with complicated influenza.

Resistance to peramivir

Influenza A/H1N1 viruses that contain the H275Y mutation have reduced sus

and oseltamivir. In a clinical trial, no statistically significant clinical bene peramivir over placebo in patients infected with the A/H1N1 virus contai Available information on influenza drug susceptibility should be taken int whether to use peramivir (see section 5.1).

Risk of bacterial infections

There is no evidence for efficacy of peramivir in any illness caused by agents other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Peramivir has not been shown to prevent such complications.

Excipients

This medicinal product contains 212.4 mg sodium per 3 vials, equivalent to 10.6% of the World Health Organization (WHO) recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

The potential for interactions of peramivir with other medicines is low, based on the known elimination pathway of peramivir.

Live attenuated influenza vaccines are not recommended to be used until 48 hours following Alpivab administration due to a theoretical risk that peramivir could reduce the immunogenicity of the vaccine.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancies outcomes) from the use of peramivir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of peramivir during pregnancy.

Breast-feeding

Available pharmacodynamic/to­xicological data in animals have shown excretion of peramivir in milk (see section 5.3).

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from peramivir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of peramivir on fertility are available. Peramivir had no effects on mating or fertility in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Peramivir has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most important serious adverse reactions associated with peramivir in patients are anaphylaxis and skin reactions, including erythema multiforme and Stevens-Johnson Syndrome.

Among 467 adult subjects with uncomplicated influenza who received a single intravenous dose of peramivir 600 mg in clinical trials, the most commonly observed adverse reactions were neutrophil count decreased (3.2 %) and nausea (2.4 %).

Tabulated list of adverse reactions

Frequencies are defined as very common (¿1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000).

Table 3: Adverse reactions in studies investigating peramivir for treatment of uncomplicated influenza in adults /XS

System Organ Class > (SOC)	Adverse Reaction According to Frequency*
	Common	Uncommon	Rare	Unknown
Blood and lymphatic system disorders	neutrophil count decreased
Immune system disorders				anaphylactic reaction*, anaphylactic shock*

System Organ Class (SOC)	Adverse Reaction According to Frequency*
	Common	Uncommon	Rare	Unknown
Metabolism and nutrition disorders	blood lactate dehydrogenase increased	decreased appetite, blood albumin decreased, blood chloride increased, blood glucose decreased, blood lactate dehydrogenase decreased, blood potassium increased, blood sodium increased, blood uric acid increased, protein total increased
Psychiatric disorders		insomnia		abnormal behaviour*, delirium*
Nervous system disorders		hypoaesthesia, paraesthesia	■cp XX
Eye disorders		vision blurred	y
Cardiac disorders		electrocardiogram QT prolonged
Gastrointestinal disorders	nausea, vomiting	abdominal pain upper, abdominal discomfort, gastritis
Hepatobiliary disorders		increased gammaglutamyl­transferase		liver disorder*, alanine aminotransferase increased*, aspartate aminotransferase increased*
Skin and subcutaneous tissue disorders		dermatitis, drug eruption, eczema, urticaria	erythema multiforme	dermatitis exfoliative*, Stevens-Johnson syndrome*
Musculoskeletal and connective tissue disorders	f	arthralgia, blood creatine phosphokinase increased
Renal and urinary disorders		blood urea increased, blood present in urine, urobilin present in urine, blood creatinine increased, urine ketone body increased		acute kidney injury*, renal impairment*
General disorders and administration site conditions		chest discomfort, fatigue

*These events reported from post-authorization use occurred with different dosage and dosing schedule to that described in the SmPC.

Paediatrics

In paediatric subjects (age 2 to 17 years) with uncomplicated influenza enrolled in a clinical trial, the safety profile of peramivir was similar to that reported in adults. Common adverse reactions not reported in adults were injection site rash, pyrexia, tympanic membrane hyperaemia, psychomotor hyperactivity, and pruritus.

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

There is no experience of acute overdose with peramivir in humans. Treatment of an overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Peramivir is cleared by renal excretion and can antidote to treat an overdose of this medicine.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code: J05AH03

Mechanism of action

Peramivir is an inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells and is also important for viral entry into uninfected cells, which causes further spread of infectious virus in the body.

In-vitro activity

Neuraminidase inhibition occurred at very low peramivir concentrations in-vitro , with median inhibitory concentration 50% (IC50) values of 0.13 nanomolar (nM) to 0.99 nM against influenza A and B strains.

Resistance

In a clinical trial in which 245 subjects were infected at baseline with influenza A/H1N1 containing the H275Y mutation, the median baseline IC50 values for peramivir, oseltamivir and zanamivir were 51.0 nM, 487.6 nM and 0.95 nM, respectively.

In clinical trials, H275Y was the only resistance-associated treatment-emergent mutation in the neuraminidase gene that occurred in virus obtained from more than one peramivir-treated subject (in 9 of 481[1.9 %] infected with the A/H1N1 influenza virus).

Cross resistance

The H275Y substitution is associated with reduced susceptibility to peramivir and oseltamivir. Crossresistance between peramivir and each of oseltamivir and zanamivir may also occur.

Clinical studies

Uncomplicated influenza in adults

A randomised, multicentre, double-blind trial conducted in Japan evaluated a single intravenous administration of peramivir 300 mg or 600 mg, or placebo administered over 30 minutes in subjects 20 to 64 years of age with uncomplicated influenza. Subjects were eligible if they had fever greater than 38 °C and a positive rapid antigen test for influenza virus, accompanied by at least two of the following symptoms: cough, nasal symptoms, sore throat, myalgia, chills/sweats, malaise, fatigue or headache.

Study treatment was started within 48 hours of onset of symptoms. Subjects participating in the trial were required to self-assess their influenza symptoms as “none’, ‘mild’, ‘moderate’ or ‘severe’ twice daily. The primary endpoint, time to alleviation of symptoms, was defined as the number of hours from initiation of study drug until the start of the 24 hour period in which all seven symptoms of influenza (cough, sore throat, nasal congestion, headache, feverishness, myalgia and fatigue) were either absent or present at a level no greater than mild for at least 21.5 hours.

The intent to treat influenza population (ITTI) included 296 subjects with influenza confirmed by polymerase chain reaction (PCR). Among the 97 subjects enrolled in the peramivir 600 mg dose group, 99 % were infected with influenza A virus (subtypes H1 and H3; 71 % and 26 %, respectively) and 1 % with influenza B virus. At enrollment 85 % of the 296 subjects had a composite influenza symptom score <15. The mean temperature at enrolment was 38.6 °C (axillary). Key efficacy results are presented in Table 4.

Table 4: Key efficacy results from study 0722T0621 (ITTI Popu latioi

	Peramivir 600 mg Z n=97	Placebo n=100
Time to alleviation of symptoms median (hours) (95 % CI)	.....- (54.4, 68.1)	81.8 (68.0, 101.5)
Time to recovery of normal temperature median (hours) (95 % CI)	X/ 30.2 Sp (25.9, 31.9)	42.4 (32.9, 46.5)

CI = Confidence Interval

Uncomplicated influenza in paediatric subjects aged 2–17 years

The safety of peramivir was evaluated in a randomised, active-controlled study of 110 subjects with uncomplicated influenza who received open label treatment with a single dose of peramivir (600 mg for subjects 13 to 17 years of age and 12 mg/kg up to a maximum dose of 600 mg in subjects 2 to 12 years of age) or oral oseltamivir administered twice daily for 5 days. The ITTI population included 84 subjects with influenza confirmed by PCR. Among the 93 subjects enrolled in the peramivir dose group, 43% were infected with influenza A virus (subtypes H1 and H3; 54 % and 46 %, respectively) and 27% with influenza B virus. Randomisation was 4:1 for peramivir and oseltamivir. Treatment was given or commenced within 48 hours of onset of symptoms of influenza. Efficacy (time to resolution of fever; time to resolution of influenza symptoms, viral shedding, virus susceptibility) was a secondary endpoint.

Subjects receiving peramivir experienced a median time to alleviation of their combined influenza symptoms of 79.0 hours and the median time to recovery to normal temperature (less than 37 °C) was approximately 40.0 hours.

Elderly patients

Clinical trials in which single intravenous doses of peramivir were administered to patients with uncomplicated influenza included few subjects aged 65 and over (n=10).

The European Medicines Agency has deferred the obligation to submit the results of studies with Alpivab in one or more subsets of the paediatric population for the treatment of influenza (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

The pharmacokinetic parameters following intravenous (IV) administration of peramivir (0.17 to 2 times the recommended dose) showed a linear relationship between dose and exposure parameters (maximum serum concentration [Cmax] and area under the curve [AUC]). Following intravenous administration of a single dose of peramivir 600 mg over 30 minutes, Cmax was reached at the end of infusion.

Distribution

In-vitro binding of peramivir to human plasma proteins is less than 30 %.

Based on a population pharmacokinetic analysis, the central volume of distribution was 12.56 L.

Biotransformation

Peramivir is not significantly metabolised in humans.

Elimination

The elimination half-life of peramivir following IV administration to healthy subjects of 600 mg as a single dose is approximately 20 hours. The major route of elimination of peramivir is via the kidney. Renal clearance of unchanged peramivir accounts for approximately 90 % of total clearance.

Special populations

Race

In simulations of a single dose of 600 mg, the predicted AUC in Asians (AUC0–24 88,800 ng^h/mL) was slightly higher as compared to Non-Asians (AUC0–24 77,200 ng^h/mL).

Gender

The pharmacokinetics of peramivir following a 600 mg intramuscular (IM) injection was similar in males and females with AUC0-, of 76,600 ng^hr/mL and 101,000 ng^hr/mL, respectively, and Cmaxof 27,760 ng/mL and 34,710 ng/mL, respectively.

Paediatrics

The pharmacokinetics peramivir has been evaluated in a study in paediatric subjects 2 to 17 years of age with uncomplica influenza. Pharmacokinetic sampling in this study was limited to approximately 3 fter administration of peramivir. Pharmacokinetics of peramivir in subjects 2 to 17 years of age (administered 12 mg/kg or 600 mg according to age and body weight) and in healthy adults (administered 600 mg) was similar (Table 5).

Table 5: Pharmacokinetic parameters in paediatric subjects

Age Group		N	C max (ng/mL)	AUC iast (ngHi/ml.)
2 years – <7 years	Mean (SD)	28	53,600 (26,200)	74,000 (30,000)
	Geometric Mean		47,400	68,100
	%CV		48.9	40.6
7 years – <13 years	Mean (SD)	39	66,800 (35,400)	87,000 (40,800)
	Geometric Mean		61200	81,000
	%CV		53.0	46.8
13 years – <18	Mean (SD)	20	54,300 (17,900)	72,400 (20,000)

	Geometric Mean		51.500	69.500
	%CV		33.0	27.6
2 years – <18 years	Mean (SD)	87	59.700 (29.700)	79.500 (34.000)
	Geometric Mean		54.200	74.000
	%CV		49.8	42.7

SD = Standard Deviation; CV = Coefficient of Variation

Elderly

The pharmacokinetics of peramivir was evaluated in 20 elderly subjects (>65 years of age) following a single 4 mg/kg IV dose of peramivir. The elderly subjects enrolled were aged 65 to 79 years, with a mean age of 70.1 years, with creatinine clearance (Cockcroft-Gault calculation) CrClcg ranging from 82.8 mL/min to 197.9 mL/min. The pharmacokinetics in elderly subjects was similar to non-elderly subjects. Mean peak concentrations of peramivir were approximately 10 % higher in elderly subjects following administration of a single dose when compared to young adults (22,647 vs. 20,490 ng/mL, respectively). Exposure (AUC0–12) to peramivir following a single dose was approximately 33 % higher in elderly subjects compared to young adults (61,334 vs. 46,200 ng^hr/mL. respectively).

Renal impairment

In a study in subjects with various degrees of renal impairment and subjects with normal renal function, a single 2 mg/kg IV dose of peramivir was administered. Serum creatinine measurements were used to calculate creatinine clearance (Cockcroft-Gault equation). The mean AUCq., was increased by 28 %, 302 % and 412 % in subjects with creatinine clearance of 50–79, 30–49 and 10–29 mL/min, respectively. Haemodialysis initiated at 2 hours afte dosing reduced systemic exposure of peramivir by 73 to 81 %.

Hepatic impairment

The pharmacokinetics of peramivir in subjects with hepatic impairment has not been studied. No clinically relevant alterations to peramivir pharmacokinetics are expected in patients with hepatic impairment based on the route of peramivir elimination.

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5.3 Preclinical safety data

Peramivir was not teratogenic in embryo-fetal development studies in rats and rabbits and had no effects on mating or fertility in rats up to 600 mg/kg/day, at which exposures were approximately 8-fold of those in humans at the clinically recommended dose. However, in an embryo-foetal development study in rats, in which dams received continuous infusions of peramivir from day 6–17 of gestation at doses of 50, 400 or 1000 mg/kg/day, dose related increases in the incidences of reduction of the renal papillae and dilatation of the ureters were observed. The teratological importance of these findings is unclear.

Carcinogenicity studies by intravenous injection of peramivir were not performed.

Peramivir was not mutagenic or clastogenic in a battery of in-vitro and in-vivo assays.

Acute renal necrosis was found in rabbits at doses > 200 mg/kg with a clear no observed adverse effect level (NOAEL) established in multiple studies at 100 mg/kg/day.

Two-week oral toxicity studies were conducted in juvenile rats and rabbits, and a four-week IV toxicity study was conducted in juvenile rats. In general, nephrotoxicity was observed in rabbits, no unexpected toxicity was observed, and no other target organ toxicity was identified in juvenile animals.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium chloride

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial 5 years

After dilution

Chemical and physical in-use stability has been demonstrated for 72 ho From a microbiological point of view, the product, once diluted, should

used immediately in-use storage times and conditions prior to use would normally not be longer than 24 hours at 2 °C to 8 °C, unless controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not refrigerate or freeze.

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

6.5 Nature and contents of container

romobutyl-rubber stopper, aluminium overseal and flip-off

Pack size of 3 single-use v

Aseptic technique should be used during the preparation of Alpivab to prevent inadvertent microbial contamination.

The following steps should be followed to prepare a diluted solution of peramivir:

• • Check the seal of each vial. Do not use if seal opening is broken or missing.
• • Visually inspect the peramivir concentrate 10 mg/mL. It must be colourless and without

particulate matter.

• • If a patient receives 600 mg peramivir the required volume of peramivir concentrate is 60 mL (3 vials with 20 mL each). In the case of a 300 mg peramivir dose, 30 mL (1*A vials) of peramivir concentrate is needed and for a 200 mg dose, only 20 mL (1 vial). Fractions of a vial may be needed for appropriate dose adjustments in children with a bodyweight of less than 50 kg.
• • Add the measured volume of peramivir concentrate into the infusion container.
• • Dilute the required dose of peramivir concentrate in sodium chloride 9 mg/mL (0.9 %) or 4.5 mg/mL (0.45 %) solution for infusion, 5 % dextrose or Ringer lactate solution to a volume of 100 mL.
• • Administer the diluted solution via intravenous infusion for 15 to 30 minutes.
• • Once a diluted peramivir solution has been prepared, administer immediately or store in a refrigerator (2 °C to 8 °C) for up to 24 hours. If refrigerated, allow the diluted peramivir solution to reach room temperature, then administer immediately.
• • Discard any unused diluted solution of peramivir after 24 hours.

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

7. MARKETING AUTHORISATION HOLDER

BioCryst Ireland Limited

Atlantic Avenue

Westpark Business Campus Shannon

V14 YX01

Ireland

Tel: +353 1223 3541

E-mail:

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1269/001

• 9. DATE OF FIRST 13/04/2018