ZTALMY 50 mg/ml Oral suspension

ZTALMY is indicated for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 to 17 years of age. ZTALMY may be continued in patients 18 years of age and older.

Treatment should be initiated and supervised by physicians with experience in the treatment of epilepsy.

Posology

Children and adolescents

ZTALMY should be titrated gradually to achieve individual clinical response and tolerability. Any patient not tolerating the dosing steps shown in the tables below, can be maintained at the lower dose for additional days before advancing to the next dose. If the next dose is still not tolerated, patients can drop back to the previous lower dose.

It is recommended that the total daily dose is administered in 3 equal doses throughout the day. If this is not tolerated by a patient, the dose can be adjusted to manage symptoms (e.g., somnolence), provided that the total daily dose is administered.

Patients weighing ≤ 28 kg

The recommended maximum daily dose is 63 mg/kg/day given in three separate doses (every 8 hours). A minimum dose of 33 mg/kg/day is generally required.

The recommended titration schedule for patients weighing 28 kg or less is shown below:

Patients weighing > 28 kg

The recommended maximum daily dose is 1 800 mg per day given in three separate doses (every 8 hours). A minimum dose of 900 mg/day is generally required.

The recommended titration schedule for patients weighing more than 28 kg is shown below:

Adults

The efficacy and safety of treatment initiation with ZTALMY in patients aged over 17 years have not yet been established. In adolescents in whom a clear treatment benefit has been demonstrated, treatment may be continued into adulthood. However, treatment initiation in adults is not recommended as efficacy and safety have not yet been established in this population (see sections 5.1 and 5.2)

Discontinuation

If ZTALMY must be discontinued, the dose should be decreased gradually. For patients weighing 28 kg or less, the decrease in total daily dose should be 15 mg/kg every four days. For patients weighing more than 28 kg, the decrease in total daily dose should be 450 mg every four days. ZTALMY may be stopped immediately and without down-titration in the case of an emergency, however, a down-titration is recommended to minimize the risk of increased seizure frequency and status epilepticus.

Missed doses

Missed doses may be taken up to 4 hours before the next scheduled dose. When the next dose is due in less than 4 hours, it is recommended to skip the dose and to continue with the next scheduled dose.

Special populations

Elderly

There is no information on the use of ZTALMY in patients with CDD who are 65 years of age and over. Doses in elderly patients should be chosen carefully based on clinical status and concomitant medicinal products. Close clinical monitoring is recommended when initiating treatment in the elderly.

Renal impairment

ZTALMY can be administered to patients with mild, moderate, or severe renal impairment without dose adjustment. There is no experience in patients with end-stage renal disease. It is not known if ZTALMY is dialysable (see section 5.2).

Hepatic impairment

Dose adjustment is not required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment (see section 4.4).

For patients with severe hepatic impairment (Child-Pugh C) the initial target dose should be one-third the recommended target dose. The dose titration should be performed as detailed in the table(s) below.

The dose in patients with severe hepatic impairment weighing 28 kg or less is shown below:

The dose in patients with severe hepatic impairment weighing more than 28 kg is shown below:

Higher or lower doses may be considered in patients with severe hepatic impairment based on individual clinical response and tolerability.

Paediatric population

There is no relevant use of ZTALMY in infants below 6 months of age. The safety and efficacy of ZTALMY in children aged less than 2 years have not yet been established. No data are available.

Method of administration

Oral use only. No data are available on the feasibility of administration through an enteral feeding tube.

ZTALMY must be taken with or shortly after meals and each dose should be administered with similar types of food, if possible (see section 5.2). Do not mix with food or drinks prior to administration.

ZTALMY should only be administered using the reusable oral dosing syringes provided in each pack for a more accurate dose administration.

Each 12 mL reusable oral syringe is graduated in 0.25 mL increments (each 0.25 mL increment corresponds to 12.5 mg ganaxolone) and each 3 mL reusable oral dosing syringe is graduated in 0.1 mL increments (each 0.1 mL increment corresponds to 5 mg ganaxolone). The calculated dose should be rounded to the nearest graduated increment. If the calculated dose is 3 mL (150 mg) or less, the smaller 3 mL oral syringe should be used. If the calculated dose is more than 3 mL (150 mg) the larger 12 mL oral syringe should be used.

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

Somnolence and sedation

ZTALMY causes somnolence and sedation (see sections 4.5 and 4.8).

Other Central Nervous System (CNS) depressants, including concomitantly used anti-seizure medicinal products, opioids, antidepressants, and alcohol, could potentiate the somnolence and sedation effect.

Suicidal behaviour and ideation

Suicidal behaviour and ideation have been reported in patients treated with anti-epileptic drugs (AEDs) in several indications. A meta-analysis of randomised placebo-controlled trials with AEDs has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known. The available data do not exclude the possibility of an increased risk with ganaxolone.

Patient's caregivers should be advised to monitor for signs of suicidal behaviour and ideation, or self-harm behaviour during treatment and when changes in the treatment regimen become necessary. Caregivers should be advised to seek medical advice should any signs of suicidal behaviour and ideation, or self-harm emerge.

Alcohol use

In animal models, ganaxolone has been shown to potentiate the effects of alcohol. Patients should not use alcohol during treatment (see section 4.5).

CYP3A4 inducers

Concomitant use with strong cytochrome P450 (CYP) 3A4 inducers e.g. carbamazepine, phenobarbital, phenytoin, primidone, rifampicin and St John's Wort should be avoided as they can reduce ganaxolone exposure (see section 4.5).

Hepatic impairment

An increase in ganaxolone exposure was seen in patients with severe hepatic impairment (Child-Pugh C) (see section 5.2). A dosage adjustment is recommended in these patients (see section 4.2).

Abuse

ZTALMY has potential for abuse (see section 5.3).

Dependence

It was not possible to assess physical dependence during clinical trials with ganaxolone; animal studies suggest that abrupt discontinuation of ganaxolone may cause withdrawal symptoms (see sections 5.1 and 5.3). It is therefore recommended that ganaxolone be tapered according to the dosage recommendations unless symptoms warrant immediate discontinuation (see section 4.2).

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per each daily dose, that is to say essentially 'sodium-free'.

This medicinal product contains 0.92 mg sodium benzoate and 0.00068 mg benzoic acid in each mL. Benzoate salt and benzoic acid may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

This medicinal product contains 0.00023 mg benzyl alcohol in each mL. Benzyl alcohol may cause allergic reactions. Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in young children. Do not give to your newborn baby (up to 4 weeks old), unless recommended by your doctor. Do not use for more than a week in young children (less than 3 years old), unless advised by your doctor or pharmacist. Increased risk due to accumulation in young children. Ask your doctor or pharmacist for advice if you are pregnant or breast-feeding, or if you have a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).

This medicinal product contains 1.02 mg methyl parahydroxybenzoate and 0.2 mg propyl parahydroxybenzoate in each mL. Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

CYP3A4 inducers

Coadministration with a strong CYP3A4 inducer will decrease ganaxolone exposure.

Concomitant use of rifampicin decreased the AUC_0-inf of ganaxolone by approximately 57-68%. Enzyme inducing antiepileptics (e.g., carbamazepine, phenytoin, phenobarbital, and primidone) and St. John's Wort may result in similarly lower plasma exposures of ganaxolone. In patients on a stable dose of ganaxolone or in patients initiating or increasing the dose of concomitant enzyme-inducing antiepileptic drugs or St. John's Wort a dose increase may be necessary; however, do not exceed the maximum daily dose (see section 4.4).

CYP3A4 inhibitors

Coadministration of ganaxolone with itraconazole, a strong CYP3A4 inhibitor, increased the ganaxolone AUC by 17% in healthy subjects (the C_max was unchanged). The changes in ganaxolone exposures when coadministered with strong, moderate, or weak CYP3A4 inhibitors are not expected to be clinically significant.

UGT inhibitors

Ganaxolone is a substrate for UGT1A3, UGT1A6, UGT1A9, and UGT2B15. No formal drug-drug interaction studies have been conducted with ganaxolone in combination with UGT inhibitors such as valproate. Dose reduction of ganaxolone and/or the UGT inhibitor may be necessary when given in combination.

Oral contraceptives

The potential interaction of ganaxolone with oral contraceptives has not been investigated.

Ethanol interaction

Concomitant use with CNS depressants (including alcohol) may increase the risk of sedation and somnolence (see section 4.4). Patients should be prohibited from drinking alcohol during treatment.

Pregnancy

There are limited data on the use of ganaxolone in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

ZTALMY is not recommended during pregnancy and in woman of childbearing potential not using contraception.

Breast-feeding

Ganaxolone and its metabolites are excreted in human milk. Based on an average milk intake, the calculated maximum relative infant dose of ganaxolone is approximately 1% of the maternal dose. The effect of ganaxolone on breastfed newborns/infants is unknown, A risk to the suckling child cannot be excluded.

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

Fertility

There are no human data on the effect of ganaxolone on fertility. Animal studies are insufficient with respect to fertility (see section 5.3).

ZTALMY has a moderate to major influence on the ability to drive and use machines because it may cause somnolence, sedation and sedation-related adverse reactions, such as fatigue and ataxia, and other CNS-related events such as dizziness (see section 4.4). Patients should be advised not to drive or use machines (see section 4.8).

Summary of the safety profile

The most commonly reported adverse drug reactions in clinical trials in patients with CDD include somnolence (29.4%) and pyrexia (23.5%).

Tabulated list of adverse reactions

Adverse reactions reported with ganaxolone in a clinical trials in patients with CDD with an average exposure duration of 411.5 days (N = 102) are listed in the table below by System Organ Class and frequency.

The frequencies are defined as follows: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Somnolence and sedation

ZTALMY can cause somnolence and sedation. In a placebo-controlled study for CDD, the incidence of somnolence and sedation was 31.4%, and 3.9% respectively in patients treated with ZTALMY, compared with 15.7%, and 3.9% respectively in patients treated with placebo. These adverse reactions appear early in treatment and are dose-related; symptoms may decrease with continued treatment.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is limited clinical trial experience regarding overdose. Adverse events of the central nervous system (e.g., somnolence, sedation) have been reported to be dose dependent.

In the event of overdose, the patient should be observed and appropriate symptomatic treatment given, including monitoring of vital signs.

Pharmacotherapeutic group: Antiepileptics, other antiepileptics, ATC code: N03AX27.

Mechanism of action

Ganaxolone is a methyl analogue of the endogenous neurosteroid allopregnanolone. Ganaxolone is a neuroactive steroid that positively and allosterically modulates gamma-aminobutyric acid type A (GABA_A) receptors in the CNS by interacting with a recognition site that is distinct from other allosteric GABA_A receptor modulators.

The precise mechanism by which ganaxolone exerts its therapeutic effects in the treatment of seizures associated with CDD is unknown, but its anticonvulsant effects are thought to result from this modulation of GABA_A receptor function providing constant, or tonic, modulation of GABA-mediated inhibitory neurotransmission.

Clinical efficacy and safety

The efficacy to treat seizures associated with CDD in patients 2 years and older was established in a single, double-blind, randomised, placebo-controlled study in patients aged 2 to 19 years (Study 1042-CDD-3001).

Patients enrolled in Study 1042-CDD-3001 had a molecular confirmation of pathogenic or likely pathogenic CDKL5 variant, their seizures were inadequately controlled by at least 2 previous concomitant AED medicinal products, and they had a minimum of 16 seizures of primary seizure type per 28 days in each 1-month period during the 2-month period prior to screening.

Totally, 101 patients were enrolled into the study (51 placebo and 50 study drug). Patients were mostly female (79.2%; consistent with the demographics of CDD) and aged between 2 and 19 years (mean [standard deviation (SD)]: 7.26 [4.55]) with the majority being paediatric (children 2 to 11 years [82.2%], adolescents [16.8%]), concomitant AEDs s were given to 96% patients. The mean (SD) number of concomitant AEDs used by subjects was 2.2 (1.14) in the placebo group and 2.6 (1.40) in the ganaxolone group. The most frequent (≥ 10 patients) concomitant AEDs were valproate, levetiracetam, clobazam and vigabatrin.

The primary efficacy endpoint was the percentage change from baseline in 28-day frequency of major motor seizures during the 17-week double blind treatment phase. Major motor seizures include bilateral tonic, bilateral clonic, atonic, generalized tonic-clonic and focal to bilateral tonic-clonic seizures. At baseline, the mean (SD) number of major motor seizures over 28-days was 104.8 (173.53) for placebo and 117.2 (138.62) for ganaxolone.

At the end of the 13-week maintenance phase, there was a statistically significant difference in the median percent change from baseline in major motor seizure frequency for patients treated with ganaxolone compared to patients receiving placebo (see table 1).

Table 1 Study 1042-CDD-3001 Change in frequency of major motor seizures per 28 days in the 13-week maintenance phase

CI=95% confidence interval.

^a Response is defined as at least 50% reduction from baseline in 28-day Seizure Primary Seizures Frequency. P-value is based on Fisher's Exact test.

The cumulative response curve shows that ganaxolone produced greater reductions than placebo in seizure frequency at all response rates (see figure 1).

Figure 1 Study 1042-CDD-3001 Cumulative Responder Curves of 28-Day Seizure Frequency for Primary Seizure Types – 13-Week Maintenance Phase, Intent-to-Treat Population

Open-label data

CDD patients who participated in the double-blind phase of 1042-CDD-3001 could continue the study and participate in an open-label extension phase. The primary objective of the open-label extension phase was long-term safety and tolerability of ganaxolone. To enter the open-label extension phase, patients underwent a blinded cross-titration to a maximum daily dose of 63 mg/kg/day in patients <28 kg or 1800 mg/day in patients who were at least 28 kg. Data are reported for 88 patients who participated in the open-label extension phase and received ganaxolone for up to 4.25 years. A total of 63.6% of patients discontinued study participation during the open-label extension phase, predominantly due to withdrawal by subject/parent (17.0%), lack of efficacy (18.2%) and adverse events (11.4%).

Adult population

The CDD population in Study 1042-CDD-3001 predominantly consisted of paediatric patients. Two patients were 19 years old at the time of study enrolment (one randomised to placebo, one to ganaxolone). Seven patients turned 18 years of age during the open-label extension phase of the study. For these patients (n=9), the median percent change in major motor seizure frequency from baseline to their last 3 months in the open-label phase was -32.1% (range -86.2% to 72.7%).

Paediatric population

The MHRA has deferred the obligation to submit the results of studies with ZTALMY in one or more subsets of the paediatric population in CDKL5 deficiency disorder (see section 4.2 for information on paediatric use).

Absorption

Ganaxolone is rapidly absorbed, with a time to maximum observed plasma concentration (T_max) of 2.0 to 3.0 hours at steady state (Css). Css is achieved within 2 to 3 days. Ganaxolone undergoes first-pass metabolism, the absolute bioavailability of ganaxolone suspension is approximately 13%.

Paediatric patients aged 2 to < 6 years (median body weight 14.8 kg), aged 6 to < 12 years (median body weight 22.6 kg), and aged 12 to < 18 years (median body weight 36.1 kg) had a C_max of 247, 269, and 293 ng/mL and AUC_0-24 of 3903, 3998, and 4106 ng*h/mL, respectively, when given a dose of 21 mg/kg with a maximum of 600 mg three times a day. C_max and AUC_0-24 in adult patients was 292 ng/mL and 4100 ng*h/mL, respectively.

Co-administration of ganaxolone with a high-fat meal increased C_max by 2-fold and AUC by 3-fold when compared to fasted levels. The effect of different types of food is not known.

Distribution

Ganaxolone is extensively distributed throughout the body and its volume of distribution is approximately 580 L. Ganaxolone is approximately 99% protein bound in serum.

Biotransformation

Ganaxolone is extensively metabolized in humans, and over 50 Phase 1 and Phase 2 metabolites have been detected. The ganaxolone metabolite pattern at steady state has not yet been characterised. The steady state metabolite pattern may be different from single dose given the long t_1/2 of ganaxolone. Ganaxolone is metabolised by CYP3A4 and CYP3A5; CYP2B6, CYP2C19, CYP2D6, UGT1A3, UGT1A6, UGT1A9, UGT2B7, and UGTB15.

Major metabolite (M2) was identified and demonstrated no activity at the GABA_A receptor.

Elimination

The half-life (t_½) for ganaxolone at steady state was 7.8 to 10.1 hours. Following a single oral dose of 300 mg [¹⁴C]-ganaxolone to healthy male subjects, 55% of the total radioactivity was recovered in feces (2% as unchanged ganaxolone) and 18% of the total radioactivity dose was recovered in urine. Metabolites of ganaxolone may have a longer t_½ than ganaxolone, up to 230 hours.

Ganaxolone is excreted in breast milk, concentrations were approximately 4-fold higher than in plasma (see section 4.6).

Dose proportionality and accumulation

The pharmacokinetics of ganaxolone are generally linear between 200 mg and 600 mg (or their paediatric equivalent). When dosing three times a day, C_max and AUC_tau accumulation ratios are 1.5-fold and 1.7-fold, respectively.

Special populations

Effect of age, sex, race

Population pharmacokinetic analyses demonstrated that there were no clinically relevant effects of age, sex, or race on exposure to ganaxolone. CL, V, and maximum absorbed dose all follow an allometric relationship with weight. No clinically relevant effects were observed in children with body weight below 28 kg due to weight-based dosing. Population pharmacokinetic simulations indicate that the ganaxolone exposure in adults was reversely correlated with body weight. The clinical relevance is currently unknown as the efficacy and safety have only been demonstrated for CDD paediatric patients with a low body weight.

Paediatric population

The observed pharmacokinetic exposures in patients in study 1042-CDD-3001 were comparable across the age groups 2 to less than 6 years of age (mean weight 14.8 kg, n=45), 6 to less than 12 years of age (mean weight 22.6 kg, n=28), and 12 to less than 18 years of age (mean weight 36.1 kg, n=16), and greater than 18 years of age (mean weight 35.1 kg, n=2). There are no pharmacokinetic data in children less than 2 years of age.

Renal impairment

The pharmacokinetics of ganaxolone were not significantly altered in patients with severe renal impairment. Following oral administration of a single 300 mg dose in subjects with severe renal impairment (creatinine clearance between 15 and 30 mL/min), the AUC_0-inf of ganaxolone decreased 8% and C_max decreased 11% as compared to that in subjects with normal renal function (creatinine clearance ≥90 mL/min as estimated by Cockcroft-Gault). Patients with end-stage renal disease were not studied.

Hepatic impairment

The influence of hepatic impairment on the pharmacokinetics of ganaxolone was studied following a single oral dose of 300 mg. No clinically significant effects on the exposures of ganaxolone were observed following administration in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. Patients with severe (Child-Pugh C) hepatic impairment had an approximately 5.8-fold increase in AUC_0-inf as compared to those with normal hepatic function (see section 4.2).

Drug interaction studies

In vitro assessment of drug interactions

In vitro studies with ganaxolone demonstrated that no other pharmacokinetic interactions are expected. Ganaxolone is not an inhibitor or an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. In vitro, ganaxolone did not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7. Ganaxolone does not inhibit BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Ganaxolone is not a substrate for BCRP, P-gp, OCT1, OCT2, OATP1B1 or OATP1B3.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology repeated dose toxicity, and genotoxicity.

Repeated dose toxicity

Primary effects in animals were central nervous system clinical observations (e.g., sedation), which were dose-limiting and attributed to exaggerated pharmacology.

In the 12-month repeat-dose toxicology study in dogs, a dose-dependent increase in heart rate at ≥ 3 mg/kg/day (similar to clinical exposure levels) was observed and there were incidences of sinus tachycardia at higher doses. There were no changes in QTc intervals, blood pressure parameters, or histopathologic correlates.

Carcinogenicity/ genotoxicity

Carcinogenicity studies have not been conducted with ganaxolone. Ganaxolone is not considered genotoxic.

Reproductive and developmental toxicity

The reproductive and developmental toxicity studies are of limited value since exposure levels were far below clinically relevant levels.

In the fertility and early embryonic development study in rats, alterations in estrous cyclicity occurred.

In the combined embryo-foetal development and pre- and post-natal development study in rats, gestation length was slightly lengthened and slight delays in offspring growth and related developmental milestones occurred.

Studies in lactating rats indicate that ganaxolone and its metabolites are excreted in milk with concentrations generally higher in milk compared with plasma.

It is not known if ganaxolone crosses the placenta.

Juvenile toxicity

Histological changes in juvenile rats were similar to those in adult rats on an AUC exposure basis. Sedation occurred at lower exposures in adults than in juvenile animals. Decreased bodyweight gain and a delay in sexual maturation occurred in juvenile males and females, with no effects on oestrous cyclicity or any fertility or reproductive parameters. Exposure levels in juvenile animals were similar or lower to the clinical exposure levels.

Ganaxolone administration caused a dose-dependent increase in neurodegeneration in multiple brain regions, consistent with findings from other GABA modulators. There were no functional, neurobehavioural consequences of this effect in the 13-week juvenile study. Exposure levels in juvenile animals were similar or lower to the clinical exposure levels.

Abuse

Ganaxolone shares an internal/subjective interoceptive cue with benzodiazepines and dose-dependently supported self-administration in a rodent model of reward, suggesting ganaxolone has reinforcing characteristics similar to benzodiazepines.

Dependence

Animal studies suggest that abrupt discontinuation of ganaxolone may cause withdrawal symptoms.

Studies with metabolites

Based on in vitro data, a potential hormonal effect of metabolite M2 at clinical exposures cannot be excluded. In a 4-week repeat-dose toxicity study with direct administration of M2, acinar atrophy and decreased secretion in the prostate gland and seminal vesicle glands was observed in male rats, which correlated with decreased prostate gland weight. This occurred at levels slightly above clinical exposure levels, and the clinical relevance remains unknown.

Hypromellose (E464)

Polyvinyl alcohol (E1203)

Sodium lauryl sulfate (E487)

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Sodium benzoate (E211)

Citric acid, anhydrous (E330)

Sodium citrate dihydrate (E331)

Artificial cherry flavour (including propylene glycol [E1520] and benzyl alcohol [E1519])

Sucralose (E955)

Simethicone emulsion (simethicone, polysorbate 65, methylcellulose, polyethylene glycolmonostearate, glycerol monostearate, xanthan gum, benzoic acid [E210], sorbic acid, and purified water)

Purified water

Not applicable.

2 years.

Use within 30 days of first opening the bottle.

This medicinal product does not require any special temperature storage conditions.

High-density polyethylene (HDPE) bottle with a polypropylene (PP) child resistant (CR) cap lined with an induction foil liner packed into a carton along with calibrated reusable oral dosing syringes (HDPE plunger and polypropylene barrel), and a bottle adaptor(s) (low-density polyethylene).

Each carton contains either:

- one 110 mL-bottle with two 3 mL oral dosing syringes, two 12 mL oral dosing syringes, and one bottle adaptor, or

- five 110 mL-bottles with five 12 mL oral dosing syringes, and five bottle adaptors.

Each 12 mL syringe is graduated in 0.25 mL increments and each 3 mL syringe is graduated in 0.1 mL increments.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material (including any used/unused bottle adaptors and reusable oral dosing syringes) should be disposed of in accordance with local requirements.