Pulmozyme 2500 U/2.5ml Nebuliser Solution

6.3     Shelf life

 

2 3 years.

 

 

10.     DATE OF REVISION OF THE TEXT

 

21 April 2017

 

 

 

4.2     Posology and method of administration

 

Posology

 

2.5 mg (corresponding to 2500 U) deoxyriboniuclease l by inhalation once daily. Inhale the contents of one ampoule (2.5 ml of solution) undiluted using a recommended jet nebuliser/compressor system (see section 6.6).

 

Some patients over the age of 21 years may benefit from twice daily dosage.

 

[….]

 

Safety and efficacy have not yet been demonstrated in patients under the age of 5 years, or in patients with forced vital capacity less than 40% of predicted.

 

Safety and efficacy have not yet been established in patients with forced vital capacity less than 40% of predicted.

 

Paediatric population

Safety and efficacy have not yet been destablished  in patients under the age of 5 years.

 

Method of administration

Inhale the contents of one ampoule (2.5 ml of solution) undiluted using a recommended nebulizser /compressor system (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

 

Traceability of PULMOZYME: In order to improve the traceability of Pulmozyme the trade name of the administered dornase alfa and the batch number should be clearly recorded in the patient file.

None.

 

4.6     Pregnancy and lactation

 

PregnancyPregnancy

The safety of dornase alfa has not been established in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, or embryofoetal development (see section 5.3). Caution should be exercised when prescribing dornase alfa to pregnant women.

 

 

LactationBreastfeeding

When dornase alfa is administered to humans according to the dosage recommendation, there is minimal systemic absorption; therefore no measurable concentrations of dornase alfa would be expected in human milk. Nevertheless, caution should be exercised when dornase alfa is administered to a breast-feeding woman (see section 5.3).

 

4.8      

Undesirable effects

[….]

 

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 national reporting system listed in Appendix V*.HPRA Pharmacovigilance, Earlsfort Terreace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@hpra.ie.

 

 

5.1     Pharmacodynamic properties

 

[….]

Mechanism of action

Recombinant human DNase is a genetically engineered version of a naturally occurring human enzyme which cleaves extracellular DNA.

[…]

 

Clinical Trial ResultsClinical efficacy and safety

Efficacy and safety was established in double-blind, placebo-controlled studies (Z0342/Z0343) in which patients over 5 years of age and with FVC over 40% predicted received 2.5 mg Pulmozyme once or twice daily over a 24-week period. Overall, 968 patients (mean age of 19 years) with a mean baseline FVC of 78% were randomised in these trials.

[.…]

 

5.2     Pharmacokinetic properties

 

AbsorptionAbsorption

 

[….]

 

DistributionDistribution

[….]

 

MetabolismMetabolism

[….]

 

EliminationElimination

[….]

 

Paediatric population Paediatric population

[….]

 

6.6     Special precautions for disposal and other handling

 

 

The contents of one 2.5 mg (2500 U) single-use ampoule of Pulmozyme sterile solution for inhalation should be inhaled once a day using a recommended jet nebuliser.

 

·          Pulmozyme should not be mixed with other drugs or solutions in the nebuliser (see section 6.2).

 

·                ·     The complete contents of a single ampoule should be placed in the bowl of Pulmozyme may be used in conjunction with a jet nebuliser/compressor system, such as the Hudson T Up-draft II/Pulmo-Aide, Airlife Misty/Pulmo-Aide, customised Respirgard/Pulmo-Aide, or AcornII/Pulmo-Aide.

 

·                   · Pulmozyme may also be used in conjunction with a reusable jet nebuliser/compressor system, such as the Pari LL/Inhalierboy, Pari LC/Inhalierboy or Master, Aiolos/2 Aiolos, Side Stream/CR50 or MobilAire or Porta-Neb.

·                 

 

·                    

·                   · The Pari eFlow Rapid nebuliser, a general purpose electronic vibrating membrane nebuliser may be used. Parity between the eFlow Rapid electronic nebuliser and the LC Plus jet nebuliser has been demonstrated in vitro and in vivo. The average droplet size distribution of the aerosol generated by the eFlow Rapid nebuliser compared with the LC Plus jet nebuliser is shown below, using an adult breath simulator profile. The mass median aerodynamic diameter (MMAD) was 4.8 ± 0.4 µm (n=16) for e Flow Rapid and 4.6 ± 0.4 µm (n=12) for LC Plus. The geometric standard deviation (GSD) was 1.80 ± 0.11 for eFlow Rapid and 2.14 ± 0.04 for LC Plus.    The drug delivery rate was 380 ± 60 µg/min (n=88) for eFlow Rapid and 93 ± 16 µg/min (n=40) for LC Plus. The total drug delivered was 567 ± 62 µg for eFlow Rapid and 570 ± 80 µg for LC Plus. The Pari eFlow Rapid nebuliser should be used with the Pari EasyCare cleaning accessory and cleaning should be performed every seventh nebulisation cycle (a cycle being defined as a nebuliszation of a single ampoule  of Pulmozyme followed by cleaning and disinfecting in accordance with  the PARI  eFlow Rapid nebuliszer system instruction for use). Using the eFlow Rapid nebuliszer without EasyCare cleaning accessory may leads to lower and more variable dose delivery, although this may not be clinically significant.

·                 

 

·                · Ultrasonic nebulisers may be unsuitable for delivery of Pulmozyme because they may inactivate Pulmozyme or have unacceptable aerosol delivery characteristics.

 

·          The manufacturers' instructions on the use and maintenance of the nebuliser and compressor should be followed.

 

·          Containment of the aerosol is not necessary.

 

·          Pulmozyme ampoules are for single administration only. Any unused product or waste material should be disposed of in accordance with local requirements.

 

 

10.     DATE OF REVISION OF THE TEXT

 

 

12 November 2015

 

 

 

 

Underlined text has been added, text with strike through deleted:

 

4.6     Pregnancy and lactation

 

Pregnancy

The safety of dornase alfa has not been established in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, or embryofoetal development (see section 5.3). Caution should be exercised when prescribing dornase alfa to pregnant women.

 

Lactation

As it is not known whether dornase alfa is excreted in human milk, caution should be exercised when dornase alfa is administered to a breast-feeding woman (see section 5.3).When dornase alfa is administered to humans according to the dosage recommendation, there is minimal systemic absorption; therefore no measurable concentrations of dornase alfa would be expected in human milk. Nevertheless, caution should be exercised when dornase alfa is administered to a breast-feeding woman (see section 5.3).

 

4.9     Overdose

 

The effect of Pulmozyme overdosage has not been established.  Single-dose inhalation studies in rats and monkeys at doses up to 180-fold higher than doses routinely used in clinical studies are well tolerated. Oral administration of dornase alfa in doses up to 200mg/kg are also well tolerated by rats.

 

In clinical studies, cystic fibrosisCF patients have inhaledreceived up to 20 mg Pulmozymedornase alfa BID twice daily (16 times the recommended daily dose) for up to six6 days and 10 mg twice dailyBID (8 times the recommended dose) intermittently (2 weeks on/2 weeks off drug) for 168 days. Six adult non-cystic fibrosis patients received a single intravenous dose of 125 μg/kg of dornase alfa, followed 7 days later by 125 μg/kg subcutaneously for two consecutive 5-day periods, without either neutralising antibodies to DNase or any change in serum antibodies against double-stranded DNA being detected.  BothAll of these doses regimens were shown to be well tolerated.

 

Systemic toxicity of Pulmozyme has not been observed and is not expected due to the poor absorption and short serum half-life of dornase alfa. Systemic treatment of overdose is therefore unlikely to be necessary (see section 5.2).

 

5.2     Pharmacokinetic properties

 

Absorption

Inhalation studies conducted in rats and non-human primates show a low percentage of dornase alfa systemic absorption, < 15% for rats and < 2% for monkeys. Consistent with the results of these animal studies, dornase alfa administered to patients as an inhaled aerosol shows low systemic exposure.

 

Absorption of dornase alfa from the gastrointestinal tract following oral administration to rats is negligible.

 

DNase is normally present in human serum.  Inhalation of up to 40 mg of dornase alfa for up to 6 days did not result in a significant elevation of serum DNase concentration above normal endogenous levels.  No increase in serum DNase concentration greater than 10 ng/ml was observed. Following administration of 2500 U (2.5 mg) of dornase alfa twice daily for 24 weeks, mean serum DNase concentrations were no different from the mean pre-treatment baseline value of 3.5 ± 0.1 ng/ml; suggesting low systemic absorption or accumulation.

 

Distribution

Studies in rats and monkeys have shown that, following intravenous administration, dornase alfa was cleared rapidly from the serum.  The initial volume of distribution was similar to serum volume in these studies.

 

Inhalation of 2500 U (2.5 mg) dornase alfa results in a mean sputum concentration of dornase alfa of approximately 3 µg/ml within 15 minutes in cystic fibrosisCF patients.  Concentrations of dornase alfa in sputum rapidly decline following inhalation.

 

Metabolism

Dornase alfa is expected to be metabolised by proteases present in biological fluids.

 

 

Elimination

Studies in rats and monkeys have shown that, following intravenous administration, rhDNase is cleared rapidly from the serum. Human intravenous studies suggested an elimination half-life from serum of 3-4 hours.

 

Studies in rats indicate that, following aerosol administration the disappearance half-life of dornase alfa from the lungs is 11 hours. In humans, sputum DNase levels declined below half of those detected immediately post-administration within 2 hours but effects on sputum rheology persisted beyond 12 hours.

 

No pharmacokinetic data are available in very young or geriatric animals.

Paediatric population

Pulmozyme, 2.5 mg by inhalation, was administered daily for 2 weeks to 98 patients aged 3 months to 9 years (65 aged 3 months to <5 years, 33 aged 5 to 9 years), and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. The Pari Baby reusable nebuliser (which uses a facemask instead of a mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger, and 2/33, 6% of the older patients). BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/ml. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 ng/ml for the 3 months to <5 year age group and by 0.8 ± 1.2 ng/ml for the 5 to 9 year age group.  The incidence of fever was more frequent in the younger than older age group (41% vs. 24%, respectively); fever is a known complication of bronchoscopy.

 

5.3     Preclinical safety data

 

Studies of dornase alfa in rabbits and rodents show no evidence of impaired fertility, teratogenicity, or effects on development.Non-clinical data based on standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction do not indicate a specific safety risk to humans.

 

In a study performed in lactating cynomolgus monkeys, receiving high doses of dornase alfa by the intravenous route (100 µg/kg bolus followed by 80 µg/kg/hour for 6 hours), low concentrations (< 0.1% of the concentrations seen in the maternal serum of pregnant cynomolgus monkeys), were detectable in the maternal milk.  When administered to humans according to the dosage recommendation, there is minimal systemic absorption of dornase alfa; therefore no measurable concentrations of dornase alfa would be expected in human milk.

 

A four-week inhalation toxicity study in juvenile rats commenced dosing 22 days after parturition at doses to the LRT of 0, 51, 102 and 260 µg/kg/day. Dornase alfa was well tolerated, and no lesions were found in the respiratory tract.

 

Underlined text = new text
Struck through text = deleted text

 

5.1     Pharmacodynamic properties

 

Clinical Trial Results

 

Efficacy and safety was established in double-blind, placebo-controlled studies (Z0342/Z0343) in which patients over 5 years of age and with FVC over 40% predicted received 2.5 mg Pulmozyme once or twice daily over a 24-week period. Overall, 968 patients (mean age of 19 years) with a mean baseline FVC of 78% were randomised in these trials.

Another placebo-controlled double-blind study (Z0713) evaluated the effect of Pulmozyme (2.5 mg once daily for 2 years) on pulmonary function in young patients (aged 6-11 years) with minimum evidence of lung disease as defined by FVC of ≥ 85% predicted. Overall, 474 patients (mean age of 8.4 years) with a mean baseline FVC of 102.3% were randomised in this trial.

 

Results of the main endpoints are shown in the following tables. A significant increase in FEV₁ was observed in the beginning of treatment with Pulmozyme and subsided over time, especially after the first year of treatment; however, the difference with placebo remained statistically significant. Pulmozyme reduced the relative risk of respiratory tract exacerbations requiring parenteral antibiotics by about 30%; this reduction did not correlate with the improvement in FEV₁ measured during the first weeks of therapy.

 

Studies Z0342/Z0343		Placebo	2.5mg QD	2.5mg BID
		N = 325	N = 322	N = 321
FEV1 (% predicted)	Mean % change from baseline
	Day 8	- 0.5%	7.9%	9.0%
	Week 24	0.1%	5.1%	3.6%
	Overall	0.0%	5.8%	5.6%
			p < 0.001	p < 0.001
% patients with exacerbations	over 24 weeks	43%	34%	33%
	Relative risk (95% CI)		0.73 (0.57 - 0.94)	0.71 (0.55 - 0.91)
			p = 0.015	p = 0.007

 

Study Z0713		Placebo	2.5mg QD
		N = 235	N = 237
Spirometry	Mean change from baseline (at Week 96)
FEV1 (% predicted)		- 3.10	0.03
			p = 0.008
FVC (% predicted)		- 2.88	- 2.23
			p = 0.54
FEF 25-75 (% predicted)		- 4.05	3.83
			p = 0.0008
% patients with exacerbations	over 96 weeks	24%	17%
	Relative risk (95% CI)		0.66 (0.44 - 0.996)
			p = 0.048

 

Post-hoc analysis of the data suggests that the effects of Pulmozyme on respiratory tract exacerbations in older patients (>21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. The percentage of older patients developing exacerbations over 24 weeks was 44% on placebo, 48% and 39% on Pulmozyme 2.5 mg daily and twice daily, respectively.

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

PL 00031/0335

PA 50/91/1

 

10.     DATE OF REVISION OF THE TEXT

 

11 March 20094 June 2010

 

LEGAL STATUS

 

POM

 

addition of PA number in section 8

Underlined text has been added, text with strike through deleted:

 

4.7     Effects on ability to drive and use machines

 

No effects on the patient's ability to drive and use machines have been reportedPulmozyme has no or negligible influence on the ability to drive and use machines.

 

4.8     Undesirable effects

 

The adverse event data reflect the clinical trial and post-marketing experience of using Pulmozyme at the recommended dose regimen.

 

Adverse reactions attributed to Pulmozyme are rare (< 1/1000).  In most cases, the adverse reactions are mild and transient in nature and do not require alterations in Pulmozyme dosing.

 

Eye disorders:
Conjunctivitis

 

Respiratory, thoracic and mediastinal disorders:
Dysphonia, dyspnea, pharyngitis, laryngitis, rhinitis (all non-infectious).

Gastrointestinal disorders:
Dyspepsia.

Skin and subcutaneous tissue disorders:
Rash, urticaria.

General disorders:
Chest pain (pleuritic/non-cardiac), pyrexia.

Investigations:

Pulmonary function tests decreased.

Body as a whole:                                 Chest pain (pleuritic / non-cardiac), fever

Special senses:                         Conjunctivitis 

Gastrointestinal system:                      Dyspepsia

Respiratory system:                Voice alteration (hoarseness), pharyngitis (inflammation of the throat), dyspnoea, laryngitis, rhinitis, decreased lung function

Skin and Appendages:             Rash, urticaria

 

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