▶ Manufacturer advises reduce dose to 150 mg once daily
with concurrent use of moderate inhibitors of CYP3A4.
l CONTRA-INDICATIONS Organ transplantation (no
l INTERACTIONS → Appendix 1: ivacaftor
▶ Frequency not known Hepatic function abnormal
SIDE-EFFECTS, FURTHER INFORMATION Manufacturer
advises interrupt treatment if transaminase levels more
than 5 times the upper limit of normal or transaminase
levels more than 3 times the upper limit of
normal and blood bilirubin more than twice the upper
limit of normal—consult product literature.
l PREGNANCY Manufacturer advises use only if potential
benefit outweighs risk—limited information available.
l BREAST FEEDING Manufacturer advises avoid—present in
l HEPATIC IMPAIRMENT Manufacturer advises caution in
moderate to severe impairment (limited information
Dose adjustments Manufacturer advises reduce dose to
150 mg once daily in moderate impairment; in severe
impairment reduce starting dose to 150 mg on alternate
days, adjust dosing interval according to clinical response
l RENAL IMPAIRMENT Caution in severe impairment.
l MONITORING REQUIREMENTS Manufacturer advises
monitor liver function before treatment, every 3 months
during the first year of treatment, then annually thereafter
(more frequent monitoring should be considered in
patients with a history of transaminase elevations).
l DIRECTIONS FOR ADMINISTRATION Tablets should be
taken with fat-containing food.
l PRESCRIBING AND DISPENSING INFORMATION Ivacaftor
should be prescribed by a physician experienced in the
l PATIENT AND CARER ADVICE Patients or carers should be
given advice on how to administer ivacaftor tablets.
Driving and skilled tasks Manufacturer advises that
patients and their carers should be counselled on the
effects on driving and skilled tasks—increased risk of
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (December
2016) that ivacaftor (Kalydeco ®) is not recommended for
use within NHS Scotland for the treatment of patients with
cystic fibrosis aged 18 years and above who have an R117H
mutation in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene, as insufficient clinical
and economic evidence was submitted.
All Wales Medicines Strategy Group (AWMSG) decisions
The All Wales Medicines Strategy Group has advised
(October 2017) that ivacaftor (Kalydeco ®) is recommended
for restricted use within NHS Wales for the treatment of
adults with cystic fibrosis (CF) who have an R117H
mutation in the CF transmembrane conductance regulator
(CFTR) gene. This recommendation will apply only when
people are treated in line with the relevant Welsh clinical
access policy and only in circumstances where the
approved Wales Patient Access Scheme (WPAS) is utilised
or where the list/contract price is equivalent or lower.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 25
▶ Kalydeco (Vertex Pharmaceuticals (UK) Ltd) A
Ivacaftor 150 mg Kalydeco 150mg tablets | 28 tablet P £7,000.00 | 56 tablet P £14,000.00
Lumacaftor with ivacaftor 24-Apr-2019
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, ivacaftor p. 293.
Cystic fibrosis (specialist use only)
▶ Adult: 400/250 mg every 12 hours
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises reduce initial dose to 200/125 mg
daily for the first week in those also taking a potent
DOSE EQUIVALENCE AND CONVERSION
▶ Dose expressed as x/y mg of lumacaftor/ivacaftor.
l CAUTIONS Forced expiratory volume in 1 second (FEV1)
less than 40% of the predicted normal value—additional
monitoring required at initiation of treatment. pulmonary
exacerbation—no information available
l INTERACTIONS → Appendix 1: ivacaftor. lumacaftor
▶ Uncommon Gynaecomastia . hepatic encephalopathy . hepatitis cholestatic . hypertension
▶ Frequency not known Cataract. chest pain
SIDE-EFFECTS, FURTHER INFORMATION Manufacturer
advises interrupt treatment if transaminase levels more
than 5 times the upper limit of normal or transaminase
levels more than 3 times the upper limit of
normal and blood bilirubin more than twice the upper
limit of normal—consult product literature.
l HEPATIC IMPAIRMENT Manufacturer advises caution in
moderate to severe impairment (risk of increased
Dose adjustments Manufacturer advises dose reduction of
evening dose to 200/125 mg in moderate impairment; in
severe impairment, dose reduction to 200/125 mg every
l PRE-TREATMENT SCREENING If the patient’s genotype is
unknown, a validated genotyping method should be
performed to confirm the presence of the F508del
mutation on both alleles of the CFTR gene before starting
l MONITORING REQUIREMENTS Manufacturer advises
monitor blood pressure periodically during treatment.
l EFFECT ON LABORATORY TESTS False positive urine
screening tests for tetrahydrocannabinol have been
reported—manufacturer advises consider alternative
l DIRECTIONS FOR ADMINISTRATION Tablets should be
taken with fat-containing food.
l PATIENT AND CARER ADVICE Patients or carers should be
given advice on how to administer tablets.
Missed doses Manufacturer advises if a dose is more than
6 hours late, the missed dose should not be taken and the
next dose should be taken at the normal time.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Lumacaftor with ivacaftor for treating cystic fibrosis
homozygous for the F508del mutation (July 2016) NICE TA398
Lumacaftor with ivacaftor (Orkambi ®) is not
recommended, within its marketing authorisation, for
treating cystic fibrosis in patients aged 12 years and older
who are homozygous for the F508del mutation in the
cystic fibrosis transmembrane conductance regulator
Patients whose treatment was started within the NHS
before this guidance was published should have the option
to continue treatment, without change to their funding
arrangements, until they (or their carers) and their NHS
clinician consider it appropriate to stop.
www.nice.org.uk/guidance/ta398
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (May 2016)
that lumacaftor with ivacaftor (Orkambi ®) is not
recommended within NHS Scotland for the treatment of
cystic fibrosis in patients aged 12 years and older who are
homozygous for the F508del mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene, as the
economic case was not demonstrated.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 25
EXCIPIENTS: May contain Propylene glycol
▶ Orkambi (Vertex Pharmaceuticals (UK) Ltd) A
Lumacaftor 100 mg, Ivacaftor 125 mg Orkambi 100mg/125mg
tablets | 112 tablet P £8,000.00 (Hospital only)
Ivacaftor 125 mg, Lumacaftor 200 mg Orkambi 200mg/125mg
tablets | 112 tablet P £8,000.00 (Hospital only)
294 Conditions affecting sputum viscosity BNF 78
Treatment of cystic fibrosis as an add-on therapy to
▶ Adult: Maintenance 400 mg twice daily, an initiation
dose assessment must be carried out under medical
supervision, for details of the initiation dose regimen,
l CONTRA-INDICATIONS Bronchial hyperresponsiveness to
inhaled mannitol . impaired lung function (forced
expiratory volume in 1 second < 30% of predicted). nonCF bronchiectasis
l CAUTIONS Asthma . haemoptysis
▶ Common or very common Chest discomfort. condition
aggravated . cough . haemoptysis . headache .respiratory
disorders .throat complaints . vomiting
disorders . hypoxia . increased risk of infection . influenza
like illness . insomnia . joint disorders . malaise . morbid
l PREGNANCY Manufacturer advises avoid.
l BREAST FEEDING Manufacturer advises avoid.
l PRE-TREATMENT SCREENING Patients must be assessed for
bronchial hyperresponsiveness to inhaled mannitol before
starting the therapeutic dose regimen; an initiation dose
assessment must be carried out under medical
supervision—for details of the initiation dose regimen,
l DIRECTIONS FOR ADMINISTRATION The dose should be
administered 5–15 minutes after a bronchodilator and
before physiotherapy; the second daily dose should be
taken 2–3 hours before bedtime.
l PATIENT AND CARER ADVICE Patients or carers should be
given advice on how to administer mannitol inhalation
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Mannitol dry powder for inhalation for treating cystic fibrosis
Mannitol (Bronchitol ®) dry powder for inhalation is
recommended as an option for treating cystic fibrosis in
. who cannot use dornase alfa (rhDNase) because of
ineligibility, intolerance or inadequate response to
. whose lung function is rapidly declining (forced
expiratory volume in 1 second decline greater than
. for whom other osmotic agents are not considered
Patients whose treatment was started within the NHS
before this guidance was published should have the option
to continue treatment, until they and their NHS clinician
consider it appropriate to stop.
www.nice.org.uk/guidance/ta266
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (December
2013) that mannitol (Bronchitol ®) is accepted for restricted
use within NHS Scotland for the treatment of cystic
fibrosis in adults as an add-on therapy to best standard of
care. Mannitol is restricted to patients who are not
currently using dornase alfa due to lack of response,
intolerance, or ineligibility and have rapidly declining lung
function and in whom other osmotic agents are considered
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Osmohale (Mawdsley-Brooks & Company Ltd)
Mannitol 5 mg Osmohale 5mg inhalation powder capsules | 1 capsule P s
Mannitol 10 mg Osmohale 10mg inhalation powder capsules | 1 capsule P s
Mannitol 20 mg Osmohale 20mg inhalation powder capsules |
Mannitol 40 mg Osmohale 40mg inhalation powder capsules | 15 capsule P s
Mannitol 40 mg Bronchitol 40mg inhalation powder capsules with
two devices | 280 capsule P £231.66
Bronchitol 40mg inhalation powder capsules with device |
Tezacaftor with ivacaftor 19-Mar-2019
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, ivacaftor p. 293.
Cystic fibrosis (in combination with ivacaftor) (specialist
▶ Adult: 100/150 mg, to be taken in the morning and,
Ivacaftor 150 mg to be taken in the evening
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ With concurrent use of potent CYP3A4 inhibitors,
manufacturer advises reduce dose to 100/150 mg
tezacaftor/ivacaftor twice a week, taken approximately
3–4 days apart; the evening dose of ivacaftor should
▶ With concurrent use of moderate CYP3A4 inhibitors,
manufacturer advises reduce dose to 100/150 mg
tezacaftor/ivacaftor every other morning, with
ivacaftor 150 mg taken in the mornings alternate to
tezacaftor/ivacaftor; the evening dose of ivacaftor
DOSE EQUIVALENCE AND CONVERSION
▶ Combination dose expressed as x/y mg of
l INTERACTIONS → Appendix 1: ivacaftor.tezacaftor
▶ Common or very common Abdominal pain . breast
▶ Frequency not known Hepatic function abnormal
SIDE-EFFECTS, FURTHER INFORMATION Manufacturer
advises interrupt treatment if transaminase levels more
than 5 times the upper limit of normal or transaminase
levels more than 3 times the upper limit of
normal and blood bilirubin more than twice the upper
limit of normal—consult product literature.
l HEPATIC IMPAIRMENT Manufacturer advises caution in
moderate to severe impairment (risk of increased
Dose adjustments Manufacturer advises omit evening dose
of ivacaftor in moderate to severe impairment; in severe
impairment, adjust dosing interval according to clinical
Missed doses Manufacturer advises if a dose is more than
6 hours late, the missed dose should not be taken and the
next dose should be taken at the normal time.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 25
▶ Symkevi (Vertex Pharmaceuticals (UK) Ltd) A
Tezacaftor 100 mg, Ivacaftor 150 mg Symkevi 100mg/150mg
tablets | 28 tablet P £6,293.91 (Hospital only)
preparations and systemic nasal
Aromatic inhalations in adults
Inhalations containing volatile substances such as
eucalyptus oil are traditionally used and although the vapour
may contain little of the additive it encourages deliberate
inspiration of warm moist air which is often comforting in
bronchitis; boiling water should not be used owing to the
risk of scalding. In practice, inhalations are also used for the
relief of nasal obstruction in acute rhinitis or sinusitis.
Cough may be a symptom of an underlying disorder, such as
asthma, gastro-oesophageal reflux disease, or rhinitis, which
should be addressed before prescribing cough suppressants.
Cough may be a side-effect of another drug, such as an ACE
inhibitor, or it can be associated with smoking or
environmental pollutants. Cough can also have a significant
habit component. When there is no identifiable cause, cough
suppressants may be useful, for example if sleep is disturbed.
They may cause sputum retention and this may be harmful
in patients with chronic bronchitis and bronchiectasis.
There is some evidence to suggest that codeine phosphate
p. 454 provides no benefit for symptoms of acute cough.
Codeine phosphate is also constipating and can cause
dependence; dextromethorphan and pholcodine below
Sedating antihistamines are used as the cough
suppressant component of many compound cough
preparations on sale to the public; all tend to cause
drowsiness which may reflect their main mode of action.
Diamorphine hydrochloride p. 456 and methadone
hydrochloride p. 502 have been used to control distressing
cough in terminal lung cancer although morphine p. 463 is
ventilatory failure as well as causing opioid dependence.
Methadone hydrochloride linctus should be avoided because
it has a long duration of action and tends to accumulate.
Demulcent and expectorant cough preparations
Demulcent cough preparations contain soothing
substances such as syrup or glycerol and some patients
believe that such preparations relieve a dry irritating cough.
Preparations such as simple linctus have the advantage of
being harmless and inexpensive; paediatric simple linctus
is particularly useful in children.
Expectorants are claimed to promote expulsion of
bronchial secretions, but there is no evidence that any drug
can specifically facilitate expectoration.
g An over-the-counter cough medicine containing the
expectorant guaifenesin may be used for acute cough; there
is some evidence to suggest it may reduce symptoms. h
Compound preparations are on sale to the public for the
treatment of cough and colds but should not be used in
children under 6 years; the rationale for some is dubious.
Care should be taken to give the correct dose and to not use
more than one preparation at a time.
Nasal decongestants for administration by mouth may not
be as effective as preparations for local application but they
do not give rise to rebound nasal congestion on withdrawal.
Pseudoephedrine hydrochloride p. 1202 is available over the
counter; it has few sympathomimetic effects.
Aromatic inhalations in children
The use of strong aromatic decongestants (applied as rubs or
to pillows) is not advised for infants under the age of
3 months. Carers of young infants in whom nasal obstruction
with mucus is a problem can readily be taught appropriate
techniques of suction aspiration but sodium chloride 0.9%
p. 1040 given as nasal drops is preferred; administration
before feeds may ease feeding difficulties caused by nasal
Cough preparations in children
The use of over-the-counter cough suppressants containing
codeine phosphate should be avoided in children under
12 years and in children of any age known to be CYP2D6
ultra-rapid metabolisers. Cough suppressants containing
similar opioid analgesics such as dextromethorphan and
pholcodine are not generally recommended in children and
should be avoided in children under 6 years;
dextromethorphan should be avoided in children under
MHRA/CHM advice (March 2008 and February 2009)
Children under 6 years should not be given over-the-counter
cough and cold medicines containing the following
. brompheniramine, chlorphenamine maleate p. 283,
diphenhydramine, doxylamine, promethazine, or
triprolidine (antihistamines);
. dextromethorphan or pholcodine (cough suppressants);
. guaifenesin or ipecacuanha (expectorants);
. Phenylephrine hydrochloride p. 189, pseudoephedrine
hydrochloride, ephedrine hydrochloride p. 1202,
oxymetazoline, or xylometazoline hydrochloride p. 1203
Over-the-counter cough and cold medicines can be
considered for children aged 6–12 years after basic principles
of best care have been tried, but treatment should be
restricted to five days or less. Children should not be given
more than 1 cough or cold preparation at a time because
different brands may contain the same active ingredient;
care should be taken to give the correct dose.
COUGH AND COLD PREPARATIONS › COUGH
▶ Child 6–11 years: 2–5 mg 3–4 times a day
▶ Child 12–17 years: 5–10 mg 3–4 times a day
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