reversibility of which is uncertain—if possible, consider
starting treatment after pubertal growth spurt (in children)
. severe dental disorders (in adults). severe ocular
disorders (in adults). severe periodontal disorders (in
adults). severe psychiatric effects (in adults)
l INTERACTIONS → Appendix 1: ribavirin
pain . fever. gastrointestinal discomfort. gastrointestinal
weakness . nasal congestion . nausea . neutropenia . oral
abnormal . sexual dysfunction . skin reactions . sleep
disorders . sarcoidosis . suicidal tendencies .thyroiditis
▶ Rare or very rare Angina pectoris . angioedema . bone
marrow disorders . cardiac inflammation . cerebral
cutaneous adverse reactions (SCARs). systemic lupus
erythematosus (SLE) . vasculitis
▶ Frequency not known Haemolytic anaemia . homicidal
ideation . nephrotic syndrome . pure red cell aplasia .renal
failure . solid organ transplant rejection .tongue
discolouration . ulcerative colitis
SIDE-EFFECTS, FURTHER INFORMATION Side effects listed
are reported when oral ribavirin is used in combination
with peginterferon alfa or interferon alfa, consult product
l CONCEPTION AND CONTRACEPTION
▶ With systemic use Exclude pregnancy before treatment in
females of childbearing age. Effective contraception
essential during treatment and for 4 months after
treatment in females and for 7 months after treatment in
males of childbearing age. Routine monthly pregnancy
tests recommended. Condoms must be used if partner of
male patient is pregnant (ribavirin excreted in semen).
▶ When used by inhalation Women planning pregnancy should
l PREGNANCY Avoid; teratogenicity in animal studies.
▶ When used by inhalation Pregnant women should avoid
l BREAST FEEDING Avoid—no information available.
l HEPATIC IMPAIRMENT Avoid oral ribavirin in severe
hepatic dysfunction or decompensated cirrhosis.
Dose adjustments No dosage adjustment required.
l RENAL IMPAIRMENT Plasma-ribavirin concentration
▶ In adults Manufacturer advises avoid oral ribavirin unless
essential if eGFR less than 50 mL/minute/1.73 m2
monitor haemoglobin concentration closely.
▶ In children Manufacturer advises avoid oral ribavirin if
estimated glomerular filtration rate less than
concentration closely. Manufacturer advises use
intravenous preparation with caution if estimated
glomerular filtration rate less than 30 mL/minute/1.73 m2
▶ When used by inhalation Monitor electrolytes closely.
Monitor equipment for precipitation.
▶ With systemic use in children Determine full blood count,
platelets, electrolytes, serum creatinine, liver function
tests and uric acid before starting treatment and then on
weeks 2 and 4 of treatment, then as indicated clinically—
adjust dose if adverse reactions or laboratory
abnormalities develop (consult product literature).
▶ With systemic use in adults Determine full blood count,
platelets, electrolytes, glucose, serum creatinine, liver
function tests and uric acid before starting treatment and
then on weeks 2 and 4 of treatment, then as indicated
clinically—adjust dose if adverse reactions or laboratory
abnormalities develop (consult product literature).
▶ With systemic use in children Test thyroid function before
treatment and then every 3 months.
▶ With oral use in children Eye examination recommended
before treatment. Eye examination also recommended
during treatment if pre-existing ophthalmological disorder
or if decrease in vision reported—discontinue treatment if
ophthalmological disorder deteriorates or if new
ophthalmological disorder develops.
l PRESCRIBING AND DISPENSING INFORMATION Flavours of
oral liquid formulations may include bubble-gum.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Peginterferon alfa and ribavirin for mild chronic hepatitis C
(August 2006 and September 2010) NICE TA200
▶ In adults The combination of peginterferon alfa and
ribavirin can be used for treating mild chronic hepatitis C
in patients over 18 years. Alternatively, treatment can be
delayed until the disease has reached a moderate stage
▶ Peginterferon alfa, interferon alfa, and ribavirin for moderate
to severe chronic hepatitis C (January 2004 and September
▶ In adults The combination of peginterferon alfa and
ribavirin should be used for treating moderate to severe
chronic hepatitis C in patients aged over 18 years:.
. not previously treated with interferon alfa or
. treated previously with interferon alfa alone or in
. whose condition did not respond to peginterferon alfa
alone or to a combination of peginterferon alfa and
ribavirin, or responded but subsequently relapsed;
Peginterferon alfa alone should be used if ribavirin is
contra-indicated or not tolerated. Interferon alfa for either
monotherapy or combined therapy should be used only if
neutropenia and thrombocytopenia are a particular risk.
Patients receiving interferon alfa may be switched to
▶ Peginterferon alfa and ribavirin for chronic hepatitis C
▶ In children Peginterferon alfa in combination with ribavirin
is recommended (within the marketing authorisation) as
an option for treating chronic hepatitis C in children.
l LESS SUITABLE FOR PRESCRIBING Ribavirin inhalation is
less suitable for prescribing.
BNF 78 Chronic hepatitis C 627
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Virazole (Meda Pharmaceuticals Ltd)
Ribavirin 100 mg per 1 ml Virazole 1.2g/12ml solution for injection
CAUTIONARY AND ADVISORY LABELS 21
▶ Rebetol (Merck Sharp & Dohme Ltd)
Ribavirin 40 mg per 1 ml Rebetol 40mg/ml oral solution | 100 ml P £67.08
CAUTIONARY AND ADVISORY LABELS 21
▶ Copegus (Roche Products Ltd)
Ribavirin 200 mg Copegus 200mg tablets | 112 tablet P £233.58 | 168 tablet P £350.37
Ribavirin 400 mg Copegus 400mg tablets | 56 tablet P £233.58
CAUTIONARY AND ADVISORY LABELS 21
▶ Rebetol (Merck Sharp & Dohme Ltd)
Ribavirin 200 mg Rebetol 200mg capsules | 168 capsule P £321.38
ANTIVIRALS › NUCLEOTIDE ANALOGUES
Ledipasvir with sofosbuvir 11-Jul-2018
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, sofosbuvir below.
l DRUG ACTION Sofosbuvir is a nucleotide analogue
inhibitor and ledipasvir is an HCV inhibitor; they reduce
viral load by inhibiting hepatitis C virus RNA replication.
Chronic hepatitis C infection (initiated by a specialist)
▶ Adult: 90/400 mg once daily, for duration of treatment
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises reduce dose of concurrent H2-
receptor antagonist if above a dose comparable to
▶ Manufacturer advises reduce dose of concurrent proton
pump inhibitor if above a dose comparable to
omeprazole 20 mg; take at the same time as sofosbuvir
DOSE EQUIVALENCE AND CONVERSION
▶ Dose expressed as x/y mg ledipasvir/sofosbuvir.
l CAUTIONS Retreatment following treatment failure—
l INTERACTIONS → Appendix 1: ledipasvir. sofosbuvir
▶ Common or very common Fatigue . headache .rash
▶ Frequency not known Angioedema . arrhythmia
l PRESCRIBING AND DISPENSING INFORMATION Dispense in
original container (contains desiccant).
Vomiting If vomiting occurs within 5 hours of
administration, an additional dose should be taken.
Missed doses If a dose is more than 18 hours late, the
missed dose should not be taken and the next dose should
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Ledipasvir–sofosbuvir for treating chronic hepatitis C
Ledipasvir with sofosbuvir is recommended as an option
for treating adults with chronic hepatitis C infection:
. of genotype 1 without cirrhosis (treatment naive
. of genotype 1 or 4 with cirrhosis (treatment naive
. of genotype 1 or 4 without cirrhosis (or with cirrhosis but
only if the person has a low risk of the disease getting
worse) that has not responded adequately to previous
In addition, ledipasvir with sofosbuvir is only
recommended in patients with cirrhosis for the durations
mentioned above if the following criteria are met:
. platelet count of 75 000/mm3 or more
. no features of portal hypertension
. no history of an HCV-associated decompensation
. not previously treated with an NS5A inhibitor
Patients whose treatment with ledipasvir with sofosbuvir
is not recommended in this NICE guidance, but was started
within the NHS before this guidance was published, should
be able to continue treatment until they and their NHS
clinician consider it appropriate to stop.
www.nice.org.uk/guidance/ta363
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (March
2015) that ledipasvir with sofosbuvir (Harvoni ®) is
accepted for restricted use within NHS Scotland for the
treatment of chronic hepatitis C infection of genotypes 1
The Scottish Medicines Consortium has advised
(September 2015) that ledipasvir with sofosbuvir
(Harvoni ®) is accepted for restricted use within NHS
Scotland for the treatment of chronic hepatitis C infection
of genotype 3 in patients who are ineligible for, or unable
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 25
▶ Harvoni (Gilead Sciences International Ltd) A
Ledipasvir 90 mg, Sofosbuvir 400 mg Harvoni 90mg/400mg
tablets | 28 tablet P £12,993.33
▶ Adult: 400 mg once daily, for duration of treatment
MHRA/CHM ADVICE: DIRECT-ACTING ANTIVIRALS TO TREAT
CHRONIC HEPATITIS C: RISK OF INTERACTION WITH VITAMIN K
ANTAGONISTS AND CHANGES IN INR (JANUARY 2017)
An EU-wide review has identified that changes in liver
antagonists; the MHRA has advised that INR should be
monitored closely in patients receiving concomitant
HEPATITIS B REACTIVATION (JANUARY 2017)
An EU-wide review has concluded that direct-acting
antiviral interferon-free regimens for chronic hepatitis C
can cause hepatitis B reactivation in patients co-infected
with hepatitis B and C viruses; the MHRA recommends
to screen patients for hepatitis B before starting
treatment—patients infected with both hepatitis B and C
viruses must be monitored and managed according to
MHRA/CHM ADVICE: DIRECT-ACTING ANTIVIRALS FOR CHRONIC
HEPATITIS C: RISK OF HYPOGLYCAEMIA IN PATIENTS WITH
glucose metabolism in patients with diabetes and result
in symptomatic hypoglycaemia if diabetic treatment is
The MHRA advises healthcare professionals:
. to monitor glucose levels closely in patients with
diabetes during direct-acting antiviral therapy for
hepatitis C, especially within the first 3 months of
treatment and modify diabetic medication or doses
. to be vigilant for changes in glucose tolerance and
advise patients of the risk of hypoglycaemia;
. to inform the healthcare professional in charge of the
diabetic care of the patient when direct-acting
antiviral therapy is initiated.
CAUTIONS, FURTHER INFORMATION Manufacturer advises
in chronic hepatitis C of genotype 1, 4, 5, or 6, only use
sofosbuvir with ribavirin dual therapy in those with
intolerance or contra-indications to peginterferon alfa
l INTERACTIONS → Appendix 1: sofosbuvir
reactions . vision blurred . vomiting . weight decreased
▶ Frequency not known Arrhythmia
SIDE-EFFECTS, FURTHER INFORMATION Side-effects listed
are reported when sofosbuvir is used in combination with
ribavirin or with ribavirin and peginterferon alfa.
l PREGNANCY Manufacturer advises avoid—limited
l BREAST FEEDING Manufacturer advises avoid—present in
l RENAL IMPAIRMENT Safety and efficacy not established if
eGFR less than 30 mL/minute/1.73 m2
l PRESCRIBING AND DISPENSING INFORMATION Dispense in
original container (contains desiccant).
Missed doses Manufacturer advises if a dose is more than
18 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
▶ Sofosbuvir for treating chronic hepatitis C (February 2015)
Sofosbuvir (Sovaldi ®) in combination with peginterferon
alfa and ribavirin is an option for treating adults with
chronic hepatitis C infection:
. of genotype 3 with cirrhosis (treatment naive patients)
. of genotype 3 that has not adequately responded to
. of genotype 4, 5, or 6 with cirrhosis.
Sofosbuvir (Sovaldi ®) in combination with ribavirin is an
option for treating adults with chronic hepatitis C
. of genotype 2 who are intolerant to or ineligible for
interferon (treatment naive patients)
. of genotype 2 that has not adequately responded to
. of genotype 3 with cirrhosis who are intolerant to or
ineligible for interferon (treatment naive patients)
. of genotype 3 with cirrhosis that has not adequately
responded to interferon-based treatment
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 and their NHS clinician consider
www.nice.org.uk/guidance/ta330
▶ Sofosbuvir for treating chronic hepatitis C (February 2015)
Sofosbuvir (Sovaldi ®) in combination with ribavirin is not
recommended for the treatment of adults with chronic
hepatitis C infection of genotypes 1, 4, 5, or 6.
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 and their NHS clinician consider
www.nice.org.uk/guidance/ta330
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (June 2014)
that sofosbuvir (Sovaldi ®) is accepted for restricted use
within NHS Scotland for the treatment of chronic hepatitis
C infection of genotypes 1 to 6; its use in combination with
ribavirin as dual therapy for chronic hepatitis C infection
of either genotype 2 (in treatment naive patients) or
genotype 3 is restricted to those who cannot use
peginterferon alfa because of intolerance or contraindications.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 21, 25
▶ Sovaldi (Gilead Sciences International Ltd) A
Sofosbuvir 400 mg Sovaldi 400mg tablets | 28 tablet P £11,660.98
Sofosbuvir with velpatasvir 24-Jul-2017
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, sofosbuvir p. 628.
l DRUG ACTION Sofosbuvir is a nucleotide analogue
inhibitor and velpatasvir is an HCV inhibitor; they reduce
viral load by inhibiting hepatitis C virus RNA replication.
Chronic hepatitis C infection, with or without ribavirin
▶ Adult: 400/100 mg once daily for 12 weeks (may extend
to 24 weeks in some circumstances—consult product
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises reduce dose of concurrent H2-
receptor antagonist if above a dose comparable to
▶ Manufacturer advises reduce dose of concurrent proton
pump inhibitor if above a dose comparable to
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