Composition:
Each film coated tablet contains:
90 mg ledipasvir.
400 mg sofosbuvir.
Excipients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose
monohydrate, magnesium stearate, microcrystalline cellulose, FD&C yellow
#6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc,
and titanium dioxide.
Mechanism of action:
Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential
for both RNA replication and the assembly of HCV virions. Biochemical confirmation
of NS5A inhibition by ledipasvir is not currently possible as NS5A has no
enzymatic function.
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA
polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide
prodrug that undergoes intracellular metabolism to form the pharmacologically
active uridine analog triphosphate (GS-461203), which can be incorporated into
HCV RNA by the NS5B polymerase and acts as a chain terminator.
Pharmacokinetics:
Absorption:
Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients,
ledipasvir median peak plasma concentration was observed at 4.0 hours
post-dose. Sofosbuvir was absorbed quickly and the median peak plasma
concentration was observed ~1 hour post-dose, regardless of dose level. Peak
plasma concentration of GS-331007 was observed at 4 hours post-dose.
Effects of food:
Relative to fasting conditions, the administration of a single dose of
Ledipasvir/sofosbuvir with a moderate fat or high fat meal increased the
sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect the
sofosbuvir Cmax. The exposures to GS-331007 and ledipasvir were not altered
in the presence of either meal type.
Distribution:
Ledipasvir is > 99.8 % bound to human plasma proteins. Sofosbuvir is
approximately 61-65 % bound to human plasma proteins and the binding is
independent of drug concentration over the range of 1 μg/mL to 20 μg/mL.
Protein binding of GS-331007 was minimal in human plasma.
Biotransformation:
Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was
almost exclusively due to the parent drug (> 98%). Unchanged ledipasvir is also
the major species present in faeces.
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically
active nucleoside analog triphosphate GS-461203. The active metabolite is not
observed.
Elimination:
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of
the [14C]-radioactivity in faeces and urine was 87%, with most of the radioactive
dose recovered from faeces (86%). Unchanged ledipasvir excreted in faeces
accounted for a mean of 70% of the administered dose and the oxidative
metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary
excretion of unchanged ledipasvir is a major route of elimination with renal
excretion being a minor pathway (approximately 1%).
Following a single 400 mg oral dose of sofosbuvir, mean total recovery of the
dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5%
recovered in urine, faeces, and expired air, respectively. The majority of the
sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was
recovered as sofosbuvir. This data indicate that renal clearance is the major
elimination pathway for GS-331007 with a large part actively secreted. The
median terminal half-livesof sofosbuvir and GS-331007 following administration
of ledipasvir/sofosbuvir were 0.5 and 27 hours, respectively.
Indications :
Ledipasvir / Sofosbuvir is indicated for the treatment of chronic hepatitis C
(CHC) in adults. For hepatitis C virus (HCV) genotype-specific activity.
Contraindications:
Hypersensitivity to the active substances or to any of the excipients.
Co-administration with rosuvastatin.
Side Effects:
Adverse drug reactions identified with Harvomed:
headache ,rash, fatigue.
Patients with decompensated cirrhosis and/or who are awaiting liver transplant
or post-liver transplant:
Decreases in haemoglobin, patients treated with ledipasvir/sofosbuvir with
ribavirin, respectively. Ribavirin was discontinued in 19% of the patients. 10% of
liver transplant recipients had a modification of their immunosuppressive agents.
Cardiac arrhythmias:
Cases of severe bradycardia and heart block have been observed when
Ledipasvir / Sofosbuvir is used with concomitant amiodarone and/or other drugs
that lower heart rate.
warnings and precautions for use:
Ledipasvir / Sofosbuvir should not be administered concomitantly with other
medicinal products containing sofosbuvir.
Genotype-specific activity:
The clinical data to support the use of Ledipasvir / Sofosbuvir in patients infected
with HCV genotype 3 are limited.
A conservative 24 weeks of therapy is advised in all treatment-experienced
genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis.
The clinical data to support the use of Ledipasvir / Sofosbuvir in patients infected
with HCV genotype 2 and 6 are limited.
Severe bradycardia and heart block:
Cases of severe bradycardia and heart block have been observed when
Ledipasvir / Sofosbuvir is used with concomitant amiodarone with or without
other drugs that lower heart rate. The mechanism is not established. All patients
receiving Ledipasvir / Sofosbuvir in combination with amiodarone with or without
other drugs that lower heart rate should also be warned of the symptoms of
bradycardia and heart block and should be advised to seek medical advice
urgently should they experience them.
Treatment of patients with prior exposure to HCV direct-acting antivirals:
In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance
mutations that substantially reduce the susceptibility to ledipasvir is seen in the
majority of cases. There are presently no data to support the effectiveness of
retreatment of patients who have failed ledipasvir/sofosbuvir with a subsequent
regimen that contains an NS5A inhibitor. Similarly, there are presently no data
to support the effectiveness of NS3/4A protease inhibitors in patients who
previously failed prior therapy that included an NS3/4A protease inhibitor. Such
patients may therefore be dependent on other drug classes for clearance of HCV
infection.
Patients with decompensated cirrhosis and/or who are awaiting liver transplant
or post-liver transplant:
The efficacy of ledipasvir/sofosbuvir in genotype 5 and genotype 6 HCV-infected
patients with decompensated cirrhosis and/or who are awaiting liver transplant
or post-liver transplant has not been investigated.
Use with moderate P-gp inducers:
Medicinal products that are moderate P-gp inducers in the intestine (e.g.
oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations
leading to reduced therapeutic effect of Harvomed. Co-administration of such
medicinal products is not recommended with Harvomed.
Use with certain HIV antiretroviral regimens:
The potential risks and benefits associated with co-administration of
Ledipasvir / Sofosbuvir with the fixed-dose combination tablet containing
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir
disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor
(e.g. atazanavir or darunavir) should be considered, particularly in patients at
increased risk of renal dysfunction. Patients receiving Ledipasvir / Sofosbuvir
concomitantly with one of previous drugs should be monitored for
tenofovir-associated adverse reactions.
Use with HMG-CoA reductase inhibitors:
Co-administration of Ledipasvir / Sofosbuvir and HMG-CoA reductase inhibitors
(statins) can significantly increase the concentration of the statin, which increases
the risk of myopathy and rhabdomyolysis.
HCV/HBV (hepatitis B virus) co-infection:
HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore
be monitored and managed according to current clinical guidelines.
Excipients:
Ledipasvir / Sofosbuvir contains the azo colouring agent sunset yellow FCF
aluminium lake (E110), which may cause allergic reactions. It also contains
lactose. Consequently, patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption
should not take this medicinal product.
pregnancy and lactation:
Women of childbearing potential / contraception in males and females:
When Ledipasvir / Sofosbuvir is used in combination with ribavirin, extreme care
must be taken to avoid pregnancy in female patients and in female partners of
male patients. Significant teratogenic and/or embryocidal effects have been
demonstrated in all animal species exposed to ribavirin. Women of childbearing
potential or their male partners must use an effective form of contraception
during treatment and for a period of time after the treatment has concluded as
recommended for ribavirin.
Pregnancy:
There are no or limited amount of data from the use of ledipasvir, sofosbuvir or
Ledipasvir / Sofosbuvir in pregnant women.
As a precautionary measure, it is preferable to avoid the use of Ledipasvir / Sofosbuvir
during pregnancy.
Breast-feeding:
It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted
in human milk.
Available pharmacokinetic data in animals has shown excretion of ledipasvir and
metabolites of sofosbuvir in milk. A risk to the newborns/infants cannot be
excluded. Therefore, Ledipasvir / Sofosbuvir should not be used during
breast-feeding.
Interactions with other medicinal products and other forms of interaction:
Patients treated with vitamin K antagonists:
As liver function may change during treatment with Harvomed, a close
monitoring of International Normalised Ratio (INR) values is recommended.
ACID REDUCING AGENTS:
Ledipasvir solubility decreases as pH increases. Medicinal products that
increase gastric pH are expected to decrease concentration of ledipasvir.
Antacids (e.g. Aluminium or magnesium hydroxide; calcium carbonate): It is
recommended to separate antacid and Ledipasvir / Sofosbuvir administration by
4 hours.
H2-receptor antagonists (Famotidine, Cimetidine, Nizatidine, Ranitidine):
H2-receptor antagonists may be administered simultaneously with or staggered
from Ledipasvir / Sofosbuvir at a dose that does not exceed doses comparable
to famotidine 40 mg twice daily.
Proton pump inhibitors (Omeprazole, Lansoprazole, Rabeprazole,
Pantoprazole, Esomeprazole): Proton pump inhibitor doses comparable to
omeprazole 20 mg can be administered simultaneously with Harvomed. Proton
pump inhibitors should not be taken before Harvomed.
ANTIARRHYTHMICS:
Amiodarone: Use only if no other alternative is available. Close monitoring is
recommended if this medicinal product is administered with Harvomed.
Digoxin: Co-administration of Ledipasvir / Sofosbuvir with digoxin may increase
the concentration of digoxin. Caution is warranted and therapeutic concentration
monitoring of digoxin is recommended when co-administered with Harvomed.
ANTICOAGULANTS:
Dabigatran etexilate: Clinical monitoring, looking for signs of bleeding and
anaemia, is recommended when dabigatran etexilate is co-administered with
Harvomed. A coagulation test helps to identify patients with an increased bleeding
risk due to increased dabigatran exposure.
Vitamin K antagonists: Close monitoring of INR is recommended with all vitamin
K antagonists. This is due to liver function changes during treatment with
Harvomed.
ANTICONVULSANTS:
Carbamazepine, Phenobarbital, Phenytoin: Ledipasvir / Sofosbuvir is contraindicated
with carbamazepine, phenobarbital and phenytoin.
Oxcarbazepine: Co-administration of Ledipasvir / Sofosbuvir with oxcarbazepine
is expected to decrease the concentration of ledipasvir and sofosbuvir leading to
reduced therapeutic effect of Harvomed. Such co-administration is not
recommended.
ANTIMYCOBACTERIALS:
Rifabutin, Rifampicin, Rifapentine: Ledipasvir / Sofosbuvir is contraindicated
with rifampicin, a potent intestinal P-gp inducer. Co-administration of Ledipasvir
/ Sofosbuvir with rifapentine is expected to decrease the concentration of
ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Harvomed.
Such co-administration is not recommended.
HCV PRODUCTS:
Simeprevir: Concentrations of ledipasvir, sofosbuvir and simeprevir are increased
when simeprevir is co-administered with Harvomed. Co-administration is not
recommended.
HIV ANTIVIRAL AGENTS:
REVERSE TRANSCRIPTASE INHIBITORS:
No dose adjustment of Ledipasvir / Sofosbuvir or efavirenz/ emtricitabine/ tenofovir
disoproxil fumarate is required.
HIV PROTEASE INHIBITORS:
No dose adjustment of Ledipasvir / Sofosbuvir or atazanavir (ritonavir boosted)
is required.
INTEGRASE INHIBITORS: Raltegravir: No dose adjustment of Ledipasvir / Sofosbuvir
or raltegravir is required.
HERBAL SUPPLEMENTS:
St. John’s wort: Ledipasvir / Sofosbuvir is contraindicated with St. John's wort,
a potent intestinal P-gp inducer.
HMG-CoA REDUCTASE INHIBITORS:
Rosuvastatin, Pravastatin: Co-administration of Ledipasvir / Sofosbuvir with
rosuvastatin may significantly increase the concentration of rosuvastatin
(several fold-increase in AUC) which is associated with increased risk of
myopathy, including rhabdomyolysis. Co-administration of Ledipasvir / Sofosbuvir
with rosuvastatin is contraindicated.
Other statins: Interactions cannot be excluded with other HMG-CoA reductase
inhibitors. When co-administered with Harvomed, a reduced dose of statins
should be considered and careful monitoring for statin adverse reactions should
be undertaken.
NARCOTIC ANALGESICS:
Methadone: No dose adjustment of Ledipasvir / Sofosbuvir or methadone is
required.
IMMUNOSUPPRESSANTS:
Ciclosporin, Tacrolimus: No dose adjustment of Ledipasvir / Sofosbuvir or
tacrolimus is required.
ORAL CONTRACEPTIVES:
Norgestimate/ ethinyl estradiol: No dose adjustment of oral contraceptives is
required.
Posology and method of administration:
Ledipasvir / Sofosbuvir treatment should be initiated and monitored by a physician
experienced in the management of patients with CHC.
Posology:
The recommended dose of Ledipasvir / Sofosbuvir is one tablet once daily with
or without food.
Recommended treatment duration for Ledipasvir / Sofosbuvir and the recommended
use of co-administered ribavirin for certain subgroups:
*Includes patients co-infected with human immunodeficiency virus (HIV).
In patients without decompensated cirrhosis requiring the addition of ribavirin to
their treatment regimen, the daily dose of ribavirin is weight based
(< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg) and administered orally in two
divided doses with food.
In patients with decompensated cirrhosis, ribavirin should be administered at a
starting dose of 600 mg given in a divided daily dose. If the starting dose is
well-tolerated, the dose can be titrated up to a maximum of 1,000-1,200 mg daily
(1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing
≥ 75 kg). If the starting dose is not well-tolerated, the dose should be reduced as
clinically indicated based on haemoglobin levels.
Dose modification of ribavirin in patients taking 1,000-1,200 mg daily:
If Ledipasvir / Sofosbuvir is used in combination with ribavirin and a patient has
a serious adverse reaction potentially related to ribavirin, the ribavirin dose
should be modified or discontinued, if appropriate, until the adverse reaction
abates or decreases in severity.
Ribavirin dose modification guideline for co-administration with Harvomed:
Patients should be instructed that if vomiting occurs within 5 hours of dosing an
additional tablet should be taken. If vomiting occurs more than 5 hours after
dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the normal time, patients should
be instructed to take the tablet as soon as possible and then patients should take
the next dose at the usual time. If it is after 18 hours then patients should be
instructed to wait and take the next dose at the usual time. Patients should be
instructed not to take a double dose.
Elderly:
No dose adjustment is warranted for elderly patients.
Renal impairment:
No dose adjustment of Ledipasvir / Sofosbuvir is required for patients with mild
or moderate renal impairment.The safety of ledipasvir/sofosbuvir has not been
assessed in patients with severe renal impairment (estimated glomerular
filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD)
requiring haemodialysis.
Hepatic impairment:
No dose adjustment of Ledipasvir / Sofosbuvir is required for patients with mild,
moderate or severe hepatic impairment. Safety and efficacy of ledipasvir/sofosbuvir
have been established in patients with decompensated cirrhosis.
Paediatric population:
The safety and efficacy of Ledipasvir / Sofosbuvir in children and adolescents
aged less than 18 years have not yet been established. No data are available.
Method of administration:
For oral use.
Patients should be instructed to swallow the tablet whole with or without food.
Due to the bitter taste, it is recommended that the film-coated tablet is not
chewed or crushed.
Overdoses:
No specific antidote is available for overdose with Harvomed. If overdose occurs
the patient must be monitored for evidence of toxicity. Treatment of overdose with
Ledipasvir / Sofosbuvir consists of general supportive measures including
monitoring of vital signs as well as observation of the clinical status of the
patient. Haemodialysis is unlikely to result in significant removal of ledipasvir as
ledipasvir is highly bound to plasma protein. Haemodialysis can efficiently
remove the predominant circulating metabolite of sofosbuvir, GS-331007, with
an extraction ratio of 53%.
Storage Conditions: Store at room temperature between (15-30)˚C, protected
from light and out of reach of children.
Packaging: Plastic bottle contains 28 Film-coated tablet.
HARVOMED (FILM COATED TABLETS)
TPP1801501 THIS IS A MEDICAMENT
A medicament is a product but unlike any other products.
A medicament is a product which affects your health, and its consumption contrary to instructions
is dangerous for you.
Follow strictly the doctor’s prescription, the method of use and the instructions of the pharmacist
who sold the medicament. The doctor and the pharmacist are experts in medicine, its
benefits and risks.
Do not by yourself interrupt the period of treatment prescribed for you.
Do not repeat the same prescription without consulting your doctor.
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KEEP MEDICAMENTS OUT OF REACH OF CHILDREN
(Council of Arab Health Ministers) (Arab Pharmacists Association)
Biomedpharma for Pharmaceutical Industries
P.O.Box 7565 Damascus - Tel.: 5961800 - 5961103
Fax: 5962493 - E-mail: biomedpharma@mail.sy
Patient
population* Treatment and duration
Patients with genotype 1, 4, 5 or 6 CHC
Patients without
cirrhosis
Ledipasvir / Sofosbuvir for 12 weeks.
- Ledipasvir / Sofosbuvir for 8 weeks may be considered
in previously untreated genotype 1-infected patients.
- Ledipasvir / Sofosbuvir + ribavirin for 12 weeks or
Ledipasvir / Sofosbuvir (without ribavirin) for 24 weeks
should be considered for previously treated patients with
uncertain subsequent retreatment options.
Patients with
compensated
cirrhosis
Ledipasvir / Sofosbuvir + ribavirin for 12 weeks or
Ledipasvir / Sofosbuvir (without ribavirin) for 24 weeks.
- Ledipasvir / Sofosbuvir (without ribavirin) for 12 weeks
may be considered for patients deemed at low risk for
clinical disease progression and who have subsequent
retreatment options.
Patients who
are post-liver
transplant without
cirrhosis or with
compensated
cirrhosis
Ledipasvir / Sofosbuvir + ribavirin for 12 weeks
- Ledipasvir / Sofosbuvir (without ribavirin) for 12 weeks
(in patients without cirrhosis) or 24 weeks (in patients
with cirrhosis) may be considered for patients who are
ineligible for or intolerant to ribavirin.
Patients with
decompensated
cirrhosis,
irrespective of
transplant status
Ledipasvir / Sofosbuvir + ribavirin for 12 weeks
- Ledipasvir / Sofosbuvir (without ribavirin) for 24 weeks
may be considered in patients who are ineligible for or
intolerant to ribavirin.
Patients with genotype 3 CHC
Patients with
compensated
cirrhosis and/or
prior treatment
failure
Ledipasvir / Sofosbuvir + ribavirin for 24 weeks
Laboratory
Values
Reduce ribavirin dose
to 600 mg/day if: Discontinue ribavirin if:
Haemoglobin in
patients with no
cardiac disease
< 10 g/dL < 8.5 g/dL
Haemoglobin in
patients with
history of stable
cardiac disease
≥ 2 g/dL decrease in
haemoglobin during any
4 week treatment period
< 12 g/dL despite 4 weeks
at reduced dose