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Harvoni 45 mg/200 mg coated granules in sachet | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Harvoni 45 mg/200 mg coated granules in sachet | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Harvoni 33.75 mg/150 mg and 45 mg/200 mg coated granules are supplied in polyester/aluminium/polyethylene film sachets in cartons. Each carton contains 28 sachets.
6.6 |
Harvoni 45 mg/200 mg coated granules in sachet | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
This medicinal product may pose a risk to the environment (See section 5.3).
7. |
Harvoni 45 mg/200 mg coated granules in sachet | Marketing authorisation holder | Gilead Sciences Ltd
280 High Holborn
London
WC1V 7EE
United Kingdom
8. Marketing authorisation number(s)
PLGB 11972/0043
9. |
Harvoni 45 mg/200 mg coated granules in sachet | Date of first authorisation/renewal of the authorisation | 01/01/2021
10. |
Harvoni 45 mg/200 mg coated granules in sachet | Date of revision of the text | 21/12/2022 |
Harvoni 45 mg/200 mg film-coated tablets | Introduction | This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.1. |
Harvoni 45 mg/200 mg film-coated tablets | Name of the medicinal product | Harvoni 45 mg/200 mg film-coated tablets
2. |
Harvoni 45 mg/200 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 45 mg ledipasvir and 200 mg sofosbuvir.
Excipients with known effect
Each film-coated tablet contains 78 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
3. |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Harvoni 45 mg/200 mg film-coated tablets
White, capsule-shaped, film-coated tablet of dimensions of approximately 14 mm x 7 mm, debossed with “GSI” on one side and “HRV” on the other side.
4. |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1).
For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1.
4.2 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Harvoni treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
Posology
The recommended dose of Harvoni in adults is 90 mg/400 mg once daily with or without food (see section 5.2).
The recommended dose of Harvoni in paediatric patients aged 3 years and above is based on weight (as detailed in Table 2) and can be taken with or without food (see section 5.2).
A granule formulation of Harvoni is available for the treatment of chronic HCV-infection in paediatric patients aged 3 years and above having difficulty swallowing film-coated tablets. Please refer to the Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.
Table 1: Recommended treatment duration for Harvoni and the recommended use of co-administered ribavirin for certain subgroups
Patient population
(including HIV co-infected patients)
Treatment and duration
Adult and paediatric patients aged 3 years and abovea with genotype 1, 4, 5 or 6 CHC
Patients without cirrhosis
Harvoni for 12 weeks.
- Harvoni for 8 weeks may be considered in previously untreated genotype 1-infected patients (see section 5.1, ION-3 study).
Patients with compensated cirrhosis
Harvoni + ribavirinb,c for 12 weeks
or
Harvoni (without ribavirin) for 24 weeks.
- Harvoni (without ribavirin) for 12 weeks may be considered for patients deemed at low risk for clinical disease progression and who have subsequent retreatment options (see section 4.4).
Patients who are post-liver transplant without cirrhosis or with compensated cirrhosis
Harvoni + ribavirinb,c for 12 weeks (see section 5.1).
- Harvoni (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
Harvoni + ribavirind for 12 weeks (see section 5.1)
- Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin.
Adult and paediatric patients 3 years of ageand abovea with genotype 3 CHC
Patients with compensated cirrhosis and/or prior treatment failure
Harvoni + ribavirinb for 24 weeks (see sections 4.4 and 5.1).
a See Table 2 for weight-based Harvoni dosing recommendations for paediatric patients aged 3 years and above..
b Adults: weight based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg), administered orally in two divided doses with food.
c Paediatric patients: for ribavirin dosing recommendations see table 4 below.
d For ribavirin dosing recommendations in adult patients with decompensated cirrhosis, see table 3 below.
Table 2: Dosing for paediatric patients aged 3 years and above using Harvoni Tablets*
Body Weight (kg)
Dosing of Harvoni Tablets
Ledipasvir/Sofosbuvir Daily Dose
≥ 35
one 90 mg/400 mg tablet once daily
or
two 45 mg/200 mg tablets once daily
90 mg/400 mg/day
17 to < 35
one 45 mg/200 mg tablet once daily
45 mg/200 mg/day
* Harvoni is also available as granules for use in paediatric patients with CHC aged 3 years and above (see section 5.1). Patients that weigh < 17 kg are not recommended to take tablets. Please refer to the Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.
Table 3: Guidance for ribavirin dosing when administered with Harvoni to adult patients with decompensated cirrhosis
Patient
Ribavirin dose*
Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant
1,000 mg per day for patients < 75 kg and 1,200 mg for those weighing ≥ 75 kg
CPT Class C cirrhosis pre-transplant
CPT Class B or C cirrhosis post- transplant
Starting dose of 600 mg, which can be titrated up to a maximum of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If the starting dose is not well tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels
* If a more normalized dose of ribavirin (by weight and renal function) cannot be reached for reasons of tolerability, 24 weeks of Harvoni + ribavirin should be considered in order to minimize the risk for relapse.
For adults when ribavirin is added to Harvoni, refer also to the Summary of Product Characteristics of ribavirin.
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where ribavirin is divided into two daily doses and given with food:
Table 4: Guidance for ribavirin dosing when administered with Harvoni to paediatric patients aged 3 years and above.
Body weight kg
Ribavirin Dose*
< 47
15 mg/kg/day
47-49
600 mg/day
50-65
800 mg/day
66-74
1000 mg/day
> or = 75
1200 mg/day
* The daily dosage of ribavirin is weight-based and administered orally in two divided doses with food.
Dose modification of ribavirin in adults taking 1,000-1,200 mg daily
If Harvoni 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. Table 5 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
Table 5: Ribavirin dose modification guideline for co-administration with Harvoni in adults
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
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin be increased to the originally assigned dose (1,000 mg to 1,200 mg daily).
Paediatric population aged < 3 years
The safety and efficacy of Harvoni in paediatric patients aged < 3 years have not been established. No data are available.
Missed dose
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 (see section 5.1).
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 (see section 5.2).
Renal impairment
No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment.
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring dialysis. Harvoni can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2).
Hepatic impairment
No dose adjustment of Harvoni is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). Safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section 5.1).
Method of administration
For oral use.
Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bitter taste, it is recommended that film-coated tablets are not chewed or crushed (see section 5.2).
4.3 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Co-administration with rosuvastatin (see section 4.5).
Use with strong P-gp inducers
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort). Co-administration will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni (see section 4.5).
4.4 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir.
Genotype-specific activity
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.
The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of Harvoni (always in combination with ribavirin) should only be considered for patients who are deemed at high risk for clinical disease progression and who do not have alternative treatment options.
The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are limited (see section 5.1).
Severe bradycardia and heart block
Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir- containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment.
Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.
Should concomitant use of amiodarone be considered necessary it is recommended that patients undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Harvoni.
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.
Use in diabetic patients
Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated.
HCV/HBV (hepatitis B virus) co-infection
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.
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 (see section 5.1). Limited data indicate that such NS5A mutations do not revert on long-term follow-up. 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 classes of medicinal products for clearance of HCV infection. Consequently, consideration should be given to longer treatment for patients with uncertain subsequent retreatment options.
Renal impairment
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Harvoni can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Harvoni is used in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min (see section 5.2).
Adults 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. Treatment with Harvoni should be guided by an assessment of the potential benefits and risks for the individual patient.
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 Harvoni.
Co-administration of such medicinal products is not recommended with Harvoni (see section 4.5).
Use with certain HIV antiretroviral regimens
Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Harvoni 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 Harvoni concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir- associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product Characteristics for recommendations on renal monitoring.
Use with HMG-CoA reductase inhibitors
Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis (see section 4.5).
Paediatric population
Harvoni is not recommended for use in paediatric patients aged < 3 years because the safety and efficacy have not been established in this population.
Excipients
Harvoni contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions. It also contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
4.5 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with Harvoni.
Potential for Harvoni to affect other medicinal products
Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters.
Potential for other medicinal products to affect Harvoni
Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not.
Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). 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 Harvoni. Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected.
Patients treated with vitamin K antagonists
As liver function may change during treatment with Harvoni, a close monitoring of International Normalised Ratio (INR) values is recommended.
Impact of DAA therapy on drugs metabolized by the liver
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus.
Interactions between Harvoni and other medicinal products
Table 6 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The medicinal product interactions described are based on studies conducted with either ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive.
Table 6: Interactions between Harvoni and other medicinal products
Medicinal product by therapeutic areas
Effects on medicinal product levels.
Mean ratio (90% confidence interval) for AUC, Cmax, Cmin a, b
Recommendation concerning co-administration with Harvoni
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
Interaction not studied.
Expected:
↓ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
(Increase in gastric pH)
It is recommended to separate antacid and Harvoni administration by 4 hours.
H2-receptor antagonists
Famotidine
(40 mg single dose)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c, d
Famotidine dosed simultaneously with Harvonid
Cimetidinee
Nizatidinee
Ranitidinee
Ledipasvir
↓ Cmax 0.80 (0.69, 0.93)
↔ AUC 0.89 (0.76, 1.06)
Sofosbuvir
↑ Cmax 1.15 (0.88, 1.50)
↔ AUC 1.11 (1.00, 1.24)
GS-331007
↔ Cmax 1.06 (0.97, 1.14)
↔ AUC 1.06 (1.02, 1.11)
(Increase in gastric pH)
H2-receptor antagonists may be administered simultaneously with or staggered from Harvoni at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
Famotidine
(40 mg single dose)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c, d
Famotidine dosed 12 hours prior to Harvonid
Ledipasvir
↓ Cmax 0.83 (0.69, 1.00)
↔ AUC 0.98 (0.80, 1.20)
Sofosbuvir
↔ Cmax 1.00 (0.76, 1.32)
↔ AUC 0.95 (0.82, 1.10)
GS-331007
↔ Cmax 1.13 (1.07, 1.20)
↔ AUC 1.06 (1.01, 1.12)
(Increase in gastric pH)
Proton pump inhibitors
Omeprazole
(20 mg once daily)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c
Omeprazole dosed simultaneously with Harvoni
Lansoprazolee
Rabeprazolee
Pantoprazolee
Esomeprazolee
Ledipasvir
↓ Cmax 0.89 (0.61, 1.30)
↓ AUC 0.96 (0.66, 1.39)
Sofosbuvir
↔ Cmax 1.12 (0.88, 1.42)
↔ AUC 1.00 (0.80, 1.25)
GS-331007
↔ Cmax 1.14 (1.01, 1.29)
↔ AUC 1.03 (0.96, 1.12)
(Increase in gastric pH)
Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered simultaneously with Harvoni. Proton pump inhibitors should not be taken before Harvoni.
ANTIARRHYTHMICS
Amiodarone
Effect on amiodarone, sofosbuvir and ledipasvir concentrations unknown.
Coadministration of amiodarone with a sofosbuvir- containing regimen may result in serious symptomatic bradycardia.
Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Harvoni (see sections 4.4 and 4.8).
Digoxin
Interaction not studied.
Expected:
↑ Digoxin
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
(Inhibition of P-gp)
Co-administration of Harvoni with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with Harvoni.
ANTICOAGULANTS
Dabigatran etexilate
Interaction not studied.
Expected:
↑ Dabigatran
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
(Inhibition of P-gp)
Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Harvoni. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.
Vitamin K antagonists
Interaction not studied.
Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Harvoni.
ANTICONVULSANTS
Phenobarbital
Phenytoin
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Harvoni is contraindicated with phenobarbital and phenytoin (see section 4.3).
Carbamazepine
Interaction not studied
Expected:
↓ Ledipasvir
Observed:
Sofosbuvir
↓ Cmax 0.52 (0.43, 0.62)
↓ AUC 0.52 (0.46, 0.59)
Cmin (NA)
GS-331007
↔ Cmax 1.04 (0.97, 1.11)
↔ AUC 0.99 (0.94, 1.04)
Cmin (NA)
(Induction of P-gp)
Harvoni is contraindicated with carbamazepine (see section 4.3).
Oxcarbazepine
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Co-administration of Harvoni with oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir leading to reduced therapeutic effect of Harvoni. Such co-administration is not recommended (see section 4.4).
ANTIMYCOBACTERIALS
Rifampicin (600 mg once daily)/ ledipasvir (90 mg single dose)d
Interaction not studied.
Expected:
Rifampicin
↔ Cmax
↔ AUC
↔ Cmin
Observed:
Ledipasvir
↓ Cmax 0.65 (0.56, 0.76)
↓ AUC 0.41 (0.36, 0.48)
(Induction of P-gp)
Harvoni is contraindicated with rifampicin (see section 4.3).
Rifampicin (600 mg once daily)/ sofosbuvir (400 mg single dose)d
Interaction not studied.
Expected:
Rifampicin
↔ Cmax
↔ AUC
↔ Cmin
Observed:
Sofosbuvir
↓ Cmax 0.23 (0.19, 0.29)
↓ AUC 0.28 (0.24, 0.32)
GS-331007
↔ Cmax 1.23 (1.14, 1.34)
↔ AUC 0.95 (0.88, 1.03)
(Induction of P-gp)
Rifabutin
Interaction not studied.
Expected:
↓ Ledipasvir
Observed:
Sofosbuvir
↓ Cmax 0.64 (0.53, 0.77)
↓ AUC 0.76 (0.63, 0.91)
Cmin (NA)
GS-331007
↔ Cmax 1.15 (1.03, 1.27)
↔ AUC 1.03 (0.95, 1.12)
Cmin (NA)
(Induction of P-gp)
Harvoni is contraindicated with rifabutin (see section 4.3).
Rifapentine
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Co-administration of Harvoni with rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Harvoni. Such co-administration is not recommended.
SEDATIVES/HYPNOTICS
Midazolam (2.5 mg single dose)/ ledipasvir (90 mg single dose)
Ledipasvir (90 mg once daily)
Observed:
Midazolam
↔ Cmax 1.07 (1.00, 1.14)
↔ AUC 0.99 (0.95, 1.04)
(Inhibition of CYP3A)
Midazolam
↔ Cmax 0.95 (0.87, 1.04)
↔ AUC 0.89 (0.84, 0.95)
(Induction of CYP3A)
Expected:
↔ Sofosbuvir
↔ GS-331007
No dose adjustment of Harvoni or midazolam is required.
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate
(600 mg/ 200 mg/ 300 mg/ once daily)/ ledipasvir
(90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Efavirenz
↔ Cmax 0.87 (0.79, 0.97)
↔ AUC 0.90 (0.84, 0.96)
↔ Cmin 0.91 (0.83, 0.99)
Emtricitabine
↔ Cmax 1.08 (0.97, 1.21)
↔ AUC 1.05 (0.98, 1.11)
↔ Cmin 1.04 (0.98, 1.11)
Tenofovir
↑ Cmax 1.79 (1.56, 2.04)
↑ AUC 1.98 (1.77, 2.23)
↑ Cmin 2.63 (2.32, 2.97)
Ledipasvir
↓ Cmax 0.66 (0.59, 0.75)
↓ AUC 0.66 (0.59, 0.75)
↓ Cmin 0.66 (0.57, 0.76)
Sofosbuvir
↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.94 (0.81, 1.10)
GS-331007
↔ Cmax 0.86 (0.76, 0.96)
↔ AUC 0.90 (0.83, 0.97)
↔ Cmin 1.07 (1.02, 1.13)
No dose adjustment of Harvoni or efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is required.
Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate
(200 mg/ 25 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Emtricitabine
↔ Cmax 1.02 (0.98, 1.06)
↔ AUC 1.05 (1.02, 1.08)
↔ Cmin 1.06 (0.97, 1.15)
Rilpivirine
↔ Cmax 0.97 (0.88, 1.07)
↔ AUC 1.02 (0.94, 1.11)
↔ Cmin 1.12 (1.03, 1.21)
Tenofovir
↔ Cmax 1.32 (1.25, 1.39)
↑ AUC 1.40 (1.31, 1.50)
↑ Cmin 1.91 (1.74, 2.10)
Ledipasvir
↔ Cmax 1.01 (0.95, 1.07)
↔ AUC 1.08 (1.02, 1.15)
↔ Cmin 1.16 (1.08, 1.25)
Sofosbuvir
↔ Cmax 1.05 (0.93, 1.20)
↔ AUC 1.10 (1.01, 1.21)
GS-331007
↔ Cmax 1.06 (1.01, 1.11)
↔ AUC 1.15 (1.11, 1.19)
↔ Cmin 1.18 (1.13, 1.24)
No dose adjustment of Harvoni or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required.
Abacavir/ lamivudine (600 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Abacavir
↔ Cmax 0.92 (0.87, 0.97)
↔ AUC 0.90 (0.85, 0.94)
Lamivudine
↔ Cmax 0.93 (0.87, 1.00)
↔ AUC 0.94 (0.90, 0.98)
↔ Cmin 1.12 (1.05, 1.20)
Ledipasvir
↔ Cmax 1.10 (1.01, 1.19)
↔ AUC 1.18 (1.10, 1.28)
↔ Cmin 1.26 (1.17, 1.36)
Sofosbuvir
↔ Cmax 1.08 (0.85, 1.35)
↔ AUC 1.21 (1.09, 1.35)
GS-331007
↔ Cmax 1.00 (0.94, 1.07)
↔ AUC 1.05 (1.01, 1.09)
↔ Cmin 1.08 (1.01, 1.14)
No dose adjustment of Harvoni or abacavir/ lamivudine is required.
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with ritonavir
(300 mg/ 100 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Atazanavir
↔ Cmax 1.07 (1.00, 1.15)
↔ AUC 1.33 (1.25, 1.42)
↑ Cmin 1.75 (1.58, 1.93)
Ledipasvir
↑ Cmax 1.98 (1.78, 2.20)
↑ AUC 2.13 (1.89, 2.40)
↑ Cmin 2.36 (2.08, 2.67)
Sofosbuvir
↔ Cmax 0.96 (0.88, 1.05)
↔ AUC 1.08 (1.02, 1.15)
GS-331007
↔ Cmax 1.13 (1.08, 1.19)
↔ AUC 1.23 (1.18, 1.29)
↔ Cmin 1.28 (1.21, 1.36)
No dose adjustment of Harvoni or atazanavir (ritonavir boosted) is required.
For the combination of tenofovir/emtricitabine + atazanavir/ritonavir, please see below.
Atazanavir boosted with ritonavir (300 mg/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 mg/ 300 mg once daily)/ ledipasvir
(90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Dosed simultaneouslyf
Atazanavir
↔ Cmax 1.07 (0.99, 1.14)
↔ AUC 1.27 (1.18, 1.37)
↑ Cmin 1.63 (1.45, 1.84)
Ritonavir
↔ Cmax 0.86 (0.79, 0.93)
↔ AUC 0.97 (0.89, 1.05)
↑ Cmin 1.45 (1.27, 1.64)
Emtricitabine
↔ Cmax 0.98 (0.94, 1.02)
↔ AUC 1.00 (0.97, 1.04)
↔ Cmin 1.04 (0.96, 1.12)
Tenofovir
↑ Cmax 1.47 (1.37, 1.58)
↔ AUC 1.35 (1.29, 1.42)
↑ Cmin 1.47 (1.38, 1.57)
Ledipasvir
↑ Cmax 1.68 (1.54, 1.84)
↑ AUC 1.96 (1.74, 2.21)
↑ Cmin 2.18 (1.91, 2.50)
Sofosbuvir
↔ Cmax 1.01 (0.88, 1.15)
↔ AUC 1.11 (1.02, 1.21)
GS-331007
↔ Cmax 1.17 (1.12, 1.23)
↔ AUC 1.31 (1.25, 1.36)
↑ Cmin 1.42 (1.34, 1.49)
When given with tenofovir disoproxil fumarate used in conjunction with atazanavir/ritonavir, Harvoni increased the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Atazanavir concentrations are also increased, with a risk for an increase in bilirubin levels/icterus. That risk is even higher if ribavirin is used as part of the HCV treatment.
Darunavir boosted with ritonavir
(800 mg/ 100 mg once daily)/ ledipasvir (90 mg once daily)d
Darunavir
↔ Cmax 1.02 (0.88, 1.19)
↔ AUC 0.96 (0.84, 1.11)
↔ Cmin 0.97 (0.86, 1.10)
Ledipasvir
↑ Cmax 1.45 (1.34, 1.56)
↑ AUC 1.39 (1.28, 1.49)
↑ Cmin 1.39 (1.29, 1.51)
No dose adjustment of Harvoni or darunavir (ritonavir boosted) is required.
For the combination of tenofovir/emtricitabine + darunavir/ritonavir, please see below.
Darunavir boosted with ritonavir
(800 mg/ 100 mg once daily)/ sofosbuvir (400 mg once daily)
Darunavir
↔ Cmax 0.97 (0.94, 1.01)
↔ AUC 0.97 (0.94, 1.00)
↔ Cmin 0.86 (0.78, 0.96)
Sofosbuvir
↑ Cmax 1.45 (1.10, 1.92)
↑ AUC 1.34 (1.12, 1.59)
GS-331007
↔ Cmax 0.97 (0.90, 1.05)
↔ AUC 1.24 (1.18, 1.30)
Darunavir boosted with ritonavir (800 mg/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 mg/ 300 mg once daily)/ ledipasvir
(90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Dosed simultaneouslyf
Darunavir
↔ Cmax 1.01 (0.96, 1.06)
↔ AUC 1.04 (0.99, 1.08)
↔ Cmin 1.08 (0.98, 1.20)
Ritonavir
↔ Cmax 1.17 (1.01, 1.35)
↔ AUC 1.25 (1.15, 1.36)
↑ Cmin 1.48 (1.34, 1.63)
Emtricitabine
↔ Cmax 1.02 (0.96, 1.08)
↔ AUC 1.04 (1.00, 1.08)
↔ Cmin 1.03 (0.97, 1.10)
Tenofovir
↑ Cmax 1.64 (1.54, 1.74)
↑ AUC 1.50 (1.42, 1.59)
↑ Cmin 1.59 (1.49, 1.70)
Ledipasvir
↔ Cmax 1.11 (0.99, 1.24)
↔ AUC 1.12 (1.00, 1.25)
↔ Cmin 1.17 (1.04, 1.31)
Sofosbuvir
↓ Cmax 0.63 (0.52, 0.75)
↓ AUC 0.73 (0.65, 0.82)
GS-331007
↔ Cmax 1.10 (1.04, 1.16)
↔ AUC 1.20 (1.16, 1.24)
↔ Cmin 1.26 (1.20, 1.32)
When given with darunavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, Harvoni increased the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Lopinavir boosted with ritonavir + emtricitabine/ tenofovir disoproxil fumarate
Interaction not studied.
Expected:
↑ Lopinavir
↑ Ritonavir
↔ Emtricitabine
↑ Tenofovir
↑ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
When given with lopinavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, Harvoni is expected to increase the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Tipranavir boosted with ritonavir
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Co-administration of Harvoni with tipranavir (ritonavir boosted) is expected to decrease the concentration of ledipasvir, leading to reduced therapeutic effect of Harvoni. Co-administration is not recommended.
HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir
(400 mg twice daily)/ ledipasvir (90 mg once daily)d
Raltegravir
↓ Cmax 0.82 (0.66, 1.02)
↔ AUC 0.85 (0.70, 1.02)
↑ Cmin 1.15 (0.90, 1.46)
Ledipasvir
↔ Cmax 0.92 (0.85, 1.00)
↔ AUC 0.91 (0.84, 1.00)
↔ Cmin 0.89 (0.81, 0.98)
No dose adjustment of Harvoni or raltegravir is required.
Raltegravir
(400 mg twice daily)/ sofosbuvir (400 mg once daily)d
Raltegravir
↓ Cmax 0.57 (0.44, 0.75)
↓ AUC 0.73 (0.59, 0.91)
↔ Cmin 0.95 (0.81, 1.12)
Sofosbuvir
↔ Cmax 0.87 (0.71, 1.08)
↔ AUC 0.95 (0.82, 1.09)
GS-331007
↔ Cmax 1.09 (0.99, 1.19)
↔ AUC 1.02 (0.97, 1.08)
Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate
(150 mg/ 150 mg/ 200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c
Interaction not studied.
Expected:
↔ Emtricitabine
↑ Tenofovir
Observed:
Elvitegravir
↔ Cmax 0.88 (0.82, 0.95)
↔ AUC 1.02 (0.95, 1.09)
↑ Cmin 1.36 (1.23, 1.49)
Cobicistat
↔ Cmax 1.25 (1.18, 1.32)
↑ AUC 1.59 (1.49, 1.70)
↑ Cmin 4.25 (3.47, 5.22)
Ledipasvir
↑ Cmax 1.63 (1.51, 1.75)
↑ AUC 1.78 (1.64, 1.94)
↑ Cmin 1.91 (1.76, 2.08)
Sofosbuvir
↑ Cmax 1.33 (1.14, 1.56)
↑ AUC 1.36 (1.21, 1.52)
GS-331007
↑ Cmax 1.33 (1.22, 1.44)
↑ AUC 1.44 (1.41, 1.48)
↑ Cmin 1.53 (1.47, 1.59)
When given with elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate, Harvoni is expected to increase the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Dolutegravir
Interaction not studied.
Expected:
↔ Dolutegravir
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
No dose adjustment required.
HERBAL SUPPLEMENTS
St. John's wort
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Harvoni is contraindicated with St. John's wort (see section 4.3).
HMG-CoA REDUCTASE INHIBITORS
Rosuvastating
↑ Rosuvastatin
(Inhibition of drug transporters OATP and BCRP)
Co-administration of Harvoni 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 Harvoni with rosuvastatin is contraindicated (see section 4.3).
Pravastating
↑ Pravastatin
Co-administration of Harvoni with pravastatin may significantly increase the concentration of pravastatin which is associated with increased risk of myopathy. Clinical and biochemical control is recommended in these patients and a dose adjustment may be needed (see section 4.4).
Other statins
Expected:
↑ Statins
Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Harvoni, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 4.4).
NARCOTIC ANALGESICS
Methadone
Interaction not studied.
Expected:
↔ Ledipasvir
No dose adjustment of Harvoni or methadone is required.
Methadone
(Methadone maintenance therapy [30 to 130 mg/ daily])/ sofosbuvir (400 mg once daily)d
R-methadone
↔ Cmax 0.99 (0.85, 1.16)
↔ AUC 1.01 (0.85, 1.21)
↔ Cmin 0.94 (0.77, 1.14)
S-methadone
↔ Cmax 0.95 (0.79, 1.13)
↔ AUC 0.95 (0.77, 1.17)
↔ Cmin 0.95 (0.74, 1.22)
Sofosbuvir
↓ Cmax 0.95 (0.68, 1.33)
↑ AUC 1.30 (1.00, 1.69)
GS-331007
↓ Cmax 0.73 (0.65, 0.83)
↔ AUC 1.04 (0.89, 1.22)
IMMUNOSUPPRESSANTS
Ciclosporing
Interaction not studied.
Expected:
↑ Ledipasvir
↔ Ciclosporin
No dose adjustment of Harvoni or ciclosporin is required at initiation of co-administration.
Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required.
Ciclosporin
(600 mg single dose)/ sofosbuvir (400 mg single dose)h
Ciclosporin
↔ Cmax 1.06 (0.94, 1.18)
↔ AUC 0.98 (0.85, 1.14)
Sofosbuvir
↑ Cmax 2.54 (1.87, 3.45)
↑ AUC 4.53 (3.26, 6.30)
GS-331007
↓ Cmax 0.60 (0.53, 0.69)
↔ AUC 1.04 (0.90, 1.20)
Tacrolimus
Interaction not studied.
Expected:
↔ Ledipasvir
No dose adjustment of Harvoni or tacrolimus is required at initiation of co-administration.
Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.
Tacrolimus
(5 mg single dose)/ sofosbuvir (400 mg single dose)h
Tacrolimus
↓ Cmax 0.73 (0.59, 0.90)
↑ AUC 1.09 (0.84, 1.40)
Sofosbuvir
↓ Cmax 0.97 (0.65, 1.43)
↑ AUC 1.13 (0.81, 1.57)
GS-331007
↔ Cmax 0.97 (0.83, 1.14)
↔ AUC 1.00 (0.87, 1.13)
ORAL CONTRACEPTIVES
Norgestimate/ ethinyl estradiol (norgestimate
0.180 mg/ 0.215 mg/
0.25 mg/ ethinyl estradiol
0.025 mg)/ ledipasvir (90 mg once daily)d
Norelgestromin
↔ Cmax 1.02 (0.89, 1.16)
↔ AUC 1.03 (0.90, 1.18)
↔ Cmin 1.09 (0.91, 1.31)
Norgestrel
↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.99 (0.82, 1.20)
↔ Cmin 1.00 (0.81, 1.23)
Ethinyl estradiol
↑ Cmax 1.40 (1.18, 1.66)
↔ AUC 1.20 (1.04, 1.39)
↔ Cmin 0.98 (0.79, 1.22)
No dose adjustment of oral contraceptives is required.
Norgestimate/ ethinyl estradiol (norgestimate
0.180 mg/ 0.215 mg/
0.25 mg/ ethinyl estradiol
0.025 mg)/ sofosbuvir (400 mg once daily)d
Norelgestromin
↔ Cmax 1.07 (0.94, 1.22)
↔ AUC 1.06 (0.92, 1.21)
↔ Cmin 1.07 (0.89, 1.28)
Norgestrel
↔ Cmax 1.18 (0.99, 1.41)
↑ AUC 1.19 (0.98, 1.45)
↑ Cmin 1.23 (1.00, 1.51)
Ethinyl estradiol
↔ Cmax 1.15 (0.97, 1.36)
↔ AUC 1.09 (0.94, 1.26)
↔ Cmin 0.99 (0.80, 1.23)
a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00.
b All interaction studies conducted in healthy volunteers. c Administered as Harvoni.
d Lack of pharmacokinetics interaction bounds 70-143%.
e These are drugs within class where similar interactions could be predicted.
f Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results.
g This study was conducted in the presence of another two direct-acting antiviral agents.
h Bioequivalence/Equivalence boundary 80-125%.
4.6 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential / contraception in males and females
When Harvoni 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 in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
Pregnancy
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or Harvoni in pregnant women.
Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Harvoni 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 (see section 5.3).
A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during breast-feeding.
Fertility
No human data on the effect of Harvoni on fertility are available. Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility.
If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin during pregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin).
4.7 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Harvoni (administered alone or in combination with ribavirin) has no or negligible influence on the ability to drive and use machines. However, patients should be advised that fatigue was more common in patients treated with ledipasvir/sofosbuvir compared to placebo.
4.8 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile in adults
The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who received Harvoni in combination with ribavirin.
The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively.
In clinical studies, fatigue and headache were more common in patients treated with ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions.
Tabulated list of adverse events
The following adverse drug reactions have been identified with Harvoni (Table 7). The adverse reactions are listed below by body system organ class and frequency. 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) or very rare (< 1/10,000).
Table 7: Adverse drug reactions identified with Harvoni
Frequency
Adverse drug reaction
Nervous system disorders:
Very common
headache
Skin and subcutaneous tissue disorders:
Common
rash
Not known
angioedema
General disorders:
Very common
fatigue
Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant
The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults with decompensated liver disease and/or those post-liver transplant was assessed in two open-label studies (SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients with decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in this study compared to studies that excluded decompensated patients and/or patients who were post- liver transplantation, the adverse events observed were those expected as clinical sequelae of advanced liver disease and/or transplantation or were consistent with the known safety profile of ribavirin (see section 5.1 for details of this study).
Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and 13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 15% of the patients.
7% of liver transplant recipients had a modification of their immunosuppressive agents.
Patients with renal impairment
Ledipasvir/sofosbuvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). In this limited clinical safety data set, the rate of adverse events was not clearly elevated from what is expected in patients with severe renal impairment.
The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patients with ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS- 331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients.
Paediatric population
The safety and efficacy of Harvoni in paediatric patients aged 3 years and above are based on data from a Phase 2, open-label clinical study (Study 1116) that enrolled 226 patients who were treated with ledipasvir/sofosbuvir for 12 or 24 weeks or ledipasvir/sofosbuvir plus ribavirin for 24 weeks. The adverse reactions observed were consistent with those observed in clinical studies of ledipasvir/sofosbuvir in adults (see Table 7).
Description of selected adverse reactions
Cardiac arrhythmias
Cases of severe bradycardia and heart block have been observed when Harvoni is used with amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5).
Skin disorders
Frequency not known: Stevens-Johnson syndrome
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.
4.9 |
Harvoni 45 mg/200 mg film-coated tablets | Clinical particulars - Overdose | Overdose
The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a single dose of 1,200 mg, respectively. In these healthy volunteer studies, there were no untoward effects observed at these dose levels, and adverse reactions were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses are not known.
No specific antidote is available for overdose with Harvoni. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Harvoni 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%.
5. Pharmacological properties
5.1 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
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 concentrations were observed ~ 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed at 4 hours post-dose.
Based on the population pharmacokinetic analysis in HCV-infected patients, geometric mean steady-state AUC0-24 for ledipasvir (n = 2,113), sofosbuvir (n = 1,542), and GS-331007 (n = 2,113) were 7,290, 1,320 and 12,000 ng•h/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir and GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (n = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected patients. Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.
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. Harvoni can be administered without regard to food.
Distribution
Ledipasvir is > 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66.
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. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.7.
Biotransformation
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. 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 analogue triphosphate GS-461203. The active metabolite is not observed. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Within ledipasvir/sofosbuvir, GS-331007 accounts for approximately 85% of total systemic exposure.
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%). The median terminal half-life of ledipasvir in healthy volunteers following administration of ledipasvir/sofosbuvir in the fasted state was 47 hours.
Following a single 400 mg oral dose of [14C]-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-lives of sofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours, respectively.
Neither ledipasvir nor sofosbuvir are substrates for hepatic uptake transporters, organic cation transporter (OCT) 1, organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3. GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or OAT3, or OCT2.
In vitro potential for ledipasvir/sofosbuvir to affect other medicinal products
At concentrations achieved in the clinic, ledipasvir is not an inhibitor of hepatic transporters including the OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound extrusion (MATE) 1 transporter, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and GS-331007 is not an inhibitor of OAT1, OCT2 and MATE1.
Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes.
Pharmacokinetics in special populations
Race and gender
No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir, sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir or GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant.
Elderly
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir or GS-331007. Clinical studies of ledipasvir/sofosbuvir included 235 patients (8.6% of total number of patients) aged 65 years and over.
Renal impairment
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Harvoni compared to subjects with normal renal function, as described in the text below, are provided in Table 21.
Table 21: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, and Ledipasvir Compared to Subjects with Normal Renal Function
HCV-Negative Subjects
HCV-Infected Subjects
Mild RI (eGFR ≥50 and <80 mL/ min/ 1.73m2)
Moderate RI (eGFR ≥30 and <50 mL/ min/ 1.73m2)
Severe RI (eGFR <30 mL/ min/ 1.73m2)
ESRD Requiring Dialysis
Severe RI (eGFR <30 mL/ min/ 1.73m2)
ESRD Requiring Dialysis
Dosed 1 hr Before Dialysis
Dosed 1 hr After Dialysis
Sofosbuvir
1.6-fold↑
2.1-fold↑
2.7-fold↑
1.3-fold↑
1.6-fold↑
~2-fold↑
1.9-fold↑
GS-331007
1.6-fold↑
1.9-fold↑
5.5-fold↑
≥10-fold↑
≥20-fold↑
~6-fold↑
23-fold↑
Ledipasvir
-
-
↔
-
-
-
1.6-fold↑
↔ indicates no clinically relevant change in the exposure of Ledipasvir.
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative adult patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault, median [range] CrCl 22 [17-29] mL/min).
The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir,relative to patients with normal renal function (eGFR > 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered sofosbuvir dose.
In HCV-infected adult patients with severe renal impairment treated with ledipasvir/sofosbuvir for 12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistent with that observed in HCV negative patients with severe renal impairment.
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks, and compared to patients without renal impairment in the ledipasvir/sofosbuvir Phase 2/3 trials.
Hepatic impairment
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative adult patients with severe hepatic impairment (CPT class C). Ledipasvir plasma exposure (AUCinf) was similar in patients with severe hepatic impairment and control patients with normal hepatic function. Population pharmacokinetics analysis in HCV-infected adult patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to ledipasvir.
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected adult patients with moderate and severe hepatic impairment (CPT class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir and GS-331007.
Body weight
Body weight did not have a significant effect on sofosbuvir exposure according to a population pharmacokinetic analysis. Exposure to ledipasvir decreases with increasing body weight but the effect is not considered to be clinically relevant.
Paediatric population
Ledipasvir, sofosbuvir, and GS-331007 exposures in paediatric patients aged 3 years and above were similar to those in adults from Phase 2/3 studies, following administration of ledipasvir/sofosbuvir. The 90% confidence intervals of geometric least-squares mean ratios for all PK parameters of interest were contained within the predetermined similarity bounds of less than 2-fold (50% to 200%) with the exception of ledipasvir Ctau in paediatric patients 12 years and above which was 84% higher (90%CI: 168% to 203%) and was not considered clinically relevant.
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in paediatric patients aged < 3 years (see section 4.2).
5.3 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Ledipasvir
No target organs of toxicity were identified in rat and dog studies with ledipasvir at AUC exposures approximately 7 times the human exposure at the recommended clinical dose.
Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
Ledipasvir was not carcinogenic in the 26-week rasH2 transgenic mouse and the 2-year rat carcinogenicity studies at exposures up to 26-times in mice and 8-times in rats higher than human exposure.
Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humans at the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir was approximately 7- and 3-fold, in males and females, respectively, the human exposure at the recommended clinical dose.
No teratogenic effects were observed in rat and rabbit developmental toxicity studies with ledipasvir.
In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibited mean decreased body weight and body weight gain when exposed in utero (via maternal dosing) and during lactation (via maternal milk) at a maternal exposure 4 times the exposure in humans at the recommended clinical dose. There were no effects on survival, physical and behavioural development and reproductive performance in the offspring at maternal exposures similar to the exposure in humans at the recommended clinical dose.
When administered to lactating rats, ledipasvir was detected in plasma of suckling rats likely due to excretion of ledipasvir via milk.
Environmental risk assessment (ERA)
Environmental risk assessment studies have shown that ledipasvir has the potential to be very persistent and very bioaccumulative (vPvB) in the environment (see section 6.6).
Sofosbuvir
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at doses which cause adverse effects was 16 times (rat) and 71 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic toxicity studies at exposures 5 times (rat) and 16 times (dog) higher than the clinical exposure. No liver or heart findings were observed in the 2-year carcinogenicity studies at exposures 17 times (mouse) and 9 times (rat) higher than the clinical exposure.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to GS-331007 in these studies was up to 17 times (mouse) and 9 times (rat) higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat and rabbit development studies. No adverse effects on behaviour, reproduction or development of offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 6 times the expected clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure margins based on the major human metabolite was approximately 5 times higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.
6. |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Copovidone
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Film-coating
Polyvinyl alcohol partially hydrolyzed
Titanium dioxide
Macrogol
Talc
Sunset yellow FCF (E110) (Harvoni 90 mg/400 mg film-coated tablet only)
6.2 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
6 years.
6.4 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Harvoni tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene child-resistant closure containing 28 film-coated tablets with a silica gel desiccant and polyester coil.
The following pack sizes are available:
• outer cartons containing 1 bottle of 28 film-coated tablets
• and for the 90 mg/400 mg tablets only; outer cartons containing 84 (3 bottles of 28) film-coated tablets.
Not all pack sizes may be marketed.
6.6 |
Harvoni 45 mg/200 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
This medicinal product may pose a risk to the environment (see section 5.3).
7. |
Harvoni 45 mg/200 mg film-coated tablets | Marketing authorisation holder | Gilead Sciences Ltd
280 High Holborn
London
WC1V 7EE
United Kingdom
8. Marketing authorisation number(s)
PLGB 11972/0041
9. |
Harvoni 45 mg/200 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 01/01/2021
10. |
Harvoni 45 mg/200 mg film-coated tablets | Date of revision of the text | 21/12/2022 |
Harvoni 90 mg/400 mg film-coated tablets | Introduction | This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.1. |
Harvoni 90 mg/400 mg film-coated tablets | Name of the medicinal product | Harvoni 90 mg/400 mg film-coated tablets
2. |
Harvoni 90 mg/400 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.
Excipients with known effect
Each film-coated tablet contains 157 mg of lactose (as monohydrate) and 47 micrograms of sunset yellow FCF.
For the full list of excipients, see section 6.1.
3. |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Harvoni 90 mg/400 mg film-coated tablets
Orange, diamond-shaped, film-coated tablet of dimensions of approximately 19 mm x 10 mm, debossed with “GSI” on one side and “7985” on the other side.
4. |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1).
For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1.
4.2 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Harvoni treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
Posology
The recommended dose of Harvoni in adults is 90 mg/400 mg once daily with or without food (see section 5.2).
The recommended dose of Harvoni in paediatric patients aged 3 years and above is based on weight (as detailed in Table 2) and can be taken with or without food (see section 5.2).
A granule formulation of Harvoni is available for the treatment of chronic HCV-infection in paediatric patients aged 3 years and above having difficulty swallowing film-coated tablets. Please refer to the Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.
Table 1: Recommended treatment duration for Harvoni and the recommended use of co-administered ribavirin for certain subgroups
Patient population
(including HIV co-infected patients)
Treatment and duration
Adult and paediatric patients aged 3 years and abovea with genotype 1, 4, 5 or 6 CHC
Patients without cirrhosis
Harvoni for 12 weeks.
- Harvoni for 8 weeks may be considered in previously untreated genotype 1-infected patients (see section 5.1, ION-3 study).
Patients with compensated cirrhosis
Harvoni + ribavirinb,c for 12 weeks
or
Harvoni (without ribavirin) for 24 weeks.
- Harvoni (without ribavirin) for 12 weeks may be considered for patients deemed at low risk for clinical disease progression and who have subsequent retreatment options (see section 4.4).
Patients who are post-liver transplant without cirrhosis or with compensated cirrhosis
Harvoni + ribavirinb,c for 12 weeks (see section 5.1).
- Harvoni (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
Harvoni + ribavirind for 12 weeks (see section 5.1)
- Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin.
Adult and paediatric patients 3 years of ageand abovea with genotype 3 CHC
Patients with compensated cirrhosis and/or prior treatment failure
Harvoni + ribavirinb for 24 weeks (see sections 4.4 and 5.1).
a See Table 2 for weight-based Harvoni dosing recommendations for paediatric patients aged 3 years and above..
b Adults: weight based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg), administered orally in two divided doses
with food.
c Paediatric patients: for ribavirin dosing recommendations see table 4 below.
d For ribavirin dosing recommendations in adult patients with decompensated cirrhosis, see table 3 below.
Table 2: Dosing for paediatric patients aged 3 years and above using Harvoni Tablets*
Body Weight (kg)
Dosing of Harvoni Tablets
Ledipasvir/Sofosbuvir Daily Dose
≥ 35
one 90 mg/400 mg tablet once daily
or
two 45 mg/200 mg tablets once daily
90 mg/400 mg/day
17 to < 35
one 45 mg/200 mg tablet once daily
45 mg/200 mg/day
* Harvoni is also available as granules for use in paediatric patients with CHC aged 3 years and above (see section 5.1). Patients that weigh < 17 kg are not recommended to take tablets. Please refer to the Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.
Table 3: Guidance for ribavirin dosing when administered with Harvoni to adult patients with decompensated cirrhosis
Patient
Ribavirin dose*
Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant
1,000 mg per day for patients < 75 kg and 1,200 mg for those weighing ≥ 75 kg
CPT Class C cirrhosis pre-transplant
CPT Class B or C cirrhosis post- transplant
Starting dose of 600 mg, which can be titrated up to a maximum of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If the starting dose is not well tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels
* If a more normalized dose of ribavirin (by weight and renal function) cannot be reached for reasons of tolerability, 24 weeks of Harvoni + ribavirin should be considered in order to minimize the risk for relapse.
For adults when ribavirin is added to Harvoni, refer also to the Summary of Product Characteristics of ribavirin.
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where ribavirin is divided into two daily doses and given with food:
Table 4: Guidance for ribavirin dosing when administered with Harvoni to paediatric patients aged 3 years and above.
Body weight kg
Ribavirin Dose*
< 47
15 mg/kg/day
47-49
600 mg/day
50-65
800 mg/day
66-74
1000 mg/day
> or = 75
1200 mg/day
* The daily dosage of ribavirin is weight-based and administered orally in two divided doses with food.
Dose modification of ribavirin in adults taking 1,000-1,200 mg daily
If Harvoni 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. Table 5 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
Table 5: Ribavirin dose modification guideline for co-administration with Harvoni in adults
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
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin be increased to the originally assigned dose (1,000 mg to 1,200 mg daily).
Paediatric population aged < 3 years
The safety and efficacy of Harvoni in paediatric patients aged < 3 years have not been established. No data are available.
Missed dose
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 (see section 5.1).
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 (see section 5.2).
Renal impairment
No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment.
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring dialysis. Harvoni can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2).
Hepatic impairment
No dose adjustment of Harvoni is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). Safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section 5.1).
Method of administration
For oral use.
Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bitter taste, it is recommended that film-coated tablets are not chewed or crushed (see section 5.2).
4.3 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Co-administration with rosuvastatin (see section 4.5).
Use with strong P-gp inducers
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort). Co-administration will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni (see section 4.5).
4.4 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir.
Genotype-specific activity
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.
The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of Harvoni (always in combination with ribavirin) should only be considered for patients who are deemed at high risk for clinical disease progression and who do not have alternative treatment options.
The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are limited (see section 5.1).
Severe bradycardia and heart block
Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir- containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment.
Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.
Should concomitant use of amiodarone be considered necessary it is recommended that patients undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Harvoni.
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.
Use in diabetic patients
Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated.
HCV/HBV (hepatitis B virus) co-infection
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.
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 (see section 5.1). Limited data indicate that such NS5A mutations do not revert on long-term follow-up. 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 classes of medicinal products for clearance of HCV infection. Consequently, consideration should be given to longer treatment for patients with uncertain subsequent retreatment options.
Renal impairment
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Harvoni can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Harvoni is used in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min (see section 5.2).
Adults 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. Treatment with Harvoni should be guided by an assessment of the potential benefits and risks for the individual patient.
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 Harvoni.
Co-administration of such medicinal products is not recommended with Harvoni (see section 4.5).
Use with certain HIV antiretroviral regimens
Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Harvoni 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 Harvoni concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir- associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product Characteristics for recommendations on renal monitoring.
Use with HMG-CoA reductase inhibitors
Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis (see section 4.5).
Paediatric population
Harvoni is not recommended for use in paediatric patients aged < 3 years because the safety and efficacy have not been established in this population.
Excipients
Harvoni contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions. It also contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
4.5 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with Harvoni.
Potential for Harvoni to affect other medicinal products
Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters.
Potential for other medicinal products to affect Harvoni
Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not.
Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). 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 Harvoni. Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected.
Patients treated with vitamin K antagonists
As liver function may change during treatment with Harvoni, a close monitoring of International Normalised Ratio (INR) values is recommended.
Impact of DAA therapy on drugs metabolized by the liver
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus.
Interactions between Harvoni and other medicinal products
Table 6 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The medicinal product interactions described are based on studies conducted with either ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive.
Table 6: Interactions between Harvoni and other medicinal products
Medicinal product by therapeutic areas
Effects on medicinal product levels.
Mean ratio (90% confidence interval) for
AUC, Cmax, Cmina, b
Recommendation concerning co-administration with Harvoni
ACID REDUCING AGENTS
Antacids
e.g. Aluminium or magnesium hydroxide; calcium carbonate
Interaction not studied.
Expected:
↓ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
(Increase in gastric pH)
Ledipasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease concentration of ledipasvir.
It is recommended to separate antacid and Harvoni administration by 4 hours.
H2-receptor antagonists
Famotidine
(40 mg single dose)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c, d
Famotidine dosed simultaneously with Harvonid
Cimetidinee
Nizatidinee
Ranitidinee
Ledipasvir
↓ Cmax 0.80 (0.69, 0.93)
↔ AUC 0.89 (0.76, 1.06)
Sofosbuvir
↑ Cmax 1.15 (0.88, 1.50)
↔ AUC 1.11 (1.00, 1.24)
GS-331007
↔ Cmax 1.06 (0.97, 1.14)
↔ AUC 1.06 (1.02, 1.11)
(Increase in gastric pH)
H2-receptor antagonists may be administered simultaneously with or staggered from Harvoni at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
Famotidine
(40 mg single dose)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c, d
Famotidine dosed 12 hours prior to Harvonid
Ledipasvir
↓ Cmax 0.83 (0.69, 1.00)
↔ AUC 0.98 (0.80, 1.20)
Sofosbuvir
↔ Cmax 1.00 (0.76, 1.32)
↔ AUC 0.95 (0.82, 1.10)
GS-331007
↔ Cmax 1.13 (1.07, 1.20)
↔ AUC 1.06 (1.01, 1.12)
(Increase in gastric pH)
Proton pump inhibitors
Omeprazole
(20 mg once daily)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c
Omeprazole dosed simultaneously with Harvoni
Lansoprazolee
Rabeprazolee
Pantoprazolee
Esomeprazolee
Ledipasvir
↓ Cmax 0.89 (0.61, 1.30)
↓ AUC 0.96 (0.66, 1.39)
Sofosbuvir
↔ Cmax 1.12 (0.88, 1.42)
↔ AUC 1.00 (0.80, 1.25)
GS-331007
↔ Cmax 1.14 (1.01, 1.29)
↔ AUC 1.03 (0.96, 1.12)
(Increase in gastric pH)
Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered simultaneously with Harvoni. Proton pump inhibitors should not be taken before Harvoni.
ANTIARRHYTHMICS
Amiodarone
Effect on amiodarone, sofosbuvir and ledipasvir concentrations unknown.
Coadministration of amiodarone with a sofosbuvir- containing regimen may result in serious symptomatic bradycardia.
Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Harvoni (see sections 4.4 and 4.8).
Digoxin
Interaction not studied.
Expected:
↑ Digoxin
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
(Inhibition of P-gp)
Co-administration of Harvoni with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with Harvoni.
ANTICOAGULANTS
Dabigatran etexilate
Interaction not studied.
Expected:
↑ Dabigatran
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
(Inhibition of P-gp)
Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Harvoni. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.
Vitamin K antagonists
Interaction not studied.
Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function
changes during treatment with Harvoni.
ANTICONVULSANTS
Phenobarbital Phenytoin
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Harvoni is contraindicated with phenobarbital and phenytoin (see section 4.3).
Carbamazepine
Interaction not studied
Expected:
↓ Ledipasvir
Observed:
Sofosbuvir
↓ Cmax 0.52 (0.43, 0.62)
↓ AUC 0.52 (0.46, 0.59)
Cmin (NA)
GS-331007
↔ Cmax 1.04 (0.97, 1.11)
↔ AUC 0.99 (0.94, 1.04)
Cmin (NA)
(Induction of P-gp)
Harvoni is contraindicated with carbamazepine (see section 4.3).
Oxcarbazepine
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Co-administration of Harvoni with oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir leading to reduced therapeutic effect of Harvoni. Such co-administration is not recommended (see section 4.4).
ANTIMYCOBACTERIALS
Rifampicin (600 mg once daily)/ ledipasvir (90 mg single dose)d
Interaction not studied.
Expected:
Rifampicin
↔ Cmax
↔ AUC
↔ Cmin
Observed:
Ledipasvir
↓ Cmax 0.65 (0.56, 0.76)
↓ AUC 0.41 (0.36, 0.48)
(Induction of P-gp)
Harvoni is contraindicated with rifampicin (see section 4.3).
Rifampicin (600 mg once daily)/ sofosbuvir (400 mg single dose)d
Interaction not studied.
Expected:
Rifampicin
↔ Cmax
↔ AUC
↔ Cmin
Observed:
Sofosbuvir
↓ Cmax 0.23 (0.19, 0.29)
↓ AUC 0.28 (0.24, 0.32)
GS-331007
↔ Cmax 1.23 (1.14, 1.34)
↔ AUC 0.95 (0.88, 1.03)
(Induction of P-gp)
Rifabutin
Interaction not studied.
Expected:
↓ Ledipasvir
Observed:
Sofosbuvir
↓ Cmax 0.64 (0.53, 0.77)
↓ AUC 0.76 (0.63, 0.91)
Cmin (NA)
GS-331007
↔ Cmax 1.15 (1.03, 1.27)
↔ AUC 1.03 (0.95, 1.12)
Cmin (NA)
(Induction of P-gp)
Harvoni is contraindicated with rifabutin (see section 4.3).
Rifapentine
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Co-administration of Harvoni with rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Harvoni. Such co-administration is not recommended.
SEDATIVES/HYPNOTICS
Midazolam (2.5 mg single dose)/ ledipasvir (90 mg single dose)
Ledipasvir (90 mg once daily)
Observed:
Midazolam
↔ Cmax 1.07 (1.00, 1.14)
↔ AUC 0.99 (0.95, 1.04)
(Inhibition of CYP3A)
Midazolam
↔ Cmax 0.95 (0.87, 1.04)
↔ AUC 0.89 (0.84, 0.95)
(Induction of CYP3A)
Expected:
↔ Sofosbuvir
↔ GS-331007
No dose adjustment of Harvoni or midazolam is required.
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate (600 mg/ 200 mg/ 300 mg/ once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Efavirenz
↔ Cmax 0.87 (0.79, 0.97)
↔ AUC 0.90 (0.84, 0.96)
↔ Cmin 0.91 (0.83, 0.99)
Emtricitabine
↔ Cmax 1.08 (0.97, 1.21)
↔ AUC 1.05 (0.98, 1.11)
↔ Cmin 1.04 (0.98, 1.11)
Tenofovir
↑ Cmax 1.79 (1.56, 2.04)
↑ AUC 1.98 (1.77, 2.23)
↑ Cmin 2.63 (2.32, 2.97)
Ledipasvir
↓ Cmax 0.66 (0.59, 0.75)
↓ AUC 0.66 (0.59, 0.75)
↓ Cmin 0.66 (0.57, 0.76)
Sofosbuvir
↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.94 (0.81, 1.10)
GS-331007
↔ Cmax 0.86 (0.76, 0.96)
↔ AUC 0.90 (0.83, 0.97)
↔ Cmin 1.07 (1.02, 1.13)
No dose adjustment of Harvoni or efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is required.
Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate (200 mg/ 25 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Emtricitabine
↔ Cmax 1.02 (0.98, 1.06)
↔ AUC 1.05 (1.02, 1.08)
↔ Cmin 1.06 (0.97, 1.15)
Rilpivirine
↔ Cmax 0.97 (0.88, 1.07)
↔ AUC 1.02 (0.94, 1.11)
↔ Cmin 1.12 (1.03, 1.21)
Tenofovir
↔ Cmax 1.32 (1.25, 1.39)
↑ AUC 1.40 (1.31, 1.50)
↑ Cmin 1.91 (1.74, 2.10)
Ledipasvir
↔ Cmax 1.01 (0.95, 1.07)
↔ AUC 1.08 (1.02, 1.15)
↔ Cmin 1.16 (1.08, 1.25)
Sofosbuvir
↔ Cmax 1.05 (0.93, 1.20)
↔ AUC 1.10 (1.01, 1.21)
GS-331007
↔ Cmax 1.06 (1.01, 1.11)
↔ AUC 1.15 (1.11, 1.19)
↔ Cmin 1.18 (1.13, 1.24)
No dose adjustment of Harvoni or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required.
Abacavir/ lamivudine (600 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Abacavir
↔ Cmax 0.92 (0.87, 0.97)
↔ AUC 0.90 (0.85, 0.94)
Lamivudine
↔ Cmax 0.93 (0.87, 1.00)
↔ AUC 0.94 (0.90, 0.98)
↔ Cmin 1.12 (1.05, 1.20)
Ledipasvir
↔ Cmax 1.10 (1.01, 1.19)
↔ AUC 1.18 (1.10, 1.28)
↔ Cmin 1.26 (1.17, 1.36)
Sofosbuvir
↔ Cmax 1.08 (0.85, 1.35)
↔ AUC 1.21 (1.09, 1.35)
GS-331007
↔ Cmax 1.00 (0.94, 1.07)
↔ AUC 1.05 (1.01, 1.09)
↔ Cmin 1.08 (1.01, 1.14)
No dose adjustment of Harvoni or abacavir/ lamivudine is required.
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with ritonavir (300 mg/ 100 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Atazanavir
↔ Cmax 1.07 (1.00, 1.15)
↔ AUC 1.33 (1.25, 1.42)
↑ Cmin 1.75 (1.58, 1.93)
Ledipasvir
↑ Cmax 1.98 (1.78, 2.20)
↑ AUC 2.13 (1.89, 2.40)
↑ Cmin 2.36 (2.08, 2.67)
Sofosbuvir
↔ Cmax 0.96 (0.88, 1.05)
↔ AUC 1.08 (1.02, 1.15)
GS-331007
↔ Cmax 1.13 (1.08, 1.19)
↔ AUC 1.23 (1.18, 1.29)
↔ Cmin 1.28 (1.21, 1.36)
No dose adjustment of Harvoni or atazanavir (ritonavir boosted) is required.
For the combination of tenofovir/emtricitabine + atazanavir/ritonavir, please see below.
Atazanavir boosted with ritonavir (300 mg/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Dosed simultaneouslyf
Atazanavir
↔ Cmax 1.07 (0.99, 1.14)
↔ AUC 1.27 (1.18, 1.37)
↑ Cmin 1.63 (1.45, 1.84)
Ritonavir
↔ Cmax 0.86 (0.79, 0.93)
↔ AUC 0.97 (0.89, 1.05)
↑ Cmin 1.45 (1.27, 1.64)
Emtricitabine
↔ Cmax 0.98 (0.94, 1.02)
↔ AUC 1.00 (0.97, 1.04)
↔ Cmin 1.04 (0.96, 1.12)
Tenofovir
↑ Cmax 1.47 (1.37, 1.58)
↔ AUC 1.35 (1.29, 1.42)
↑ Cmin 1.47 (1.38, 1.57)
Ledipasvir
↑ Cmax 1.68 (1.54, 1.84)
↑ AUC 1.96 (1.74, 2.21)
↑ Cmin 2.18 (1.91, 2.50)
Sofosbuvir
↔ Cmax 1.01 (0.88, 1.15)
↔ AUC 1.11 (1.02, 1.21)
GS-331007
↔ Cmax 1.17 (1.12, 1.23)
↔ AUC 1.31 (1.25, 1.36)
↑ Cmin 1.42 (1.34, 1.49)
When given with tenofovir disoproxil fumarate used in conjunction with atazanavir/ritonavir, Harvoni increased the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Atazanavir concentrations are also increased, with a risk for an increase in bilirubin levels/icterus. That risk is even higher if ribavirin is used as part of the HCV treatment.
Darunavir boosted with ritonavir
(800 mg/ 100 mg once daily)/ ledipasvir (90 mg once daily)d
Darunavir
↔ Cmax 1.02 (0.88, 1.19)
↔ AUC 0.96 (0.84, 1.11)
↔ Cmin 0.97 (0.86, 1.10)
Ledipasvir
↑ Cmax 1.45 (1.34, 1.56)
↑ AUC 1.39 (1.28, 1.49)
↑ Cmin 1.39 (1.29, 1.51)
No dose adjustment of Harvoni or darunavir (ritonavir boosted) is required.
For the combination of tenofovir/emtricitabine + darunavir/ritonavir, please see below.
Darunavir boosted with ritonavir
(800 mg/ 100 mg once daily)/ sofosbuvir (400 mg once daily)
Darunavir
↔ Cmax 0.97 (0.94, 1.01)
↔ AUC 0.97 (0.94, 1.00)
↔ Cmin 0.86 (0.78, 0.96)
Sofosbuvir
↑ Cmax 1.45 (1.10, 1.92)
↑ AUC 1.34 (1.12, 1.59)
GS-331007
↔ Cmax 0.97 (0.90, 1.05)
↔ AUC 1.24 (1.18, 1.30)
Darunavir boosted with ritonavir (800 mg/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d
Dosed simultaneouslyf
Darunavir
↔ Cmax 1.01 (0.96, 1.06)
↔ AUC 1.04 (0.99, 1.08)
↔ Cmin 1.08 (0.98, 1.20)
Ritonavir
↔ Cmax 1.17 (1.01, 1.35)
↔ AUC 1.25 (1.15, 1.36)
↑ Cmin 1.48 (1.34, 1.63)
Emtricitabine
↔ Cmax 1.02 (0.96, 1.08)
↔ AUC 1.04 (1.00, 1.08)
↔ Cmin 1.03 (0.97, 1.10)
Tenofovir
↑ Cmax 1.64 (1.54, 1.74)
↑ AUC 1.50 (1.42, 1.59)
↑ Cmin 1.59 (1.49, 1.70)
Ledipasvir
↔ Cmax 1.11 (0.99, 1.24)
↔ AUC 1.12 (1.00, 1.25)
↔ Cmin 1.17 (1.04, 1.31)
Sofosbuvir
↓ Cmax 0.63 (0.52, 0.75)
↓ AUC 0.73 (0.65, 0.82)
GS-331007
↔ Cmax 1.10 (1.04, 1.16)
↔ AUC 1.20 (1.16, 1.24)
↔ Cmin 1.26 (1.20, 1.32)
When given with darunavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, Harvoni increased the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Lopinavir boosted with ritonavir + emtricitabine/ tenofovir disoproxil fumarate
Interaction not studied.
Expected:
↑ Lopinavir
↑ Ritonavir
↔ Emtricitabine
↑ Tenofovir
↑ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
When given with lopinavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, Harvoni is expected to increase the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Tipranavir boosted with ritonavir
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Co-administration of Harvoni with tipranavir (ritonavir boosted) is expected to decrease the concentration of ledipasvir, leading to reduced therapeutic effect of Harvoni. Co-administration is not recommended.
HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir
(400 mg twice daily)/ ledipasvir (90 mg once daily)d
Raltegravir
↓ Cmax 0.82 (0.66, 1.02)
↔ AUC 0.85 (0.70, 1.02)
↑ Cmin 1.15 (0.90, 1.46)
Ledipasvir
↔ Cmax 0.92 (0.85, 1.00)
↔ AUC 0.91 (0.84, 1.00)
↔ Cmin 0.89 (0.81, 0.98)
No dose adjustment of Harvoni or raltegravir is required.
Raltegravir
(400 mg twice daily)/ sofosbuvir (400 mg once daily)d
Raltegravir
↓ Cmax 0.57 (0.44, 0.75)
↓ AUC 0.73 (0.59, 0.91)
↔ Cmin 0.95 (0.81, 1.12)
Sofosbuvir
↔ Cmax 0.87 (0.71, 1.08)
↔ AUC 0.95 (0.82, 1.09)
GS-331007
↔ Cmax 1.09 (0.99, 1.19)
↔ AUC 1.02 (0.97, 1.08)
Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate
(150 mg/ 150 mg/ 200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c
Interaction not studied.
Expected:
↔ Emtricitabine
↑ Tenofovir
Observed:
Elvitegravir
↔ Cmax 0.88 (0.82, 0.95)
↔ AUC 1.02 (0.95, 1.09)
↑ Cmin 1.36 (1.23, 1.49)
Cobicistat
↔ Cmax 1.25 (1.18, 1.32)
↑ AUC 1.59 (1.49, 1.70)
↑ Cmin 4.25 (3.47, 5.22)
Ledipasvir
↑ Cmax 1.63 (1.51, 1.75)
↑ AUC 1.78 (1.64, 1.94)
↑ Cmin 1.91 (1.76, 2.08)
Sofosbuvir
↑ Cmax 1.33 (1.14, 1.56)
↑ AUC 1.36 (1.21, 1.52)
GS-331007
↑ Cmax 1.33 (1.22, 1.44)
↑ AUC 1.44 (1.41, 1.48)
↑ Cmin 1.53 (1.47, 1.59)
When given with elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate, Harvoni is expected to increase the concentration of tenofovir.
The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.
The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).
Dolutegravir
Interaction not studied.
Expected:
↔ Dolutegravir
↔ Ledipasvir
↔ Sofosbuvir
↔ GS-331007
No dose adjustment required.
HERBAL SUPPLEMENTS
St. John's wort
Interaction not studied.
Expected:
↓ Ledipasvir
↓ Sofosbuvir
↔ GS-331007
(Induction of P-gp)
Harvoni is contraindicated with St. John's wort (see section 4.3).
HMG-CoA REDUCTASE INHIBITORS
Rosuvastating
↑ Rosuvastatin
(Inhibition of drug transporters OATP and BCRP)
Co-administration of Harvoni 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 Harvoni with rosuvastatin is contraindicated (see section 4.3).
Pravastating
↑ Pravastatin
Co-administration of Harvoni with pravastatin may significantly increase the concentration of pravastatin which is associated with increased risk of myopathy. Clinical and biochemical control is recommended in these patients and a dose adjustment may be needed (see section 4.4).
Other statins
Expected:
↑ Statins
Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Harvoni, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 4.4).
NARCOTIC ANALGESICS
Methadone
Interaction not studied.
Expected:
↔ Ledipasvir
No dose adjustment of Harvoni or methadone is required.
Methadone
(Methadone maintenance therapy [30 to 130 mg/ daily])/ sofosbuvir (400 mg once daily)d
R-methadone
↔ Cmax 0.99 (0.85, 1.16)
↔ AUC 1.01 (0.85, 1.21)
↔ Cmin 0.94 (0.77, 1.14)
S-methadone
↔ Cmax 0.95 (0.79, 1.13)
↔ AUC 0.95 (0.77, 1.17)
↔ Cmin 0.95 (0.74, 1.22)
Sofosbuvir
↓ Cmax 0.95 (0.68, 1.33)
↑ AUC 1.30 (1.00, 1.69)
GS-331007
↓ Cmax 0.73 (0.65, 0.83)
↔ AUC 1.04 (0.89, 1.22)
IMMUNOSUPPRESSANTS
Ciclosporing
Interaction not studied.
Expected:
↑ Ledipasvir
↔ Ciclosporin
No dose adjustment of Harvoni or ciclosporin is required at initiation of co-administration.
Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required.
Ciclosporin
(600 mg single dose)/ sofosbuvir (400 mg single dose)h
Ciclosporin
↔ Cmax 1.06 (0.94, 1.18)
↔ AUC 0.98 (0.85, 1.14)
Sofosbuvir
↑ Cmax 2.54 (1.87, 3.45)
↑ AUC 4.53 (3.26, 6.30)
GS-331007
↓ Cmax 0.60 (0.53, 0.69)
↔ AUC 1.04 (0.90, 1.20)
Tacrolimus
Interaction not studied.
Expected:
↔ Ledipasvir
No dose adjustment of Harvoni or tacrolimus is required at initiation of co-administration.
Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.
Tacrolimus
(5 mg single dose)/ sofosbuvir (400 mg single dose)h
Tacrolimus
↓ Cmax 0.73 (0.59, 0.90)
↑ AUC 1.09 (0.84, 1.40)
Sofosbuvir
↓ Cmax 0.97 (0.65, 1.43)
↑ AUC 1.13 (0.81, 1.57)
GS-331007
↔ Cmax 0.97 (0.83, 1.14)
↔ AUC 1.00 (0.87, 1.13)
ORAL CONTRACEPTIVES
Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ ledipasvir (90 mg once daily)d
Norelgestromin
↔ Cmax 1.02 (0.89, 1.16)
↔ AUC 1.03 (0.90, 1.18)
↔ Cmin 1.09 (0.91, 1.31)
Norgestrel
↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.99 (0.82, 1.20)
↔ Cmin 1.00 (0.81, 1.23)
Ethinyl estradiol
↑ Cmax 1.40 (1.18, 1.66)
↔ AUC 1.20 (1.04, 1.39)
↔ Cmin 0.98 (0.79, 1.22)
No dose adjustment of oral contraceptives is required.
Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ sofosbuvir (400 mg once daily)d
Norelgestromin
↔ Cmax 1.07 (0.94, 1.22)
↔ AUC 1.06 (0.92, 1.21)
↔ Cmin 1.07 (0.89, 1.28)
Norgestrel
↔ Cmax 1.18 (0.99, 1.41)
↑ AUC 1.19 (0.98, 1.45)
↑ Cmin 1.23 (1.00, 1.51)
Ethinyl estradiol
↔ Cmax 1.15 (0.97, 1.36)
↔ AUC 1.09 (0.94, 1.26)
↔ Cmin 0.99 (0.80, 1.23)
a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00.
b All interaction studies conducted in healthy volunteers. c Administered as Harvoni.
d Lack of pharmacokinetics interaction bounds 70-143%.
e These are drugs within class where similar interactions could be predicted.
f Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results.
g This study was conducted in the presence of another two direct-acting antiviral agents.
h Bioequivalence/Equivalence boundary 80-125%.
4.6 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential / contraception in males and females
When Harvoni 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 in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
Pregnancy
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or Harvoni in pregnant women.
Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Harvoni 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 (see section 5.3).
A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during breast-feeding.
Fertility
No human data on the effect of Harvoni on fertility are available. Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility.
If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin during pregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin).
4.7 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Harvoni (administered alone or in combination with ribavirin) has no or negligible influence on the ability to drive and use machines. However, patients should be advised that fatigue was more common in patients treated with ledipasvir/sofosbuvir compared to placebo.
4.8 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile in adults
The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who received Harvoni in combination with ribavirin.
The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively.
In clinical studies, fatigue and headache were more common in patients treated with ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions.
Tabulated list of adverse events
The following adverse drug reactions have been identified with Harvoni (Table 7). The adverse reactions are listed below by body system organ class and frequency. 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) or very rare (< 1/10,000).
Table 7: Adverse drug reactions identified with Harvoni
Frequency
Adverse drug reaction
Nervous system disorders:
Very common
headache
Skin and subcutaneous tissue disorders:
Common
rash
Not known
angioedema
General disorders:
Very common
fatigue
Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant
The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults with decompensated liver disease and/or those post-liver transplant was assessed in two open-label studies (SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients with decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in this study compared to studies that excluded decompensated patients and/or patients who were post- liver transplantation, the adverse events observed were those expected as clinical sequelae of advanced liver disease and/or transplantation or were consistent with the known safety profile of ribavirin (see section 5.1 for details of this study).
Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and 13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 15% of the patients.
7% of liver transplant recipients had a modification of their immunosuppressive agents.
Patients with renal impairment
Ledipasvir/sofosbuvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). In this limited clinical safety data set, the rate of adverse events was not clearly elevated from what is expected in patients with severe renal impairment.
The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patients with ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS- 331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients.
Paediatric population
The safety and efficacy of Harvoni in paediatric patients aged 3 years and above are based on data from a Phase 2, open-label clinical study (Study 1116) that enrolled 226 patients who were treated with ledipasvir/sofosbuvir for 12 or 24 weeks or ledipasvir/sofosbuvir plus ribavirin for 24 weeks. The adverse reactions observed were consistent with those observed in clinical studies of ledipasvir/sofosbuvir in adults (see Table 7).
Description of selected adverse reactions
Cardiac arrhythmias
Cases of severe bradycardia and heart block have been observed when Harvoni is used with amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5).
Skin disorders
Frequency not known: Stevens-Johnson syndrome
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.
4.9 |
Harvoni 90 mg/400 mg film-coated tablets | Clinical particulars - Overdose | Overdose
The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a single dose of 1,200 mg, respectively. In these healthy volunteer studies, there were no untoward effects observed at these dose levels, and adverse reactions were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses are not known.
No specific antidote is available for overdose with Harvoni. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Harvoni 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%.
5. Pharmacological properties
5.1 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
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 concentrations were observed ~ 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed at 4 hours post-dose.
Based on the population pharmacokinetic analysis in HCV-infected patients, geometric mean steady-state AUC0-24 for ledipasvir (n = 2,113), sofosbuvir (n = 1,542), and GS-331007 (n = 2,113) were 7,290, 1,320 and 12,000 ng•h/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir and GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (n = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected patients. Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.
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. Harvoni can be administered without regard to food.
Distribution
Ledipasvir is > 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66.
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. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.7.
Biotransformation
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. 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 analogue triphosphate GS-461203. The active metabolite is not observed. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Within ledipasvir/sofosbuvir, GS-331007 accounts for approximately 85% of total systemic exposure.
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%). The median terminal half-life of ledipasvir in healthy volunteers following administration of ledipasvir/sofosbuvir in the fasted state was 47 hours.
Following a single 400 mg oral dose of [14C]-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-lives of sofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours, respectively.
Neither ledipasvir nor sofosbuvir are substrates for hepatic uptake transporters, organic cation transporter (OCT) 1, organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3. GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or OAT3, or OCT2.
In vitro
potential for ledipasvir/sofosbuvir to affect other medicinal products
At concentrations achieved in the clinic, ledipasvir is not an inhibitor of hepatic transporters including the OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound extrusion (MATE) 1 transporter, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and GS-331007 is not an inhibitor of OAT1, OCT2 and MATE1.
Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes.
Pharmacokinetics in special populations
Race and gender
No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir, sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir or GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant.
Elderly
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir or GS-331007. Clinical studies of ledipasvir/sofosbuvir included 235 patients (8.6% of total number of patients) aged 65 years and over.
Renal impairment
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Harvoni compared to subjects with normal renal function, as described in the text below, are provided in Table 21.
Table 21: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, and Ledipasvir Compared to Subjects with Normal Renal Function
HCV-Negative Subjects
HCV-Infected Subjects
Mild RI (eGFR ≥50 and <80 mL/ min/ 1.73m2)
Moderate RI (eGFR ≥30 and <50 mL/ min/ 1.73m2)
Severe RI (eGFR <30 mL/ min/ 1.73m2)
ESRD Requiring Dialysis
Severe RI (eGFR <30 mL/ min/ 1.73m2)
ESRD Requiring Dialysis
Dosed 1 hr Before Dialysis
Dosed 1 hr After Dialysis
Sofosbuvir
1.6-fold↑
2.1-fold↑
2.7-fold↑
1.3-fold↑
1.6-fold↑
~2-fold↑
1.9-fold↑
GS-331007
1.6-fold↑
1.9-fold↑
5.5-fold↑
≥10-fold↑
≥20-fold↑
~6-fold↑
23-fold↑
Ledipasvir
-
-
↔
-
-
-
1.6-fold↑
↔ indicates no clinically relevant change in the exposure of Ledipasvir.
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative adult patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault, median [range] CrCl 22 [17-29] mL/min).
The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR
≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir,relative to patients with normal renal function (eGFR > 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered sofosbuvir dose.
In HCV-infected adult patients with severe renal impairment treated with ledipasvir/sofosbuvir for 12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistent with that observed in HCV negative patients with severe renal impairment.
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks, and compared to patients without renal impairment in the ledipasvir/sofosbuvir Phase 2/3 trials.
Hepatic impairment
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative adult patients with severe hepatic impairment (CPT class C). Ledipasvir plasma exposure (AUCinf) was similar in patients with severe hepatic impairment and control patients with normal hepatic function. Population pharmacokinetics analysis in HCV-infected adult patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to ledipasvir.
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected adult patients with moderate and severe hepatic impairment (CPT class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir and GS-331007.
Body weight
Body weight did not have a significant effect on sofosbuvir exposure according to a population pharmacokinetic analysis. Exposure to ledipasvir decreases with increasing body weight but the effect is not considered to be clinically relevant.
Paediatric population
Ledipasvir, sofosbuvir, and GS-331007 exposures in paediatric patients aged 3 years and above were similar to those in adults from Phase 2/3 studies, following administration of ledipasvir/sofosbuvir. The 90% confidence intervals of geometric least-squares mean ratios for all PK parameters of interest were contained within the predetermined similarity bounds of less than 2-fold (50% to 200%) with the exception of ledipasvir Ctau in paediatric patients 12 years and above which was 84% higher (90%CI: 168% to 203%) and was not considered clinically relevant.
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in paediatric patients aged < 3 years (see section 4.2).
5.3 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Ledipasvir
No target organs of toxicity were identified in rat and dog studies with ledipasvir at AUC exposures approximately 7 times the human exposure at the recommended clinical dose.
Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
Ledipasvir was not carcinogenic in the 26-week rasH2 transgenic mouse and the 2-year rat carcinogenicity studies at exposures up to 26-times in mice and 8-times in rats higher than human exposure.
Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humans at the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir was approximately 7- and 3-fold, in males and females, respectively, the human exposure at the recommended clinical dose.
No teratogenic effects were observed in rat and rabbit developmental toxicity studies with ledipasvir.
In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibited mean decreased body weight and body weight gain when exposed in utero (via maternal dosing) and during lactation (via maternal milk) at a maternal exposure 4 times the exposure in humans at the recommended clinical dose. There were no effects on survival, physical and behavioural development and reproductive performance in the offspring at maternal exposures similar to the exposure in humans at the recommended clinical dose.
When administered to lactating rats, ledipasvir was detected in plasma of suckling rats likely due to excretion of ledipasvir via milk.
Environmental risk assessment (ERA)
Environmental risk assessment studies have shown that ledipasvir has the potential to be very persistent and very bioaccumulative (vPvB) in the environment (see section 6.6).
Sofosbuvir
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at doses which cause adverse effects was 16 times (rat) and 71 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic toxicity studies at exposures 5 times (rat) and 16 times (dog) higher than the clinical exposure. No liver or heart findings were observed in the 2-year carcinogenicity studies at exposures 17 times (mouse) and 9 times (rat) higher than the clinical exposure.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to GS-331007 in these studies was up to 17 times (mouse) and 9 times (rat) higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat and rabbit development studies. No adverse effects on behaviour, reproduction or development of offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 6 times the expected clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure margins based on the major human metabolite was approximately 5 times higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.
6. |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Copovidone
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Film-coating
Polyvinyl alcohol partially hydrolyzed
Titanium dioxide
Macrogol
Talc
Sunset yellow FCF (E110) (Harvoni 90 mg/400 mg film-coated tablet only)
6.2 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
6 years.
6.4 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Harvoni tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene child-resistant closure containing 28 film-coated tablets with a silica gel desiccant and polyester coil.
The following pack sizes are available:
• outer cartons containing 1 bottle of 28 film-coated tablets
• and for the 90 mg/400 mg tablets only; outer cartons containing 84 (3 bottles of 28) film-coated tablets.
Not all pack sizes may be marketed.
6.6 |
Harvoni 90 mg/400 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
This medicinal product may pose a risk to the environment (see section 5.3).
7. |
Harvoni 90 mg/400 mg film-coated tablets | Marketing authorisation holder | Gilead Sciences Ltd
280 High Holborn
London
WC1V 7EE
United Kingdom
8. Marketing authorisation number(s)
PLGB 11972/0017
9. |
Harvoni 90 mg/400 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 01/01/2021
10. |
Harvoni 90 mg/400 mg film-coated tablets | Date of revision of the text | 21/12/2022 |
Humatrope 24mg powder and solvent for solution for injection | Name of the medicinal product | Humatrope® 6 mg, powder and solvent for solution for injection
Humatrope® 12 mg, powder and solvent for solution for injection
Humatrope® 24 mg, powder and solvent for solution for injection
2. |
Humatrope 24mg powder and solvent for solution for injection | Qualitative and quantitative composition | Humatrope 6 mg:
The cartridge contains 6 mg of somatropin
When reconstituted contains 2.08 mg/ml
Humatrope 12 mg:
The cartridge contains 12 mg of somatropin
When reconstituted contains 4.17 mg/ml
Humatrope 24 mg:
The cartridge contains 24 mg of somatropin
When reconstituted contains 8.33 mg/ml
Somatropin is produced in Escherichia coli cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical form | Powder and solvent for solution for injection.
The powder is a white or almost white powder. The solvent is a clear solution.
4. |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Therapeutic indications | Therapeutic indications
Paediatric patients
Humatrope is indicated for the long-term treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatrope is also indicated for the treatment of short stature in children with Turner Syndrome, confirmed by chromosome analysis.
Humatrope is also indicated for the treatment of growth retardation in prepubertal children with chronic renal insufficiency.
Humatrope is also indicated for the treatment of patients who have growth failure associated with SHOX deficiency, as confirmed by DNA analysis.
Humatrope is also indicated for growth disturbance (current height SDS < -2.5 and parental adjusted height SDS < -1) in short children born small for gestational age (SGA), with a birth weight and/or length below -2 SD, who failed to show catch-up growth (height velocity SDS < 0 during the last year) by 4 years of age or later.
Adult patients
Humatrope is indicated for replacement therapy in adults with pronounced growth hormone deficiency.
Patients with severe growth hormone deficiency in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one known deficiency of a pituitary hormone not being prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a growth deficiency. In patients with childhood onset isolated GH deficiency (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be recommended, except for those having low IGF-I concentrations <-2 SDS, who may be considered for one test. The cut-off point of the dynamic test should be strict.
4.2 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage and administration schedule should be personalised for each individual; however for:
Growth hormone deficient paediatric patients
The recommended dosage is 0.025-0.035 mg/kg of body weight per day by subcutaneous injection. This is the equivalent to approximately 0.7-1.0 mg/m2 body surface area per day.
Growth hormone deficient adult patients
The recommended starting dose is 0.15-0.30 mg/day. A lower starting dose may be necessary in older and obese patients.
This dose should be gradually increased according to individual patient requirements based on the clinical response and serum IGF-I concentrations.
Total daily dose usually does not exceed 1 mg.
IGF-I concentrations should be maintained below the upper limit of the age-specific normal range. The minimum effective dose should be used and dose requirements may decline with increasing age.
Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time. This means that there is a risk that women, especially those on oral oestrogen therapy are under-treated while men are over-treated.
The dosage of somatropin should be decreased in cases of persistent oedema or severe paraesthesia, in order to avoid the development of carpal tunnel syndrome (see section 4.8).
Patients with Turner Syndrome
The recommended dosage is 0.045-0.050 mg/kg of body weight per day, given as a subcutaneous injection, to be administered preferably in the evening.
This is equivalent to approximately 1.4 mg/m2 per day.
Prepubertal paediatric patients with Chronic Renal Insufficiency
The recommended dosage is 0.045-0.050 mg/kg of body weight per day, given as a subcutaneous injection.
Paediatric patients with SHOX deficiency
The recommended dosage is 0.045-0.050 mg/kg of body weight per day, given as a subcutaneous injection.
Paediatric patients born Small for Gestational Age (SGA)
The recommended dose is 0.035 mg/kg of body weight per day (equivalent to 1 mg/m2 body surface area per day) given as a subcutaneous injection, until final height is reached (see section 5.1). Treatment should be discontinued after the first year of treatment, if the height velocity SDS is below +1.0 SDS. Treatment should be discontinued if height velocity is < 2cm/year and, if confirmation is required, bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of epiphyseal growth plates.
Method of administration
Humatrope is administered by subcutaneous injection after reconstitution
The subcutaneous injection sites should be varied in order to avoid lipoatrophy.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Contraindications | Contraindications
Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.
Humatrope should not be reconstituted with the supplied solvent for patients with a known sensitivity to either metacresol or glycerol.
Humatrope should not be used for growth promotion in children with closed epiphyses.
Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
The maximum recommended daily dose should not be exceeded (see section 4.2).
Previous paediatric subjects, who had been treated with growth hormone during childhood until final height was attained, should be re-evaluated for growth hormone deficiency after epiphyseal closure before replacement therapy is commenced at the doses recommended for adults.
Diagnosis and therapy with Humatrope should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with growth hormone deficiency.
There is so far no evidence to suspect that growth hormone replacement influences the recurrence rate or regrowth of intracranial neoplasms, but standard clinical practice requires regular pituitary imaging in patients with a history of pituitary pathology. A baseline scan is recommended in these patients before instituting growth hormone replacement therapy.
In childhood cancer survivors, a higher risk of a second neoplasm (benign or malignant) has been reported in patients treated with somatropin. Intracranial tumours, in particular, were the most common of these second neoplasms.
In cases of severe or recurrent headache, visual problems, nausea and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth hormone treatment should be discontinued.
At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.
Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any child with the onset of a limp during growth hormone therapy should be evaluated.
Growth hormone increases the extrathyroidal conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.
For paediatric patients, the treatment should be continued until the end of the growth has been reached. It is advisable not to exceed the recommended dosage in view of the potential risks of acromegaly, hyperglycaemia and glucosuria.
Before instituting treatment with somatropin for growth retardation secondary to chronic renal insufficiency, patients should have been followed for one year to verify growth disturbance. Conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status for one year prior to the treatment) should have been established and should be maintained during treatment. Treatment with somatropin should be discontinued at the time of renal transplantation.
The effects of growth hormone on recovery were studied in two placebo-controlled clinical trials involving 522 adult patients who were critically ill due to complications following open heart or abdominal surgery, multiple accidental trauma, or who were having acute respiratory failure. Mortality was higher (41.9% vs. 19.3%) among growth hormone-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing growth hormone in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation in patients having acute critical illnesses should be weighed against the potential risks.
If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects (see section 4.5). If a change of the route of oestrogen administration (oral to transdermal or vice versa) is made, growth hormone should be newly titrated. An increasing sensitivity to growth hormone (expressed as change in serum IGF-I per growth hormone dose) over time may be observed, particularly in men.
Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment (see section 4.5).
Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in patients with Prader-Willi syndrome, who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.
Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.
Elderly patients (age ≥ 65 years) are more sensitive to the action of Humatrope; they may be more prone to develop (severe) adverse events.
Experience in patients above 80 years is limited. Experience with prolonged treatment in adults is lacking.
In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
In children born SGA it is recommended to measure fasting plasma insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered until the patient has been stabilised for diabetes care. Then growth hormone may be introduced with careful monitoring of the diabetic metabolic control. An increase in insulin dosage may be required.
In children born SGA it is recommended to measure the plasma IGF-I concentration before the start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for sex, age and pubertal status, the IGF-I / IGFBP-3 ratio should be taken into account to consider dose adjustment.
Initiating Humatrope treatment in children born SGA and in children with SHOX deficiency, near onset of puberty, is not recommended because of limited experience.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before reaching final height.
Pancreatitis
Although rare, pancreatitis should be considered in somatropin-treated patients who develop abdominal pain, especially in children.
Progression of scoliosis in paediatric patients
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment.
Excipients with known effect
This medicinal product contains less than 1 mmol sodium per dose (23 mg), i.e. essentially sodium free.
4.5 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Patients with diabetes mellitus who receive concomitant somatropin may require adjustment of their doses of insulin and/or other anti-hyperglycaemic agents.
Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective (see section 4.4).
In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4).
Somatropin can increase cytochrome P450 (CYP) enzyme activity in humans and may result in reduced plasma concentrations and decreased effectiveness of drugs metabolised by CYP3A such as sex steroids, corticosteroids, cyclosporine and anticonvulsants.
4.6 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with Humatrope. It is not known whether Humatrope can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Humatrope should be given to a pregnant woman only if clearly needed.
There have been no studies conducted with Humatrope in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humatrope is administered to a nursing woman.
4.7 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Humatrope has no known effect on ability to drive or use machines.
4.8 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Undesirable effects | Undesirable effects
The following table of undesirable effects and frequencies is based on clinical trial and post-marketing spontaneous reports.
Immune system disorders
Hypersensitivity to solvent (metacresol/glycerol): 1%-10%
Hypersensitivity to the active substance: Frequency not known (cannot be estimated from the available data)
Endocrine disorders
Hypothyroidism: 1%-10%
Reproductive system and breast disorders
Gynaecomastia: 0.1 %-1 %
Metabolism and nutrition disorders
Mild hyperglycaemia: 1% paediatrics; 1%-10% adults
Type 2 diabetes mellitus: 0.1 % - 1 % paediatrics; adult cases were reported spontaneously with unknown frequency
Insulin resistance
Nervous system disorders
Benign intracranial hypertension: 0.01%-0.1%
Headache: >10% adults
Insomnia: <0.01% paediatrics; 1%-10% adults
Paraesthesia: 0.01%-0.1% paediatrics; 1%-10% adults
Carpal tunnel syndrome: 1%-10% adults
Vascular disorders
Hypertension: <0.01% paediatrics; 1%-10% adults
Respiratory, thoracic and mediastinal disorders
Dyspnoea: 1%-10% adults
Sleep apnoea: 1%-10% adults
Musculoskeletal and connective tissue disorders
Localised muscle pain (myalgia): 1%-10% adults; 0.01%-0.1% paediatrics
Joint pain and disorder (arthralgia): >10% adults
Progression of scoliosis: 1 %-10 % paediatrics
General disorders and administration site conditions
Weakness: 0.1%-1%
Injection site pain (reaction): 1%-10%
Oedema (local and generalised): 1%-10% paediatrics; 10% adults
Investigations
Glucosuria: <0.01% paediatrics; 0.01-0.1% adults
Paediatric patients
In clinical trials with growth hormone deficient patients, approximately 2% of the patients developed antibodies to growth hormone. In trials in Turner Syndrome, where higher doses were used, up to 8% of patients developed antibodies to growth hormone. The binding capacity of these antibodies was low and growth rate was not affected adversely. Testing for antibodies to growth hormone should be carried out in any patient who fails to respond to therapy.
A mild and transient oedema was observed early during the course of treatment.
Leukaemia has been reported in a small number of children who have been treated with growth hormone. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposing factors.
Adult patients
In patients with adult onset growth hormone deficiency, oedema, muscle pain and joint pain and disorder, were reported early in therapy and tended to be transient.
Adult patients treated with growth hormone, following diagnosis of growth hormone deficiency in childhood, reported side-effects less frequently than those with adult onset growth hormone deficiency.
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.
4.9 |
Humatrope 24mg powder and solvent for solution for injection | Clinical particulars - Overdose | Overdose
Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Long-term overdosage could result in signs and symptoms of acromegaly consistent with the known effects of excess human growth hormone.
5. Pharmacological properties
5.1 |
Humatrope 24mg powder and solvent for solution for injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
A dose of 100 µg/kg to adult male volunteers will give a peak serum level (Cmax) of about 55 ng/ml, a half-life (t½) of nearly four hours and maximal absorption (AUC [0 to ∞]) of about 475 ng*hr/ml.
5.3 |
Humatrope 24mg powder and solvent for solution for injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Humatrope is human growth hormone produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Long term animal studies for carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have not been performed. There has been no evidence to date of Humatrope induced mutagenicity.
6. |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical particulars - List of excipients | List of excipients
Cartridges of powder: mannitol, glycine, dibasic sodium phosphate, phosphoric acid and sodium hydroxide.
Solvent syringes: glycerol, metacresol, water for injections, hydrochloric acid and sodium hydroxide.
6.2 |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical particulars - Shelf life | Shelf life
Before reconstitution: 3 years.
After reconstitution: The product may be stored for a maximum of 28 days at 2°C-8°C. Daily room temperature exposure should not exceed 30 minutes.
6.4 |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2°C-8°C). Do not freeze.
6.5 |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Humatrope is available in the following pack sizes:
Humatrope 6 mg:
1 cartridge (glass type I) with 6 mg of powder for solution for injection, and 3.17 ml of solvent solution in a pre-filled syringe (glass type I) with a plunger (rubber). Pack size of 1, 5 and 10.
Humatrope 12 mg:
1 cartridge (glass type I) with 12 mg of powder for solution for injection, and 3.15 ml of solvent solution in a pre-filled syringe (glass type I) with a plunger (rubber). Pack size of 1, 5 and 10.
Humatrope 24 mg:
1 cartridge (glass type I) with 24 mg of powder for solution for injection, and 3.15 ml of solvent solution in a pre-filled syringe (glass type I) with a plunger (rubber). Pack size of 1, 5 and 10.
Not all pack sizes may be marketed.
6.6 |
Humatrope 24mg powder and solvent for solution for injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Instructions for preparation and handling
Reconstitution: Each cartridge of Humatrope should be reconstituted using the accompanying solvent syringe. To reconstitute, attach the cartridge to the pre-filled solvent syringe and then inject the entire contents of the pre-filled solvent syringe into the cartridge. The solvent needle aims the stream of liquid against the glass wall of the cartridge. Following reconstitution, gently invert the cartridge up and down 10 times until the contents are completely dissolved. DO NOT SHAKE. The resulting solution should be clear, without particulate matter. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
Humatrope cartridges can be used in conjunction with compatible CE marked pen injection systems. The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the Humatrope injection.
The solvent syringe is for single use only. Discard it after use. A sterile needle should be used for each administration of Humatrope.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Humatrope 24mg powder and solvent for solution for injection | Marketing authorisation holder | Eli Lilly Nederland B.V.
Papendorpseweg 83
3528 BJ Utrecht
The Netherlands
8. Marketing authorisation number(s)
PL 14895/0290
Cartridges 6 mg
PL 14895/0291
Cartridges 12 mg
PL 14895/0292
Cartridges 24 mg
PL 14895/0293
Solvent (6 mg)
PL 14895/0294
Solvent (12 and 24 mg)
9. |
Humatrope 24mg powder and solvent for solution for injection | Date of first authorisation/renewal of the authorisation | Date of last common renewal: 22 November 2006
10. |
Humatrope 24mg powder and solvent for solution for injection | Date of revision of the text | 01 July 2021
LEGAL CATEGORY
POM
HT032 |
Humatrope 6mg powder and solvent for solution for injection | Name of the medicinal product | Humatrope® 6 mg, powder and solvent for solution for injection
Humatrope® 12 mg, powder and solvent for solution for injection
Humatrope® 24 mg, powder and solvent for solution for injection
2. |
Humatrope 6mg powder and solvent for solution for injection | Qualitative and quantitative composition | Humatrope 6 mg:
The cartridge contains 6 mg of somatropin
When reconstituted contains 2.08 mg/ml
Humatrope 12 mg:
The cartridge contains 12 mg of somatropin
When reconstituted contains 4.17 mg/ml
Humatrope 24 mg:
The cartridge contains 24 mg of somatropin
When reconstituted contains 8.33 mg/ml
Somatropin is produced in Escherichia coli cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical form | Powder and solvent for solution for injection.
The powder is a white or almost white powder. The solvent is a clear solution.
4. |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Therapeutic indications | Therapeutic indications
Paediatric patients
Humatrope is indicated for the long-term treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatrope is also indicated for the treatment of short stature in children with Turner Syndrome, confirmed by chromosome analysis.
Humatrope is also indicated for the treatment of growth retardation in prepubertal children with chronic renal insufficiency.
Humatrope is also indicated for the treatment of patients who have growth failure associated with SHOX deficiency, as confirmed by DNA analysis.
Humatrope is also indicated for growth disturbance (current height SDS < -2.5 and parental adjusted height SDS < -1) in short children born small for gestational age (SGA), with a birth weight and/or length below -2 SD, who failed to show catch-up growth (height velocity SDS < 0 during the last year) by 4 years of age or later.
Adult patients
Humatrope is indicated for replacement therapy in adults with pronounced growth hormone deficiency.
Patients with severe growth hormone deficiency in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one known deficiency of a pituitary hormone not being prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a growth deficiency. In patients with childhood onset isolated GH deficiency (no evidence of hypothalamic-pituitary disease or cranial irradiation), two dynamic tests should be recommended, except for those having low IGF-I concentrations <-2 SDS, who may be considered for one test. The cut-off point of the dynamic test should be strict.
4.2 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage and administration schedule should be personalised for each individual; however for:
Growth hormone deficient paediatric patients
The recommended dosage is 0.025-0.035 mg/kg of body weight per day by subcutaneous injection. This is the equivalent to approximately 0.7-1.0 mg/m2 body surface area per day.
Growth hormone deficient adult patients
The recommended starting dose is 0.15-0.30 mg/day. A lower starting dose may be necessary in older and obese patients.
This dose should be gradually increased according to individual patient requirements based on the clinical response and serum IGF-I concentrations.
Total daily dose usually does not exceed 1 mg.
IGF-I concentrations should be maintained below the upper limit of the age-specific normal range. The minimum effective dose should be used and dose requirements may decline with increasing age.
Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time. This means that there is a risk that women, especially those on oral oestrogen therapy are under-treated while men are over-treated.
The dosage of somatropin should be decreased in cases of persistent oedema or severe paraesthesia, in order to avoid the development of carpal tunnel syndrome (see section 4.8).
Patients with Turner Syndrome
The recommended dosage is 0.045-0.050 mg/kg of body weight per day, given as a subcutaneous injection, to be administered preferably in the evening.
This is equivalent to approximately 1.4 mg/m2 per day.
Prepubertal paediatric patients with Chronic Renal Insufficiency
The recommended dosage is 0.045-0.050 mg/kg of body weight per day, given as a subcutaneous injection.
Paediatric patients with SHOX deficiency
The recommended dosage is 0.045-0.050 mg/kg of body weight per day, given as a subcutaneous injection.
Paediatric patients born Small for Gestational Age (SGA)
The recommended dose is 0.035 mg/kg of body weight per day (equivalent to 1 mg/m2 body surface area per day) given as a subcutaneous injection, until final height is reached (see section 5.1). Treatment should be discontinued after the first year of treatment, if the height velocity SDS is below +1.0 SDS. Treatment should be discontinued if height velocity is < 2cm/year and, if confirmation is required, bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of epiphyseal growth plates.
Method of administration
Humatrope is administered by subcutaneous injection after reconstitution
The subcutaneous injection sites should be varied in order to avoid lipoatrophy.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Contraindications | Contraindications
Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.
Humatrope should not be reconstituted with the supplied solvent for patients with a known sensitivity to either metacresol or glycerol.
Humatrope should not be used for growth promotion in children with closed epiphyses.
Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
The maximum recommended daily dose should not be exceeded (see section 4.2).
Previous paediatric subjects, who had been treated with growth hormone during childhood until final height was attained, should be re-evaluated for growth hormone deficiency after epiphyseal closure before replacement therapy is commenced at the doses recommended for adults.
Diagnosis and therapy with Humatrope should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with growth hormone deficiency.
There is so far no evidence to suspect that growth hormone replacement influences the recurrence rate or regrowth of intracranial neoplasms, but standard clinical practice requires regular pituitary imaging in patients with a history of pituitary pathology. A baseline scan is recommended in these patients before instituting growth hormone replacement therapy.
In childhood cancer survivors, a higher risk of a second neoplasm (benign or malignant) has been reported in patients treated with somatropin. Intracranial tumours, in particular, were the most common of these second neoplasms.
In cases of severe or recurrent headache, visual problems, nausea and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth hormone treatment should be discontinued.
At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.
Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any child with the onset of a limp during growth hormone therapy should be evaluated.
Growth hormone increases the extrathyroidal conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.
For paediatric patients, the treatment should be continued until the end of the growth has been reached. It is advisable not to exceed the recommended dosage in view of the potential risks of acromegaly, hyperglycaemia and glucosuria.
Before instituting treatment with somatropin for growth retardation secondary to chronic renal insufficiency, patients should have been followed for one year to verify growth disturbance. Conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status for one year prior to the treatment) should have been established and should be maintained during treatment. Treatment with somatropin should be discontinued at the time of renal transplantation.
The effects of growth hormone on recovery were studied in two placebo-controlled clinical trials involving 522 adult patients who were critically ill due to complications following open heart or abdominal surgery, multiple accidental trauma, or who were having acute respiratory failure. Mortality was higher (41.9% vs. 19.3%) among growth hormone-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing growth hormone in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation in patients having acute critical illnesses should be weighed against the potential risks.
If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects (see section 4.5). If a change of the route of oestrogen administration (oral to transdermal or vice versa) is made, growth hormone should be newly titrated. An increasing sensitivity to growth hormone (expressed as change in serum IGF-I per growth hormone dose) over time may be observed, particularly in men.
Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment (see section 4.5).
Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in patients with Prader-Willi syndrome, who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.
Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.
Elderly patients (age ≥ 65 years) are more sensitive to the action of Humatrope; they may be more prone to develop (severe) adverse events.
Experience in patients above 80 years is limited. Experience with prolonged treatment in adults is lacking.
In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
In children born SGA it is recommended to measure fasting plasma insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered until the patient has been stabilised for diabetes care. Then growth hormone may be introduced with careful monitoring of the diabetic metabolic control. An increase in insulin dosage may be required.
In children born SGA it is recommended to measure the plasma IGF-I concentration before the start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for sex, age and pubertal status, the IGF-I / IGFBP-3 ratio should be taken into account to consider dose adjustment.
Initiating Humatrope treatment in children born SGA and in children with SHOX deficiency, near onset of puberty, is not recommended because of limited experience.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before reaching final height.
Pancreatitis
Although rare, pancreatitis should be considered in somatropin-treated patients who develop abdominal pain, especially in children.
Progression of scoliosis in paediatric patients
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment.
Excipients with known effect
This medicinal product contains less than 1 mmol sodium per dose (23 mg), i.e. essentially sodium free.
4.5 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Patients with diabetes mellitus who receive concomitant somatropin may require adjustment of their doses of insulin and/or other anti-hyperglycaemic agents.
Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective (see section 4.4).
In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4).
Somatropin can increase cytochrome P450 (CYP) enzyme activity in humans and may result in reduced plasma concentrations and decreased effectiveness of drugs metabolised by CYP3A such as sex steroids, corticosteroids, cyclosporine and anticonvulsants.
4.6 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with Humatrope. It is not known whether Humatrope can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Humatrope should be given to a pregnant woman only if clearly needed.
There have been no studies conducted with Humatrope in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humatrope is administered to a nursing woman.
4.7 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Humatrope has no known effect on ability to drive or use machines.
4.8 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Undesirable effects | Undesirable effects
The following table of undesirable effects and frequencies is based on clinical trial and post-marketing spontaneous reports.
Immune system disorders
Hypersensitivity to solvent (metacresol/glycerol): 1%-10%
Hypersensitivity to the active substance: Frequency not known (cannot be estimated from the available data)
Endocrine disorders
Hypothyroidism: 1%-10%
Reproductive system and breast disorders
Gynaecomastia: 0.1 %-1 %
Metabolism and nutrition disorders
Mild hyperglycaemia: 1% paediatrics; 1%-10% adults
Type 2 diabetes mellitus: 0.1 % - 1 % paediatrics; adult cases were reported spontaneously with unknown frequency
Insulin resistance
Nervous system disorders
Benign intracranial hypertension: 0.01%-0.1%
Headache: >10% adults
Insomnia: <0.01% paediatrics; 1%-10% adults
Paraesthesia: 0.01%-0.1% paediatrics; 1%-10% adults
Carpal tunnel syndrome: 1%-10% adults
Vascular disorders
Hypertension: <0.01% paediatrics; 1%-10% adults
Respiratory, thoracic and mediastinal disorders
Dyspnoea: 1%-10% adults
Sleep apnoea: 1%-10% adults
Musculoskeletal and connective tissue disorders
Localised muscle pain (myalgia): 1%-10% adults; 0.01%-0.1% paediatrics
Joint pain and disorder (arthralgia): >10% adults
Progression of scoliosis: 1 %-10 % paediatrics
General disorders and administration site conditions
Weakness: 0.1%-1%
Injection site pain (reaction): 1%-10%
Oedema (local and generalised): 1%-10% paediatrics; 10% adults
Investigations
Glucosuria: <0.01% paediatrics; 0.01-0.1% adults
Paediatric patients
In clinical trials with growth hormone deficient patients, approximately 2% of the patients developed antibodies to growth hormone. In trials in Turner Syndrome, where higher doses were used, up to 8% of patients developed antibodies to growth hormone. The binding capacity of these antibodies was low and growth rate was not affected adversely. Testing for antibodies to growth hormone should be carried out in any patient who fails to respond to therapy.
A mild and transient oedema was observed early during the course of treatment.
Leukaemia has been reported in a small number of children who have been treated with growth hormone. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposing factors.
Adult patients
In patients with adult onset growth hormone deficiency, oedema, muscle pain and joint pain and disorder, were reported early in therapy and tended to be transient.
Adult patients treated with growth hormone, following diagnosis of growth hormone deficiency in childhood, reported side-effects less frequently than those with adult onset growth hormone deficiency.
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.
4.9 |
Humatrope 6mg powder and solvent for solution for injection | Clinical particulars - Overdose | Overdose
Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Long-term overdosage could result in signs and symptoms of acromegaly consistent with the known effects of excess human growth hormone.
5. Pharmacological properties
5.1 |
Humatrope 6mg powder and solvent for solution for injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
A dose of 100 µg/kg to adult male volunteers will give a peak serum level (Cmax) of about 55 ng/ml, a half-life (t½) of nearly four hours and maximal absorption (AUC [0 to ∞]) of about 475 ng*hr/ml.
5.3 |
Humatrope 6mg powder and solvent for solution for injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Humatrope is human growth hormone produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Long term animal studies for carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have not been performed. There has been no evidence to date of Humatrope induced mutagenicity.
6. |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical particulars - List of excipients | List of excipients
Cartridges of powder: mannitol, glycine, dibasic sodium phosphate, phosphoric acid and sodium hydroxide.
Solvent syringes: glycerol, metacresol, water for injections, hydrochloric acid and sodium hydroxide.
6.2 |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical particulars - Shelf life | Shelf life
Before reconstitution: 3 years.
After reconstitution: The product may be stored for a maximum of 28 days at 2°C-8°C. Daily room temperature exposure should not exceed 30 minutes.
6.4 |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2°C-8°C). Do not freeze.
6.5 |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Humatrope is available in the following pack sizes:
Humatrope 6 mg:
1 cartridge (glass type I) with 6 mg of powder for solution for injection, and 3.17 ml of solvent solution in a pre-filled syringe (glass type I) with a plunger (rubber). Pack size of 1, 5 and 10.
Humatrope 12 mg:
1 cartridge (glass type I) with 12 mg of powder for solution for injection, and 3.15 ml of solvent solution in a pre-filled syringe (glass type I) with a plunger (rubber). Pack size of 1, 5 and 10.
Humatrope 24 mg:
1 cartridge (glass type I) with 24 mg of powder for solution for injection, and 3.15 ml of solvent solution in a pre-filled syringe (glass type I) with a plunger (rubber). Pack size of 1, 5 and 10.
Not all pack sizes may be marketed.
6.6 |
Humatrope 6mg powder and solvent for solution for injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Instructions for preparation and handling
Reconstitution: Each cartridge of Humatrope should be reconstituted using the accompanying solvent syringe. To reconstitute, attach the cartridge to the pre-filled solvent syringe and then inject the entire contents of the pre-filled solvent syringe into the cartridge. The solvent needle aims the stream of liquid against the glass wall of the cartridge. Following reconstitution, gently invert the cartridge up and down 10 times until the contents are completely dissolved. DO NOT SHAKE. The resulting solution should be clear, without particulate matter. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
Humatrope cartridges can be used in conjunction with compatible CE marked pen injection systems. The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the Humatrope injection.
The solvent syringe is for single use only. Discard it after use. A sterile needle should be used for each administration of Humatrope.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Humatrope 6mg powder and solvent for solution for injection | Marketing authorisation holder | Eli Lilly Nederland B.V.
Papendorpseweg 83
3528 BJ Utrecht
The Netherlands
8. Marketing authorisation number(s)
PL 14895/0290
Cartridges 6 mg
PL 14895/0291
Cartridges 12 mg
PL 14895/0292
Cartridges 24 mg
PL 14895/0293
Solvent (6 mg)
PL 14895/0294
Solvent (12 and 24 mg)
9. |
Humatrope 6mg powder and solvent for solution for injection | Date of first authorisation/renewal of the authorisation | Date of last common renewal: 22 November 2006
10. |
Humatrope 6mg powder and solvent for solution for injection | Date of revision of the text | 01 July 2021
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