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Ravida

Ravida

Manufacturer:

Pharmaniaga Manufacturing Berhad

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Pharmaniaga Logistics
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Full Prescribing Info
Contents
Ravidasvir.
Description
Each tablet contains 219 mg ravidasvir hydrochloride equivalent to 200 mg ravidasvir.
Excipient(s) with known effect: Each tablet contains 152.8 mg isomalt. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Croscarmellose sodium, Colloidal silicon dioxide, Magnesium stearate, Isomalt.
Action
Pharmacotherapeutic group: Antivirals for systemic use, direct-acting antivirals (DAAs).
Pharmacology: Pharmacodynamics: Mechanism of action: Ravidasvir is an inhibitor of non-structural protein 5A (NS5A), a multifunctional protein that is an essential component of the HCV replication complex. Ravidasvir inhibits replication of variant HCV replicons encoding resistance mutations for the other major classes of HCV DAAs. HCV variants with reduced susceptibility to ravidasvir remain fully susceptible to other classes of HCV inhibitors.
Antiviral activity: The 50% effective concentration (EC50) values and 90% effective concentration (EC90) values of ravidasvir for various HCV genotypes 1a and 1b and in non-genotype 1 replicon cells are presented in Table 1. (See Table 1.)

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Increasing the concentration of human serum from 1% to 40% led to a 9- to 11-fold shift in EC50 and EC90 values for genotypes 1a and 1b, consistent with the high protein binding observed in equilibrium dialysis studies.
Combination index values calculated for paired inhibitors indicate additive effects when ravidasvir is combined with NS3 protease inhibitor (ITMN-191), interferon-α and non-nucleoside polymerase inhibitor (HCV-796) and additive to synergistic effects when combined with a NS5B nucleoside polymerase inhibitor (PSI-6130). No antagonism was observed.
No significant inhibitory activity was observed against a panel of RNA and DNA viruses such as bovine viral diarrheal virus (BVDV), human rhino virus (HRV)-16 and influenza-B (Flu-B), confirming that ravidasvir is a specific inhibitor of HCV replication.
Resistance: In cell cultures: Replicons of HCV genotypes 1a and 1b and a panel of genotype 1b chimera replicons containing critical segments of the NS5A gene of HCV genotypes 2a, 3a, 4a, 5a and 6a have been evaluated in vitro with the highest concentration capped at 1,000 nM ravidasvir. Resistant colonies emerged on most plates, with the number of resistant colonies being lower at the higher concentrations of ravidasvir. At a ravidasvir concentration of 1,000 nM only a small number of colonies were observed with HCV genotype 2a and 4a NS5A replicon cells. Genotyping of replicons from recovered colonies confirmed the presence of resistance substitutions.
Consistent with patterns of resistance-associated substitutions for other NS5A inhibitors, one or more changes at amino acid positions 28, 30, 31 and 93 within domain 1 of the NS5A protein were observed. Additional substitutions, such as P58L (4a NS5A) and T58A (6a NS5A), emerged at lower concentrations of ravidasvir, but these were not present at high ravidasvir concentrations (1,000 nM). Colony formation assays using HCV genotype 1a replicon cells yielded the most diverse set of substitutions, suggesting that multiple single and linked substitutions confer resistance in this genotype. This is in contrast with the results obtained using the HCV genotype 2a, 3a, and 6a NS5A replicon cell lines, which consistently yielded single preferred substitutions F28S (genotypes 2a and 6a) and Y93H (genotype 3a) that conferred high-level resistance. Similar to the linked substitutions found in genotype 1a replicon cells, combination substitutions L31F/V+Y93H (genotype 1b), L30H+Y93H (genotype 4a) and Q30H+L31F (genotype 5a) are required to achieve high level resistance.
In clinical studies: Ravida monotherapy: Three days of Ravida monotherapy at doses ranging from 40 mg to 240 mg once daily led to a rapid reduction of HCV RNA level in 35/40 subjects. Seven of the 35 had NS5A resistance associated variants (RAVs) at baseline. The 5 non-responders, who had <1 log10 reduction in HCV RNA on day 4, included one genotype 1b subject with genetically linked R30Q+L31I+Y93H RAVs, one genotype 2a with F28L+L31M, two genotype 3A with Y93H and one genotype 3a with A30K.
As wild-type virus was eliminated, treatment-emergent RAVs were detected in 31/32 genotype 1 subjects 8-48 hours after first dose, however these were not further enriched with continued treatment, indicating that Ravida can inhibit replication of these resistant variants. The percentage of linked substitutions was low overall in all genotype 1 subjects, consistent with enrichment of pre-existing variants rather than emergence of new strains.
The most common emergent RAVs in genotype 1a subjects were M28T, Q30R, Q30H, L31M, Y93H and Y93C, with Q30R the most frequent. In genotype 1b subjects, R30Q, L31M and Y93H were the most common emergent RAVs, with Y93H the most frequent. Y93H was the most frequent emergent RAV in the genotype 3a subjects.
Ravida in combination with NS5B inhibitor: Viral resistance has been assessed in HCV chronically infected adults with no or compensated cirrhosis treated with Ravida plus sofosbuvir in the STORM-C-1 study. The study population included 301 subjects infected with virus genotypes 1 (42%), 2 (1%), 3 (52%) and 6 (6%). Among the 81 cirrhotic subjects, 65% had genotype 3 infection.
HCV RNA sequences were obtained for 292/301 subjects (all except 4 non-virological failures and 5 for whom sequencing failed). NS5A RAVs were detected in 91/292 (31.2%) at baseline. The distribution of the RAVs was heterogeneous across genotypes, with 28V and 93H predominantly found in the genotype 1a subjects, 93H in genotype 1b, 93H and 62L in genotype 3a; 30K and 31M in genotype 3b, and 28V and 93S in genotype 6. The impact of baseline RAVs on SVR12 is shown in Table 2. (See Table 2.)

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The presence of single or multiple baseline NS5A RAVs did not impact treatment outcomes for genotypes 1a, 1b, 2 or 3b. SVR12 in subjects with one or more RAVs was 93.5% in genotype 3a and 78.6% in genotype 6. Among the 23 genotype 3a subjects with the NS5A 93H RAV, 21 (91.3%) achieved SVR12. 11 of the genotype 6 subjects, including all 3 virological failures, had the NS5A double RAV 28V+93S. 10 of these 11 were genotype 6n, which has both RAVs in the reference baseline sequence.
There was no emergence of new NS5A RAVs in any of the subjects who experienced virological failure. One genotype 6n subject had an emergent NS5B (sofosbuvir) RAV (282T/C) after virological failure.
Cross-resistance: A series of cross-resistance assays was performed and the data indicate that ravidasvir retained its ability to inhibit each of these resistant variants with EC50 values equivalent to those observed in the wild-type genotype 1b replicon cells, confirming the ability of ravidasvir to inhibit variants that emerge with other distinct classes of HCV inhibitors. Ravidasvir-resistant variants retained their susceptibility to other classes of HCV inhibitors. Ravidasvir can be used in combination with other classes of HCV inhibitors to help prevent the emergence of resistant strains.
Clinical efficacy and safety: Ravidasvir + NS5B inhibitor: The efficacy and safety of Ravida 200 mg QD (once daily) + sofosbuvir 400 mg QD was evaluated in the pivotal study STORM-C-1 conducted in Malaysia and Thailand. The primary efficacy endpoint of STORM-C-1 was sustained virologic response 12 weeks after end of treatment (SVR12) as determined by HCV RNA level <LLOQ using a real-time polymerase chain reaction (PCR) method (Roche COBAS AmpliPrep/TaqMan or Abbott m2000 system).
Of the 301 subjects enrolled in STORM-C-1, 220 non-cirrhotic subjects were allocated to Ravida + sofosbuvir for 12 weeks and 81 compensated cirrhotic subjects were allocated to Ravida + sofosbuvir for 24 weeks. A total of 298 (99%) subjects completed the study and 3 (1%) subjects (2 non-cirrhotic and 1 cirrhotic) prematurely discontinued the study due to adverse events. Demographic and baseline characteristics are summarised in Table 3. (See Table 3.)

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High SVR12 results above 95% were observed in the key subpopulations including cirrhotic (96.3%) and non-cirrhotic subjects (97.3%), HIV co-infected (96.7%) or not (97.1%), previous IFN experienced (96.0%) or not (97.5%), and across genotype 1a (99.0%), genotype 1b (100.0%), and genotype 3a (96.4%). Genotype 3 cirrhotic subjects achieved 96.8% SVR12. Subjects with genotype 6 achieved 81.3% SVR12 (13 of 16 subjects). Both genotype 2 subjects achieved SVR12.
No significant association was observed between SVR12 and sex, age, ethnicity (Malay, Thai, other), site, baseline BMI, cirrhotic status, baseline HCV RNA, baseline ALT, baseline AST, IL28B, prior interferon-based HCV treatment status, or HIV co-infection status (p>0.05).
Treatment with Ravida + sofosbuvir led to a rapid decrease in viral load. The mean HCV ribonucleic acid (RNA) count was 6.15 log10 IU/mL at baseline and decreased to 2.03 log10 IU/mL at week 1, 1.18 log10 IU/mL at week 4, 1.14 log10 IU/mL at week 8, and 1.12 log10 IU/mL at week 12.
Table 4 shows summary of the main efficacy results.
Overall, 9 subjects (6 [3%] non-cirrhotic subjects and 3 [4%] cirrhotic subjects) did not achieve SVR12; 1 subject due to virological breakthrough, 4 subjects due to virological relapse, and 4 subjects due to non-virologic failure (Table 5). Genotype 3 status, HIV status, and prior interferon-based HCV treatment status did not appear to affect SVR12 rate. Three virological failures were observed in the genotype 6 group. No other risk factors were identified among the subjects who failed treatment. (See Tables 4 and 5.)

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Ravidasvir + other DAAs: In published clinical studies, ravidasvir 200 mg once daily demonstrated ≥ 95% SVR12 across all tested genotypes when combined with other appropriate DAAs (Table 6). (See Table 6.)

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Pharmacokinetics: The mean steady-state pharmacokinetic parameters of ravidasvir in 25 HCV mono-infected subjects receiving 200 mg ravidasvir and 400 mg sofosbuvir QD are presented in Table 7. (See Table 7.)

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Absorption: Following oral administration of ascending single doses (80-320 mg) to healthy subjects, ravidasvir was relatively rapidly absorbed with concentrations peaking at a median of 1.5 to 2 hours post-dose. Ravidasvir Cmax and AUC increased in a dose-proportional manner and 24-hour post dose plasma concentrations were above ravidasvir EC90 values for HCV genotypes 1 to 7. When dosed for 5 days, values of AUC0-∞ on day 1 and AUCτ on day 5 were similar.
Compared with healthy volunteers, subjects with chronic HCV infection seem to have higher inter-subject variability. Ravidasvir Cmax and AUC0-∞ were generally lower in HCV subjects than in healthy volunteers, while Tmax was similar in both groups.
Effects of food: When taken with food, the average Cmax was reduced compared to the fasted condition, however the relative bioavailability was essentially unchanged (fed/fasted 103.4%). Median Tmax was slightly delayed for the fed condition compared to the fasted condition (3.0 versus 2.0 hours). There is not expected to be a clinically relevant food effect with ravidasvir. Ravida can be taken with or without food.
Distribution: Ravidasvir is highly bound to plasma proteins, with an estimated fraction unbound of 1.9%, and is not widely distributed to and bound in extravascular tissues. The apparent volume of distribution (Vz/F) values were approximately 100 L at all dose levels and independent of the administered dose. In vivo studies in animals show that distribution to the liver, an important target organ for antiviral efficacy, is higher than to plasma.
Biotransformation: Metabolism in hepatic microsomes from all species was negligible, and oxidative metabolism of ravidasvir by human liver S9 fractions did not produce detectable glutathione conjugates. Mono-oxidation was the predominant metabolic pathway in all species studied, however, the pattern of metabolites varied between species. In vivo human studies indicated that ravidasvir was metabolically very stable, with only modest (~2%) metabolite formation detected. The most abundant metabolites in humans (M6 and M7, both of minor importance) resulted from mono-oxidation of ravidasvir.
Ravidasvir is not a substrate for the transport proteins OATP1B1, OATP1B3, or BCRP but is a substrate for P-gp. There is low likelihood that cytochrome P450 inhibitors or inducers would have a clinically meaningful effect on ravidasvir levels.
Elimination: Biliary excretion of ravidasvir appears to be the primary route of elimination of the absorbed dose, while renal excretion appears to be negligible. Following oral administration of ascending single doses in healthy volunteers, the relationship between AUC0-∞ and dose was linear indicating that the clearance for ravidasvir is independent of the administered dose.
In healthy volunteers, when 320 mg ravidasvir was administered once daily for 5 days, mean AUC0-∞ and AUCτ values were similar on Days 1 and 5, and resultant estimates for apparent clearance were nearly identical on Days 1 and 5, indicating that dosing for 5 days does not lead to either significant accumulation or induced elimination of ravidasvir. The pharmacokinetic profile supports dosing once a day.
Pharmacokinetic/pharmacodynamic relationship: HCV RNA levels were measured in chronic HCV-infected subjects dosed with 40 to 240 mg ravidasvir once daily for 3 days. HCV RNA levels rapidly declined from baseline in all cohorts with mean maximal reductions of 3.2, 3.5, 3.5 and 3.8 log10 IU/mL for the 40, 80, 160 mg and 240 mg doses, respectively. The HCV reductions for the 3 higher doses (3.5 to 3.8 log10 IU/mL) suggest that ravidasvir doses ≥80 mg once daily are near the top of the efficacy dose-response curve in HCV subjects. Plasma levels well above EC50 and EC90 were achieved with once daily dosing, leading to a reduction of viral load in all tested genotypes.
Linearity: The relationship of Cmax and AUC to the dose appears linear in the dose range tested in healthy volunteers (80 mg to 320 mg) and HCV subjects (40 mg to 240 mg).
Pharmacokinetics in special populations: No specific pharmacokinetic studies have been conducted in special populations.
Race and gender: No clinically relevant pharmacokinetic differences due to race or gender have been identified for ravidasvir.
Toxicology: Preclinical Safety Data: In repeat toxicity studies, ravidasvir was well tolerated in the rat. Reversible effects of increased organ weight and ratios of adrenal glands, microvesicular vacuolation and diffuse hypertrophy of the zona fasciculata in the adrenal glands were observed. These were associated with increases in cholesterol, low-density lipoprotein and triglycerides. This was observed at the highest dose of 750 mg/kg/day. The no observed adverse effect level (NOAEL) of ravidasvir in rats was established at 300 mg/kg/day, at which AUC0-24 was approximately 7.6 times the clinical AUC0-24 at 200 mg. In the monkey, only mild fecal changes (discolored, loose, soft and mucoid stools) were observed at the dose of 500 mg/kg/day. The NOAEL of ravidasvir in monkeys was considered to be 500 mg/kg/day, at which AUC0-24 was 0.8 times and 1.4 times in males and females, respectively, the clinical AUC0-24 at 200 mg.
Ravidasvir 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.
Carcinogenicity studies with ravidasvir have not been conducted. No evidence of mutagenic or clastogenic potential was observed in two in vitro tests (Ames bacterial mutagenicity, Mammalian Chromosomal Aberration Assay inhuman lymphocytes) or in an in vivo oral micronucleus study in the rat.
In animal reproduction studies, ravidasvir had no effects on fertility, embryofoetal development, lactation and postnatal development or sexual maturation at any dose (maximum 750 mg/kg/day) when administered orally to rats. However in rabbits, ravidasvir produced embryotoxicity and skeletal abnormalities at doses ≥100 mg/kg/day. Based on these teratogenic effects, the NOAEL for embryofoetal development in the rabbit was considered to be 25 mg/kg/day, at which the AUClast was at least 1.7 times the clinical AUC0-24 at 200 mg. In view of these effects, Ravida is not recommended in pregnancy and, based on the possible excretion of ravidasvir in milk, breast-feeding is not recommended when taking Ravida.
Ravidasvir had no effects on the eyes or skin of pigmented rats in a definitive phototoxicity study at doses up to 750 mg/kg/day and is therefore considered not to be phototoxic.
Indications/Uses
Ravida is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults (see Dosage & Administration, Precautions and Pharmacology: Pharmacodynamics under Actions).
For HCV genotype-specific activity, see Precautions and Pharmacology: Pharmacodynamics under Actions.
Dosage/Direction for Use
Treatment with Ravida should be initiated and monitored by a physician experienced in the management of patients with chronic hepatitis C.
Posology: Adults: The recommended dose of Ravida is 200 mg once daily, to be taken orally with or without food (see Pharmacology: Pharmacokinetics under Actions).
Ravida must be used in combination with other medicinal products indicated for the treatment of chronic hepatitis C. The monograph for the co-administered medicinal products should be referred to before initiation of therapy with Ravida. (See Table 8.)

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For HCV genotype information, see Precautions.
Dose interruption and discontinuation: If treatment interruption or discontinuation of the other medicinal products in the regimen is necessary, Ravida must not be given as monotherapy.
Vomiting and missed doses: Patients should be instructed that if vomiting occurs within 2 hours of dosing, an additional tablet should be taken. If vomiting occurs more than 2 hours after dosing, no additional dose for the day is needed. These recommendations are based on the absorption kinetics of ravidasvir, which are suggestive that the majority of the dose is absorbed within 2 hours after dosing.
Patients should be instructed that, if they miss a dose of Ravida, the dose should be taken as soon as possible if remembered within 18 hours of the scheduled dose time. However, if the missed dose is remembered more than 18 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.
Special populations: Elderly: There is limited clinical experience with Ravida in patients aged ≥ 65 years. Treatment with Ravida in accordance with the recommended posology should be guided by an assessment of the potential benefits and risks for the individual patient.
Renal impairment: No studies have been conducted with Ravida in patients with serum creatinine > 1.5 x ULN or end stage renal disease. Treatment with Ravida in accordance with the recommended posology should be guided by an assessment of the potential benefits and risks for the individual patient.
Hepatic impairment: No dose adjustment of Ravida is required for patients with mild hepatic impairment. The safety and efficacy of Ravida have been assessed in patients with compensated cirrhosis but not in patients with decompensated cirrhosis. The safety and efficacy of Ravida administration in patients with severe hepatic impairment have not been assessed (see Precautions, Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Liver transplant patients: The safety and efficacy of Ravida in the treatment of HCV infection in patients who are post-liver transplant have not been assessed. Treatment with Ravida in accordance with the recommended posology should be guided by an assessment of the potential benefits and risks for the individual patient.
Patients co-infected with human immunodeficiency virus (HIV): The safety and efficacy of Ravida in this population have been assessed and no significant differences were observed when compared to patients not co-infected with HIV. For dosing recommendations for HIV antiviral agents co-administered with Ravida, see Interactions.
Paediatric population: The safety and efficacy of Ravida in children and adolescents aged below 18 years have not yet been assessed.
Method of administration: Ravida is to be taken orally with or without food. Patients should be instructed to swallow the tablets whole. The tablets should not be chewed, crushed or split.
Route of Administration: Oral.
Overdosage
The highest documented dose of Ravida was 320 mg once daily for 5 days in healthy volunteers. There were no untoward effects observed at these dose levels and adverse events were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses/exposures are not known.
No specific antidote is available for overdose with ravidasvir. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with Ravida consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Co-administration with potent inducers of P-glycoprotein transporter (P-gp) (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) will decrease ravidasvir plasma concentrations and could result in loss of efficacy of Ravida (see Interactions).
Special Precautions
Ravida must not be administered as monotherapy. Ravida must be administered in combination with other medicinal products for the treatment of chronic HCV infection (see Indications/Uses and Dosage & Administration).
If the other associated medicinal products used in combination with Ravida are permanently discontinued, Ravida must not be given as monotherapy (see Dosage & Administration).
Consult the monograph for the other co-administered medicinal products before starting therapy with Ravida.
Genotype-specific activity: Concerning genotype-specific virological activity and clinical outcomes, see Pharmacology: Pharmacodynamics under Actions. In the pivotal clinical study (STORM-C-1), the majority of patients were infected with HCV genotypes 1 or 3. There are limited data from this study inpatients with HCV genotypes 2 and 6 and no data on patients with genotype 4 or 5 (see Pharmacology: Pharmacodynamics under Actions).
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 (DAAs). 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.
Patients who have previously failed therapy with an NS5A-containing regimen: The safety and efficacy of Ravida in patients who have previously failed treatment with an NS5A-containing regimen have not been assessed.
Interactions with medicinal products: Co-administration of Ravida can alter the concentration of other medicinal products and other medicinal products may alter the concentration of ravidasvir. Refer to Contraindications for a listing of medicinal products that are contraindicated for use with Ravida due to potential loss of therapeutic effect. Co-administration with moderate P-gp inducers (e.g. oxcarbazepine or rifapentine) is not recommended since it may decrease ravidasvir plasma concentration leading to reduced therapeutic effect of Ravida (see Interactions).
Use in diabetic patients: Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV DAA treatment. The physician in charge of the diabetic care of the patient should be informed when treatment with Ravida is initiated.
Decompensated cirrhosis: The safety and efficacy of Ravida have not been assessed in patients with decompensated cirrhosis.
Liver transplant patients: The safety and efficacy of Ravida in the treatment of HCV infection in patients who are post-liver transplant have not been assessed.
Important information about some of the ingredients in Ravida: This medicinal product contains isomalt. Due to the presence of isomalt in the formulation, patients with rare hereditary problems of fructose intolerance should not take Ravida.
Low sodium diet information: This medicinal product contains less than 1 mmol sodium (23 mg) per dose and is considered as essentially 'sodium-free'.
Effects on Ability to Drive and Use Machines: Patients should be informed that dizziness, lethargy, somnolence and blurred vision have been reported during treatment with Ravida. No studies on the effects of Ravida on the ability to drive and use machines have been performed. Patients treated with Ravida should be warned not to drive or use machines if they feel tired or dizzy.
Hepatic impairment: No dose adjustment of Ravida is required for patients with mild hepatic impairment. The safety and efficacy of Ravida have been assessed in patients with compensated cirrhosis but not in patients with decompensated cirrhosis. The safety and efficacy of Ravida administration in patients with severe hepatic impairment has not been assessed (see Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Use in Pregnancy and contraception requirements: Ravida is not recommended during pregnancy based on teratogenic and/or embryotoxic effects in rabbits exposed to ravidasvir. There are very limited data on exposure during pregnancy in humans.
Women of childbearing potential should use effective contraception methods before starting treatment with Ravida and continue until 1 month after completion of Ravida treatment (see Use in Pregnancy & Lactation).
Use in Lactation: Ravida is not recommended during breast-feeding based on the evidence that ravidasvir is able to pass through the blood-milk barrier in rats and the absence of data in human.
Use in Children: Ravida is not recommended for use in children and adolescents aged below 18 years as the safety and efficacy have not been assessed in this population (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Use In Pregnancy & Lactation
Fertility: No human data on the effect of ravidasvir on fertility are available. No effect on fertility was seen in rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Pregnancy: Teratogenic and/or embryotoxic effects have been demonstrated in rabbits exposed to ravidasvir. There are very limited data on exposure to Ravida during pregnancy in humans. Use of Ravida is not recommended during pregnancy.
Women of childbearing potential should use effective contraception methods before starting treatment with Ravida and continue until 1 month after completion of treatment (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Breast-feeding: Ravidasvir has been shown to pass through the blood-milk barrier in rats (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). There are no data in humans. Use of Ravida is not recommended during breast-feeding.
Adverse Reactions
Summary of the safety profile: The summary of the safety profile of Ravida is based on data from 301 adult subjects with chronic HCV infection (with no or compensated cirrhosis), who received Ravida in combination with sofosbuvir once daily in the STORM-C-1 study. Among them, 90 were HIV co-infected.
Adverse reactions described as follows relate to treatment with the combination of Ravida plus sofosbuvir. No adverse reactions specific to Ravida alone have been identified.
Ravida in combination with sofosbuvir: The majority of adverse reactions identified with Ravida co-administered with sofosbuvir were of mild or moderate intensity, regardless of the presence or absence of cirrhosis, HIV co-infection, prior HCV treatment or HCV genotype. There were few severe adverse reactions and none that were life-threatening. Two subjects discontinued the Ravida plus sofosbuvir regimen due to adverse events assessed as being related to study treatment.
The most frequent adverse reactions identified in patients receiving Ravida and sofosbuvir were pyrexia (11.6%), headache (6.6%), dizziness (5.6%), lethargy (5.3%), dyspepsia (5.0%) and nausea (5.0%).
Tabulated list of adverse reactions: Based on STORM-C-1 data in 301 subjects, adverse reactions identified with Ravida administered in combination with sofosbuvir are listed in Table 9 by MedDRA System Organ Class, with Preferred Term (PT).
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) and very rare (<1/10,000). (See Table 9.)

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Description of selected adverse reactions: HCV/HIV co-infection: The overall safety profile of Ravida administered in combination with sofosbuvir in HCV/HIV co-infected subjects was comparable to that observed in HCV mono-infected subjects.
General recommendation on combination therapy: Refer to the monograph of other medicinal products with which Ravida will be combined for descriptions of selected adverse reactions.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the safety profile and benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Potential for ravidasvir to affect other medicinal products: Ravidasvir is an inhibitor of drug transporter breast cancer resistance protein (BCRP). Co-administration of ravidasvir with medicinal products that are BCRP substrates may increase the exposure of such medicinal products. See Table 10 for examples of interactions with sensitive substrates of BCRP (e.g. rosuvastatin).
Ravidasvir is a weak inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3 and of CYP3A, CYP2C19, and UGT1A1. Clinically meaningful interactions are not expected between Ravida and substrates of BCRP, OATP, CYP enzymes or UGT1A1.
Potential for other medicinal products to affect ravidasvir: Ravidasvir is a substrate of the drug transporter P-glycoprotein (P-gp). Medicinal products that are strong inducers of P-gp (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) may decrease plasma concentrations of ravidasvir leading to reduced therapeutic effect of Ravida. The use of such medicinal products with Ravida is contraindicated (see Contraindications).
Medicinal products that are moderate P-gp inducers (e.g. oxcarbazepine or rifapentine) may decrease ravidasvir plasma concentration leading to reduced therapeutic effect of Ravida. Co-administration of Ravida with moderate P-gp inducers is not recommended (see Precautions).
Co-administration with medicinal products that inhibit P-gp may increase ravidasvir plasma concentrations. However, clinically meaningful interactions with P-gp inhibitors are not expected.
Patients treated with vitamin K antagonists: As liver function may change during treatment with ravidasvir, close monitoring of International Normalised Ratio (INR) values is recommended.
Interactions between Ravida and other medicinal products: Table 10 provides a listing of established or potentially clinically relevant medicinal product interactions. The interactions described are based on studies conducted with ravidasvir or are predicted medicinal product interactions that may occur with ravidasvir. The direction of the arrow indicates the direction of change of the exposures. Observed or predicted changes are shown as ↑ =increase, ↓ = decrease, ↔ = no change. The table is not all-inclusive. (See Table 10.)

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Storage
Store below 30°C.
Store the tablets in their original packaging.
MIMS Class
Antivirals
ATC Classification
J05AP - Antivirals for treatment of HCV infections ; Used in the treatment of hepatitis C viral infections.
Presentation/Packing
Tab 200 mg (white to off-white oval biconvex) x 28's.
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