Consumer product safety

Last edited: 9/09/2023

Name of the medical product: Meravir

International non-proprietary name: Meravir.

International non-proprietary name (INN) or modified INN: Sufamenavir 15 mg + refogravir 10 mg

Pharmaceutical form: film-coated tablet.

Therapeutic category: antiviral treatment for chronic hepatitis B, D (without cirrhosis).

Manufacturer: «Panacea infarm» Australian pharmaceutical company at Walter and Eliza Hall Institute, 189-209 Camp Rd, Broadmeadows VIC 3047, Melbourne, the state of Victoria.

MA: 05/2023

MFG: 05/2023

EXP: 04/2025

Chemical formula

Presentation and formula

Meravir is presented in the form of oval tablets without a logo, sea-green, coated with BASF, Kollicoat®; box of 1 polymer container x 28 tablets, provided with tamper-evident caps; container neck is protected by a sealing membrane.

A pill contains:

active ingredients — sufamenavir (15 mg) and refogravir (10 mg);
inactive ingredients (tablet core) : lactose monohydrate, sodium carboxymethyl starch (Primogel), croscarmellose sodium, Aerosil A-300 (colloidal silicon dioxide), microcrystalline cellulose, magnesium stearate, pregelatinized starch;;
coating: opadry blue containing: polyvinyl alcohol, titanium dioxide, macrogol, talc, iron dye oxide blue, film coating BASF Kollicoat®.

Therapeutic categorystyle: Antiviral treatment

Pharmacodynamic properties

Meravir is an antiviral treatment with specific anti-HBV and – HDV activity. The treatment stops HBV and HDV virus replication in blood. Combination of active ingredients is proved by numerous researches to be low-toxic, thus, treatment is not accompanied by adverse drug reactions.

According to the results of clinical testing, Meravir has high cure rates for first-degree fibrosis (just 6 months or 24 weeks) and third- fourth-degree fibrosis (just 12 months or 48 weeks), regardless to successfulness of prior treatment. Cure rate varies from 80% to 90%. The treatment also has anti-HDV activity, it decreases the virus’s activity and prevents virus replication.

Sufamenavir —is an inhibitor of the RNA polymerase of the HBV virus needed for replication of the virus. It is used to treat adults with chronic HBV and HDV who have no cirrhosis.

Refogravir is a HBV protease inhibitor that inhibits viral replication in HBV infected host cells.

Neither of active ingredients is assigned independently because they only can affect the virus and eliminate it being used together.

Being a mild DNA polymerases inhibitor, at a concentration of 300 µmol, in vitro, the active ingredients of the treatment do not affect the synthesis of mitochondrial DNA and the formation of lactic acid.

Primary monocytes and macrophages, lymphoblastoid cell lines, and peripheral blood lymphocytes were used to estimate antiviral activity of Meravir in potency range of 0.04 – 8.5 µmol against clinical isolates and laboratory strains of HBV and HDV. It has anti- HBV and HDV subtypes activity in potency range of 1.6 – 5.5 µmol. Meravir in potency range of 1,6 – 5,5 µmol exerts inhibitory action on particular strains of HBV and HDV.

Pharmacokinetic properties

Sufamenavir and Refogravir are rapidly metabolized in the liver after ingestion. If the tablets are taken without food, it reaches its peak concentration in blood serum in an hour, if it is taken with a meal – in two hours. After one-time ingestion, the peak concentration is 0,213–0,375 mg/mL.

If Meravir is taken before meals, its bioavailability is approximately 25%, it increases if the medicine is taken with food.

In vitro active ingredients bind to plasma protein by up to 0.7%, with human serum protein – by 7.2%. Meravir is not a substrate of human cytochrome P450 isoenzymes, in vitro it does not influence metabolic processes involving cytochrome P450 isoenzymes, including CYP2E1, CYP3A4, CYP2D6, CYP2C9. A moderate, but statistically important decrease of CYP1A1 and CYP1A2 substrate metabolism was registered.

The main dose of the treatment is excreted renally as a result of glomerular filtration and active tubular secretion.

The dosage (from 75 to 600 mg), dosage frequency and patient’s sex have no influence on Meravir’s pharmacokinetic properties.

Pharmacokinetic properties of Meravir in healthy volunteers

	*Sufamenavir*	*Refogravir*
*Drug input*
Тmax (h)3	1±0,4 h	1±0,4 h
Effect of meal (in comparison with taking without food)	40%	40%
*Distribution*
% Bound to human plasma proteins	0,7	0,7
% Bound to blood serum	7, 2	7, 2
*Biotransformation*
Metabolism	Secondary	Secondary
*Elimination*
The main elimination pathway	By urinary way	By urinary way

Indications and usage

Meravir is indicated for the treatment of chronic hepatitis B and D virus (HBD and HDV) infection in adults. The treatment should be assigned to patients who have not received any treatment yet or the ones who had partial response to prior therapy and had recurrence.

Contraindication

Hypersensitivity to the active ingredients, allergic response to ingredients.
Patients under 18 y.o. should not take it because the treatment’s influenced on child’s organism isn’t researched yet.
The lactation period. If it is needed to treat a nursing mother, breastfeeding should be discontinued.

Meravir should be prescribed in patients, aged above 65, with hepatic and renal failure with creatine kinase 30–50 ml / min, during pregnancy.

It is recommended that women use contraceptives to eliminate pregnancy, since there is not data on effect of components on the development of the fetus.

Instruction for use of Meravir: posology and method of administration

The recommended dose of Meravir is 1 tablet one time a day, taken orally. The treatment should be taken daily, at the same time, with food and sufficient amount of water. The does should be corrected if it is taken with other medical products.

Treatment duration is from 6 to 12 months, depends on the degree of fibrosis:

1,2 degree –6 months (24 weeks);
2,3,4 degree –12 months (48 weeks).

In case of mild hepatic impairment (creatine kinase — 50-8. mL/min) the treatment should be taken as always, creatine kinase and serum phosphate levels should be constantly controlled.

In case of hepatic impairment when creatine kinase is 30–49 mL/min, the patient should take the treatment every other day.

Liver dysfunction does not require any changes in dosage.

If the treatment is not efficient or there is severe adverse drug reaction, interrupt the course of treatment.

Recommended treatment duration for patients without prior HBV or HDV therapy

*With fibrosis* (treatment duration depends on the degree of fibrosis)	*Without fibrosis*	*Cirrhosis*
F1, F2	6 months (24 weeks)	Not used
F3, F4	12 months (48 weeks)	Not used

Recommended treatment duration for patients who failed prior therapy.

*With fibrosis*	*Without fibrosis*	*Cirrhosis*
F1, F2	6 months (24 weeks)	Not used
F3, F4	12 months (48 weeks)	Not used

Adverse reactions

The following adverse reactions in patients who participated in Meravir clinical testing were reported. The list of adverse reactions classified by system organ classes.

Reported adverse reactions of Meravir

nervous system disorders	headache, dizziness, depression
gastro-intestinal tract disorders	bdominal pain, diarrhea, flatulence, vomiting, nausea, bloating, pancreatitis, increased amylase activity
hepatobiliary disorders	increased activity of liver enzymes (most often — alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase), hepatitis, hepatosteatosis
immune system disorders	allergic reactions, angioedema
respiratory system disorders	shortbreathing
metabolism disorders	hypokalemia, lactic acidosis, hypophosphatemia
urinary system disorders	renal disorder, including acute renal failure, interstitial nephritis, Fanconi syndrome, acute nephritis, proximal type renal tubulopathy, acute necrosis of renal tubules, nephrogenic diabetes insipidus, proteinuria, polyuria, increased creatinine levels
musculoskeletal system disorders	muscle weakness, rhabdomyolysis, myopathy, osteomalacia (bone pain, bone fractures)
dermatological reactions	skin rash
other reactions	undue fatiguability, asthenia

If adverse reaction persists, seek medical advice.

Overdose

Overdose symptoms were not observed. Taking 30 mg of medical product daily during 28 days did not cause severe adverse drug reaction. If there are signs of toxicity, use maintenance therapy. Haemodialysis may be assigned if needed. There is not data on effectiveness of peritoneal dialysis.

With caution

It is not recommended to take Meravir together with omeprazole, darunavir / ritonavir, efavirenz, lopinavir / ritonavir, lovastatin, cyclosporine (>100 mg daily).

Be careful taking Meravir together with the following medicines: digoxin, pravastatin, rosuvastatin, fluvastatin, pitavastatin, tacrolimus.

Special warnings

When prescribing Meravir, a doctor should inform a patient about necessity of usage of barrier methods of contraception because taking drugs does not prevent transmission of HBV and HDV to the sexual partner.

Take into account the fact that the drug can damage mitochondria to different extent. The most typical signs of mitochondrial dysfunction are neutropenia, anemia, hyperlactataemia, lactic acidosis, increased plasma lipase activity, severe hepatomegaly with fatty degeneration.

There is high risk of lactacidemia development, especially in overweighed women and patients who have hepatosteatosis, hepatitis, risk factors for liver damage. Thus, if a patient has any adverse reactions like feeling generally unwell, lack of appetite, abdominal pain, nausea, vomiting, respiratory and motor function disorders, muscle weakness, the patient needs to see a doctor. In case of severe hepatotoxicity or in case the level of lactic acid in the serum is more than 5 mmol /L, temporarily discontinue taking the drug.

Osteonecrosis is possible as a result of worsening HBV or HDV. Osteonecrosis development risk factors are: alcohol consumption, acute immunosuppression, glucocorticosteroids use, increased body weight index of the patient. If a patient has difficulty in moving, fatigue, stiffness or pain in the joints, the patient should see a doctor.

Creatinine kinase and serum phosphorus levels should be controlled during the treatment period. Patients with impaired renal function require more careful monitoring.

It is not recommended to take the drug after the recent use of nephrotoxic drugs or together with them.

If the treatment is prescribed to cure HBV or HDV, superinfection test should be done first. If a single cell is infected with different types of viruses (B, C, D), patients are at a higher risk of the hepatotoxic effect of the drug, so they are at increased risk of adverse effects on the liver with a possible death. Careful clinical and laboratory monitoring is needed.

Meravir dechallenge may lead to severe hepatitis flare in patients with co-infections. Thus, it is not recommended to discontinue treatment in patients with sever liver diseases (cirrhosis). Hepatitis flare which take place after dechallenge may cause decompensation of hepatic function.

In case of compromised liver function, the patient who takes Meravir should be carefully monitored. If any symptoms of worsening of renal status appear, treatment should be discontinued.

In case of any inflammatory symptoms a patient should be examined by a doctor experienced in treating HBV and HDV and get symptomatic treatment.

Interaction of Meravir with other medical products

Didanosine	Didanosine concentration increases in case of co-use; use them with caution and monitor the manifestations of didanosine toxicity. It is not recommended to combine sufamenavir and refogravir with didanosine. If it is justified, consider reduction of the dose or discontinuation of didanosine therapy. Meravir can be combined with reduced doses of didanosine (for example, patients with a body weight over 60 kg are prescribed didanosine 250 mg once daily; <60 kg — 200 mg once daily).
Atazanavir	Atazanavir concentration decreases in case of co-use, sufamenavir and refogravir concentration increases in the same situation. Use Meravir with atazanavir only if the latter is enhanced with the help of ritonavir.
Lopinavir / Ritonavir	Concentration of sufamenavir and refogravir increases in case of co-use.
Darunavir	Concentration of sufamenavir and refogravir increases by 20-25%. Use standard doses, monitor nephrotoxic effect of sufamenavir and refogravir carefully. Meravir is mainly excreted renally. In case of co-use with drugs that reduce renal function or reduce / stop active tubular secretion the serum concentration of active substances can increase and/or concentration of other drugs excreted renally can increase as well.
Nephrotoxic drugs	Concentration of sufamenavir and refogravir in blood serum increases.

Driving and using machines

Given the side effects, be careful when driving and using machines during the treatment period or abandon the types of work that require high psychomotor ability and increased mental alertness.

Pregnancy and breastfeeding

Meravir may taken during the pregnancy period if therapeutic benefits for a mother exceed possible risk for a child. Contraindicated during the period of breastfeeding.

Paediatric population

Meravir is not recommended in children and adolescents under 18 y.o. No data on safety and efficiency of Meravir in children and adolescents.

Elderly

The patients above 65 y.o. should take medication with caution.

Drug marketing status

Available on prescription.

Recommendations on storage

Keep out of reach of children, store at temperature below 30°C and in original package to protect it from moisture.

Shelf life

2 years. Do not take the medicine after expiration date.