Rekambys (Suspension) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Cilag, AG (Switzerland)

ATC Code

J05AG05 (Rilpivirine)

Active Substance

Rilpivirine (Rec.INN registered by WHO)

Dosage Forms

	Rekambys	Prolonged-release suspension for intramuscular administration 600 mg/1 ml: vial 2 ml
		Prolonged-release suspension for intramuscular administration 900 mg/1 ml: vial 3 ml

Dosage Form, Packaging, and Composition

Prolonged-release suspension for intramuscular administration white or almost white, free from visible foreign particles.

Excipients: poloxamer 338, dextrose monohydrate, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, sodium hydroxide (for pH adjustment), water for injections.

2 ml – vials (1) – cardboard packs.

Prolonged-release suspension for intramuscular administration white or almost white, free from visible foreign particles.

Excipients: poloxamer 338, dextrose monohydrate, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, sodium hydroxide (for pH adjustment), water for injections.

3 ml – vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; non-nucleoside reverse transcriptase inhibitors

Pharmacological Action

Antiviral agent, a diarylpyrimidine non-nucleoside inhibitor of HIV-1 reverse transcriptase. The activity of rilpivirine is mediated by non-competitive inhibition of HIV-1 reverse transcriptase. Rilpivirine does not inhibit human cellular alpha-, beta-, gamma-DNA polymerases.

Rilpivirine is active against laboratory wild-type HIV-1 strains in acutely infected T-cell lines with a mean EC₅₀ for HIV-1/IIIB of 0.73 nM (0.27 ng/ml).

Rilpivirine has antiviral activity against a wide range of HIV-1 group M representatives (subtypes A, B, C, D, E, F, G, H), for which its mean effective dose (EC₅₀) ranges from 0.07 to 1.01 nM (0.03-0.37 ng/ml), and primary isolates of group O, for which its mean effective dose (EC₅₀) ranges from 2.88 to 8.45 nM (1.06-3.10 ng/ml).

Rilpivirine has additive antiviral activity in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, emtricitabine, stavudine, tenofovir), with protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir, and saquinavir), with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (efavirenz, etravirine, and nevirapine), as well as in combination with the fusion inhibitor enfuvirtide and the CCR5 co-receptor antagonist maraviroc. Rilpivirine produces a synergistic or additive antiviral effect in combination with the nucleoside reverse transcriptase inhibitors lamivudine and zidovudine, as well as the integrase inhibitor raltegravir.

Pharmacokinetics

After oral administration, C_max of rilpivirine in plasma was reached within 4-5 hours. The absolute bioavailability of rilpivirine is unknown. The bioavailability of rilpivirine was approximately 40% lower when the drug was taken on an empty stomach than when taken simultaneously with a normal-calorie meal (533 kcal) or a high-fat meal (928 kcal). When taken with a protein-enriched beverage, bioavailability was 50% lower than when taken simultaneously with food.

Plasma protein binding, predominantly to albumin, is 99.7%. The distribution of rilpivirine in biological fluids (cerebrospinal fluid, genital tract secretions) has not been studied.

In vitro studies have shown that Rilpivirine undergoes oxidative metabolism mediated by the CYP3A isoenzyme system.

The terminal T_1/2 of rilpivirine is approximately 45 hours. After oral administration of a single dose of ¹⁴C-rilpivirine, approximately 85% and 6.1% of the radioactively labeled dose was found in feces and urine, respectively.

The amount of rilpivirine found unchanged in feces averaged 25% of the administered dose. Only a negligible amount of unchanged rilpivirine (less than 1% of the administered dose) was found in urine.

Indications

Treatment of infection caused by human immunodeficiency virus type 1 (HIV-1) in adult patients – in combination with other antiretroviral drugs as first-line therapy.

ICD codes

Dosage Regimen

Administer by intramuscular injection only, as a prolonged-release suspension.

Use only in combination with other antiretroviral agents.

Initiate therapy with an oral lead-in period of at least one month using rilpivirine 25 mg tablets once daily with a meal to assess tolerability.

For the 600 mg/1 ml suspension, the recommended dose is 600 mg (1 ml) once monthly.

For the 900 mg/1 ml suspension, the recommended dose is 900 mg (1 ml) once monthly.

Administer the first two initiation injections one month apart, preferably on the same calendar date each subsequent month.

If a monthly injection is missed by more than 7 days, re-initiate therapy with the oral lead-in dosing for one month before resuming injections.

Inject slowly into the gluteal muscle; alternate buttocks for each subsequent injection.

Do not administer intravenously, subcutaneously, or into a blood vessel.

Visually inspect the suspension for particulate matter and discoloration prior to administration; do not use if foreign particles are present.

Adverse Reactions

Digestive system: frequently – decreased appetite, abdominal pain, vomiting, nausea; infrequently – abdominal discomfort.

Central nervous system: frequently – depression, insomnia, abnormal dreams, sleep disorder, dizziness, headache; infrequently – depressed mood, drowsiness.

Skin and subcutaneous tissue: frequently – rash; with combined antiretroviral therapy, lipodystrophy may occur in HIV-infected patients, characterized by loss of subcutaneous fat in the periphery (upper and lower limbs) and facial area, accumulation of adipose tissue in the intraperitoneal and visceral areas, breast hypertrophy, and accumulation of subcutaneous fat in the dorsocervical area (“buffalo hump”).

Immune system: in HIV-infected patients with severe immunodeficiency who have just started combined antiretroviral therapy, an inflammatory response to the presence of opportunistic agents may develop against the background of immune system recovery, with the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome).

Laboratory parameters: frequently – increased transaminase activity. Cases of decreased hemoglobin, platelet, leukocyte concentration, increased AST, ALT, pancreatic amylase, lipase activity, increased bilirubin, total cholesterol, LDL and triglycerides have also been observed. The mean change in fasting total cholesterol concentration was 2 mg/dL, fasting HDL – 4 mg/dL, fasting LDL – 1 mg/dL, and fasting triglycerides – 7 mg/dL. An increase in serum creatinine was observed during the first four weeks of therapy and remained stable up to week 48; the mean change after 48 weeks of therapy was 0.09 mg/dL (range: -0.20 mg/dL to 0.62 mg/dL); in patients with mild or moderate renal impairment, the observed increase in serum creatinine was comparable to the increase in serum creatinine in patients with normal renal function (these changes were considered clinically insignificant).

General reactions: frequently – fatigue.

Patients co-infected with hepatitis B and/or hepatitis C virus: the frequency of increased liver enzyme levels was higher than in patients with HIV infection only. The pharmacokinetic effect of rilpivirine in co-infected patients is comparable to that in patients without co-infection.

Contraindications

Severe hepatic impairment (Child-Pugh class C); children and adolescents under 18 years of age; simultaneous use with drugs that significantly reduce the plasma concentration of rilpivirine (as this may lead to loss of virological response or development of resistance to rilpivirine or to the entire class of non-nucleoside reverse transcriptase inhibitors) – anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifabutin, rifampicin, rifapentine); proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), systemic corticosteroids (dexamethasone when taken more than once), preparations of St. John’s wort (Hypericum perforatum); hypersensitivity to rilpivirine.

Use in Pregnancy and Lactation

No adequate and well-controlled clinical or pharmacokinetic studies of the use of rilpivirine during pregnancy have been conducted. Use is possible only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Women of childbearing age are advised to use effective contraception during treatment.

It is not known whether Rilpivirine is excreted in human breast milk. Due to the risk of HIV transmission and the possible development of adverse events in breastfed infants, breastfeeding is not recommended during therapy.

In preclinical studies in animals, no signs of embryotoxicity or effects on reproductive function were identified.

Special Precautions

Rilpivirine should be used with caution in combination with drugs that can cause torsades de pointes ventricular tachycardia. Data on the potential interaction between rilpivirine and drugs that prolong the QT interval are limited. A study in healthy volunteers found that Rilpivirine at high doses (75 mg once daily and 300 mg once daily) prolongs the QT interval on the ECG.

Patients should be informed that current antiretroviral therapy cannot cure HIV infection, nor can it prevent the transmission of HIV through blood or sexual contact. Necessary precautions should be taken to prevent HIV infection.

Cases of depressive disorders (mood deterioration, depression, dysphoria, major depression, behavioral instability, negative thoughts, suicidal ideation, suicide attempts) have been reported during the use of rilpivirine. If the association with rilpivirine intake is proven, the risk should be weighed against the benefit of continuing therapy.

Combined antiretroviral therapy can cause redistribution of subcutaneous adipose tissue (lipodystrophy) in HIV-infected patients. The exact mechanism of occurrence and long-term consequences of this phenomenon are currently unknown. A link is suggested between the development of visceral lipomatosis and the use of protease inhibitors, and between lipoatrophy and NRTIs. An increased risk of developing lipodystrophy is associated with individual factors such as older age, as well as drug-related factors, such as a longer course of antiretroviral therapy and associated metabolic disorders. Clinical examination of patients should include an assessment of physical signs of subcutaneous fat redistribution.

At the start of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to the presence of asymptomatic opportunistic agents with the appearance or exacerbation of symptoms of a previously asymptomatic disease (immune reconstitution syndrome), which may require further careful monitoring and treatment. Such reactions are usually observed within the first few weeks after starting treatment. Similar examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis pneumonia. Any symptoms of inflammation should be assessed and, if necessary, treatment should be prescribed.

Effect on the ability to drive vehicles and operate machinery

Rilpivirine has a minor effect on the ability to drive vehicles and operate machinery.

Drug Interactions

Rilpivirine is metabolized with the participation of CYP3A isoenzymes, therefore drugs that induce or inhibit CYP3A affect the elimination of rilpivirine.

Concomitant use of rilpivirine and drugs that can induce CYP3A may lead to a decrease in the plasma concentration of rilpivirine and a reduction in the therapeutic efficacy of rilpivirine.

Concomitant use of rilpivirine and drugs that inhibit CYP3A may lead to an increase in the plasma concentration of rilpivirine.

Concomitant use of rilpivirine and drugs that increase gastric pH may lead to a decrease in the plasma concentration of rilpivirine and a possible reduction in the therapeutic efficacy of rilpivirine.

It is not recommended to use Rilpivirine with other NNRTIs, including delavirdine, efavirenz, etravirine, nevirapine.

When rilpivirine is used concomitantly with darunavir/ritonavir, an increase in the plasma concentration of rilpivirine may be observed due to inhibition of the CYP3A isoenzyme (dose adjustment is not required).

When rilpivirine is used concomitantly with lopinavir/ritonavir, an increase in the plasma concentrations of rilpivirine may be observed due to inhibition of CYP3A isoenzymes (dose adjustment is not required).

When rilpivirine is used concomitantly with ketoconazole, an increase in the plasma concentrations of rilpivirine may be observed due to inhibition of CYP3A isoenzymes (dose adjustment is not required).

Rilpivirine should be used with caution concomitantly with histamine H₂-receptor blockers, as this may lead to a significant decrease in the plasma concentration of rilpivirine due to an increase in gastric pH. Histamine H₂-receptor blockers should be taken at least 12 hours before or 4 hours after taking rilpivirine.

Data on the potential interaction between rilpivirine and drugs that prolong the QT interval are limited. Rilpivirine at high doses (75 mg once daily and 300 mg once daily) has been shown to prolong the QT interval on the ECG. Therefore, Rilpivirine should be used with caution in combination with drugs that can cause torsades de pointes ventricular tachycardia.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.