Piveltra (Tablets) Instructions for Use

Marketing Authorization Holder

MSD Pharmaceuticals, LLC (Russia)

Manufactured By

MSD International, GmbH (Ireland)

Packaging and Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

Contact Information

MSD Pharmaceuticals LLC (Russia)

ATC Code

J05AG06 (Doravirine)

Active Substance

Doravirine (Rec.INN registered by WHO)

Dosage Form

Piveltra

Film-coated tablets, 100 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oval, biconvex, engraved with the company logo (graphic symbol) and “700” on one side and smooth on the other.

Excipients: hypromellose acetate succinate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, film coating (hypromellose, titanium dioxide, lactose monohydrate, triacetin), carnauba wax.

30 pcs. – high-density polyethylene bottles (1) – cardboard packs with first-opening control (self-adhesive stickers).

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

The drug Piveltra is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus-1 (HIV-1).

Mechanism of action

Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication through non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit human cellular DNA polymerases α, β and mitochondrial DNA polymerase γ.

Antiviral activity in cell culture

Doravirine demonstrated an EC₅₀ value of 12.0 ±4.4 nmol/L against laboratory wild-type HIV-1 strains when tested in the presence of 100% healthy human serum using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad group of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC₅₀ values ranging from 1.2 nmol/L to 10.0 nmol/L.

Antiviral activity in combination with other HIV drugs

The antiviral activity of doravirine was not antagonistic when co-administered with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zalcitabine, or zidovudine; protease inhibitors darunavir or indinavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.

Resistance

In cell culture

Doravirine-resistant strains were selected in cell culture, starting from wild-type HIV-1 of various origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in reverse transcriptase (RT) included: V106A, V106M, V106I, V108I, F227L, F227C, F227V, H221Y, M230I, L234I, P236L, Y318F. In vitro studies did not identify the most common NNRTI resistance mutations (K103N, Y181C). The V106A mutation (fold resistance approximately 19) appeared as an initial substitution in subtype B virus, V106A or M in subtypes A and C. Subsequently, F227 (L/C/V) or L234I mutations emerged in addition to the V106 substitution (double mutations leading to fold resistance >100).

In clinical studies

In the doravirine treatment groups, in the DRIVE-FORWARD and DRIVE-AHEAD studies in treatment-naive patients (n=747), emergent doravirine resistance mutations were observed in 7 out of 23 patients in the resistance analysis subset (patients with HIV-1 RNA level greater than 400 copies/mL at virologic failure or at early study discontinuation with resistance data). In the darunavir + ritonavir (DRV+ r) treatment group of the DRIVE-FORWARD study (n=383), no emergent darunavir resistance mutations were observed in 11 patients in the resistance analysis subset. In the efavirenz/emtricitabine/tenofovir disoproxil (EFV/FTC/TDF) treatment group of the DRIVE-AHEAD study (n=364), emergent efavirenz resistance mutations were observed in 12 out of 24 patients in the resistance analysis subset.

Emergent doravirine resistance mutations in RT included one or more of the following: A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R and Y318Y/F.

Cross-resistance

Laboratory HIV-1 strains carrying common NNRTI-associated mutations K103N, Y181C or K103N/Y181C in RT are characterized by less than a 3-fold decrease in sensitivity to doravirine compared to wild-type virus when assessed in the presence of 100% healthy human serum. Doravirine was able to inhibit the following NNRTI-associated substitutions: K103N, Y181C, G190A and E138K mutations at clinically relevant concentrations.

A panel of 96 different clinical isolates containing NNRTI-associated mutations was studied for sensitivity to doravirine in the presence of 10% fetal bovine serum. Clinical isolates containing the Y188L substitution or V106 substitutions in combination with A98G, H221Y, P225H, F227C or Y318F were characterized by a more than 100-fold decrease in sensitivity to doravirine.

Other established NNRTI substitutions were characterized by a 5-10-fold decrease in sensitivity (G190S (5.7), K103N/P225H (7.9), V108I/Y181C, Y181V (5.1)). The clinical significance of a 5-10-fold decrease in sensitivity is unknown.

Mutations associated with resistance to doravirine that emerged after initiation of treatment may cause cross-resistance to efavirenz, rilpivirine, nevirapine and etravirine. In baseline studies, of the 7 patients who developed high-level resistance to doravirine, 6 patients had phenotypic resistance to efavirenz and nevirapine, 3 patients to rilpivirine, and 2 patients had partial resistance to etravirine.

Pharmacokinetics

Effect of food on oral administration

Administration of doravirine 100 mg tablets with a high-fat meal in healthy volunteers resulted in a 16% and 36% increase in doravirine AUC and C₂₄, respectively, with a minor effect on C_max.

The pharmacokinetics of doravirine were studied in healthy volunteers and HIV-1-infected patients. The pharmacokinetics of doravirine are similar in healthy volunteers and HIV-1-infected patients. Steady state was typically achieved by the second day with once-daily dosing, with an accumulation ratio of 1.2 to 1.4 for AUC_0-24, C_max, and C₂₄. Steady-state pharmacokinetic parameters of doravirine after administration of 100 mg once daily in HIV-1-infected patients based on population pharmacokinetic analysis are presented below.

GM: geometric mean; %CV: geometric coefficient of variation.

Absorption

Following oral administration, plasma C_max is reached within 2 hours. The absolute bioavailability of doravirine was estimated to be approximately 64% for the 100 mg tablet.

Distribution

Based on intravenous microdose administration, the V_d of doravirine is 60.5 L. Doravirine is approximately 76% bound to plasma proteins.

Metabolism

Based on in vitro data, Doravirine is primarily metabolized via CYP3A isoenzymes.

Excretion

The terminal T_1/2 of doravirine is approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism mediated by the CYP3A isoenzyme. Biliary excretion of unchanged drug may contribute to the elimination of doravirine, but this route of elimination is not expected to be significant. Renal excretion of unchanged drug is negligible.

Pharmacokinetics in special patient groups

Renal impairment. Renal excretion of doravirine is negligible. In a study comparing 8 patients with severe renal impairment and 8 patients without renal impairment, exposure to a single dose of doravirine was 43% higher in patients with severe renal impairment. In a population pharmacokinetic analysis that included patients with CrCl as low as 17 mL/min, renal function did not have a clinically significant effect on the pharmacokinetics of doravirine. Dose adjustment is not required in patients with mild, moderate, or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or in patients on dialysis (see section “Dosage Regimen”).

Hepatic impairment. Doravirine is primarily metabolized and eliminated by the liver. No clinically significant differences in the pharmacokinetics of doravirine were noted in a study comparing 8 patients with moderate hepatic impairment (Child-Pugh class B mainly due to increased severity of encephalopathy and ascites) and 8 patients without hepatic impairment. Dose adjustment is not required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see section “Dosage Regimen”). It is not known whether doravirine exposure is increased in patients with severe hepatic impairment, so no dose adjustment recommendations are available.

Elderly patients. No clinically significant differences in the pharmacokinetics of doravirine were identified in a Phase 1 study or in a population pharmacokinetic analysis in patients over 65 years of age compared to patients under 65 years of age.

Gender. No clinically significant differences in the pharmacokinetics of doravirine between men and women were identified.

Pediatric patients. The pharmacokinetics and dosing recommendations for Piveltra in patients under 18 years of age have not been established (see section “Pharmacological Action”).

Race. Based on data from a population pharmacokinetic analysis of doravirine in healthy volunteers and HIV-1-infected patients, no clinically significant racial differences in the pharmacokinetics of doravirine were identified.

Indications

• Treatment of HIV-1 infection as part of combination antiretroviral therapy.

ICD codes

Dosage Regimen

Treatment should be prescribed by a physician experienced in the treatment of HIV infection. The drug should be prescribed in combination with other antiretroviral drugs.

Piveltra is taken orally, once daily, with or without food.

Adults

Adult HIV-1 infected patients previously untreated with antiretroviral therapy, and adult HIV-1 infected patients previously treated with antiretroviral therapy without known doravirine resistance mutations: 1 tablet (100 mg) once daily in combination with other antiretroviral drugs.

Dose adjustment

If Piveltra is co-administered with rifabutin: 1 tablet (100 mg) of Piveltra should be taken twice daily (approximately 12 hours apart) (see section “Drug Interactions”).

Co-administration of Piveltra with other moderate inducers (such as dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) has not been studied. If co-administration cannot be avoided, 1 tablet of Piveltra should be taken within 12 hours of the initial dose of Piveltra (see section “Drug Interactions”).

Missed dose

If a dose of Piveltra is missed by less than 12 hours from the usual time of administration, the patient should take Piveltra as soon as possible and take the next dose of Piveltra at the usual scheduled time. If a dose of Piveltra is missed by more than 12 hours from the usual time of administration, the patient should not take the missed dose, instead the patient should take the next dose at the scheduled time. Two doses should not be taken at the same time.

Special patient groups

Dose adjustment of Piveltra in elderly patients is not required.

Dose adjustment of Piveltra in patients with mild, moderate, or severe renal impairment is not required. Treatment with Piveltra has not been studied in patients with end-stage renal disease and in patients on dialysis (see section “Pharmacological Action”).

Dose adjustment of Piveltra in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment is not required. Treatment with Piveltra has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see section “Pharmacological Action”). It is not known whether doravirine exposure is increased in patients with severe hepatic impairment, so no dose adjustment recommendations are available.

The safety and efficacy of Piveltra have not been studied in patients under 18 years of age. No data on use are available.

Adverse Reactions

The most frequently reported adverse reactions assessed as possibly or probably related to doravirine were nausea (6%) and headache (5%).

Adverse reactions with a presumed (at least possible) relationship to treatment are listed below by system organ class and frequency. Within each frequency group, adverse events are presented in order of decreasing severity. Frequency is defined as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100) or rare (from 1/10,000 to <1/1000).

Infections and infestations uncommon – pustular rash.

Metabolism and nutrition disorders uncommon – hypomagnesemia, hypophosphatemia.

Psychiatric disorders common – abnormal dreams, insomnia, nightmares, depression¹; uncommon – anxiety², irritability, aggression, hallucinations, adjustment disorder, confusion, mood altered, somnambulism, suicidal thoughts.

Nervous system disorders common – headache, dizziness, somnolence; uncommon – attention disturbance, memory impairment, hypertonia, paresthesia, poor quality sleep.

Cardiac disorders uncommon – hypertension.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, tonsillar hypertrophy.

Gastrointestinal disorders common – nausea, diarrhea, abdominal pain³, vomiting; uncommon – constipation, flatulence, abdominal discomfort⁴, abdominal distension, dyspepsia, mushy stools⁵, gastrointestinal hypermotility⁶, painful defecation.

Skin and subcutaneous tissue disorders common – rash⁷; uncommon – pruritus, allergic dermatitis, rosacea.

Musculoskeletal and connective tissue disorders uncommon – musculoskeletal pain, myalgia, arthralgia.

Renal and urinary disorders uncommon – acute kidney injury, renal impairment, kidney stones, urolithiasis.

General disorders and administration site conditions common – fatigue; uncommon – asthenia, chest pain, malaise, chills, pain, thirst.

Investigations uncommon – increased ALT, increased lipase, increased AST, increased amylase, decreased hemoglobin, increased blood CPK.

¹ Depression includes: depression, depressed mood, major depressive episode, persistent depressive disorder.

² Anxiety includes: anxiety and generalized anxiety disorder.

³ Abdominal pain includes: abdominal pain and upper abdominal pain.

⁴Abdominal discomfort includes: abdominal discomfort and epigastric discomfort.

⁵ Mushy stools includes: mushy stools and atypical stools.

⁶ Gastrointestinal hypermotility includes: gastrointestinal hypermotility and increased gastrointestinal motility.

⁷ Rash includes: rash, macule, erythematous rash, generalized rash, maculopapular rash, papular rash and urticaria.

Contraindications

• Hypersensitivity to doravirine or to any of the components of the drug;
• Concomitant use with drugs that are strong inducers of cytochrome P450 (CYP) 3A4 (due to a significant decrease in plasma concentrations of doravirine):
  • Carbamazepine, oxcarbazepine, phenobarbital, phenytoin;
  • Rifampin, rifapentine;
  • Herbal preparations of St. John’s wort (Hypericum perforatum);
  • Mitotane;
  • Enzalutamide;
  • Lumacaftor.
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption (Piveltra contains lactose monohydrate);
• Age under 18 years (lack of data on efficacy and safety);
• Pregnancy (see section “Pregnancy and Lactation”);
• Breastfeeding period (see section “Pregnancy and Lactation”);
• Patients with end-stage renal disease and patients on hemodialysis (lack of data on efficacy and safety);
• Patients with severe hepatic impairment (Child-Pugh class C) (lack of data on efficacy and safety).

With caution

The drug should be used with caution when co-administered with the following drugs: dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl (see sections “Drug Interactions” and “Special Instructions”).

Use in Pregnancy and Lactation

Pregnancy

Data on the use of doravirine in pregnant women are absent or limited.

Antiretroviral Pregnancy Registry

An Antiretroviral Pregnancy Registry has been established to monitor pregnancy outcomes in patients exposed to antiretroviral drugs during pregnancy. Healthcare providers are encouraged to register patients in this registry.

Animal studies with doravirine do not indicate direct or indirect harmful effects regarding reproductive toxicity.

The use of Piveltra during pregnancy is contraindicated.

Breastfeeding period

There are no data on the excretion of doravirine in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk. Due to the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, mothers receiving Piveltra should discontinue breastfeeding.

Effect on Fertility

There are no data on the effect of doravirine on human fertility. Animal studies do not indicate harmful effects of doravirine on fertility at exposures exceeding human exposure at the recommended clinical dose.

Use in Hepatic Impairment

No dose adjustment of the drug is required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

The use of the drug is contraindicated in patients with severe hepatic insufficiency (Child-Pugh class C).

Use in Renal Impairment

No dose adjustment of the drug is required in patients with mild, moderate, or severe renal impairment.

The use of the drug is contraindicated in patients with end-stage renal disease and patients on hemodialysis.

Pediatric Use

The use of the drug is contraindicated in individuals under 18 years of age.

Geriatric Use

No dose adjustment of the drug is required in elderly patients.

Special Precautions

Effective antiviral suppression with antiretroviral therapy has been proven to significantly reduce the risk of sexual transmission of HIV-1; however, a residual risk cannot be excluded. Precautions should be taken to prevent virus transmission in accordance with national guidelines.

NNRTI Substitutions and Doravirine Use

The use of doravirine was studied in a limited number of treatment-naive patients with transmitted NNRTI resistance (see the “Resistance” subsection). The use of doravirine has not been studied in patients with prior virological failure of any other antiretroviral therapy. NNRTI-associated mutations detected at screening were exclusion criteria in phase 2b/3 studies. The clinical efficacy reduction threshold associated with various NNRTI substitutions has not been established.

Use with CYP3A Enzyme Inducers

Caution should be exercised when prescribing Piveltra concomitantly with drugs that may reduce doravirine exposure (see the “Drug Interactions” section).

Immune Reconstitution Syndrome

Immune reactivation syndrome has been described in patients receiving combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may require further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reactivation; however, the time to onset is variable and can occur many months after initiation of treatment.

Lactose

Piveltra contains lactose monohydrate. The use of Piveltra is contraindicated in patients with lactase deficiency, lactose intolerance, or glucose-galactose malabsorption.

Effect on Ability to Drive and Use Machines

Piveltra has no or negligible influence on the ability to drive and use machines. Patients should be informed that increased fatigue, dizziness, and drowsiness have been reported during treatment with Piveltra (see the “Adverse Reactions” section). This should be considered when assessing a patient’s ability to drive or operate machinery.

Overdose

There is no information on potential acute symptoms and signs of Piveltra overdose.

Drug Interactions

Effect of Other Drugs on Doravirine

Doravirine is primarily metabolized by the CYP3A enzyme, and drugs that induce or inhibit the CYP3A enzyme affect doravirine clearance (see the “Pharmacodynamics” section). Piveltra is contraindicated for concomitant use with drugs that are strong inducers of the CYP3A enzyme, as a significant decrease in doravirine plasma concentration is expected, which may reduce the efficacy of doravirine (see the “Contraindications” and “Pharmacokinetics” sections).

Concomitant use with the moderate CYP3A inducers rifabutin and efavirenz reduces doravirine plasma concentration. When used concomitantly with rifabutin, a dose of Piveltra should be taken 12 hours after the initial dose of Piveltra (see the “Dosage and Administration” section).

Concomitant use of Piveltra with other moderate CYP3A inducers has not been studied. If concomitant use of Piveltra with other moderate CYP3A inducers cannot be avoided, an additional dose of Piveltra should be taken 12 hours after the initial dose of Piveltra (see the “Pharmacokinetics” section).

Concomitant use of Piveltra and drugs that are CYP3A enzyme inhibitors may lead to an increase in doravirine plasma concentration.

Effect of Doravirine on Other Drugs

It is unlikely that administration of Piveltra at a dose of 100 mg (1 tablet) once daily will have a clinically significant effect on the plasma concentration of drugs that depend on transporter proteins for absorption and/or elimination or that are metabolized via CYP enzymes.

However, concomitant administration of doravirine and the sensitive CYP3A substrate midazolam resulted in an 18% decrease in midazolam exposure, indicating that Doravirine may be a weak inducer of CYP3A. Therefore, caution should be exercised when doravirine is co-administered with drugs that are sensitive CYP3A substrates which may also have a narrow therapeutic window (e.g., tacrolimus and sirolimus).

Interaction Table

Interactions between Piveltra and co-administered drugs are presented in the table below (decrease is denoted as ↓, no change is denoted as ↔).

The table lists established and other potentially significant drug interactions with Piveltra, but is not all-inclusive.

Table. Interactions with Other Drugs and Dosing Recommendations

↑ = increase;

↓ = decrease;

↔ = no change;

CI = confidence interval;

* AUC_0-∞ – for single dose, AUC_0-24 – for once daily administration;

^× This interaction was studied only with ritonavir.

Storage Conditions

The drug should be stored in the original packaging in a place inaccessible to children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.