4.1. Therapeutic indications

Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults, and adolescents aged 12 years and older weighing at least 35 kg infected with human immunodeficiency virus type 1 (HIV‑1) without past or present evidence of resistance to the non-nucleoside reverse transcriptase inhibitors (NNRTI) class (see sections 4.4 and 5.1).

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

The recommended dose is one 100 mg tablet taken orally once daily with or without food.

Dose adjustment

If Pifeltro is co-administered with rifabutin, one 100 mg tablet of Pifeltro should be taken twice daily (approximately 12 hours apart) (see section 4.5).

Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, one 100 mg tablet of Pifeltro should be taken twice daily (approximately 12 hours apart).

Missed dose

If the patient misses a dose of Pifeltro within 12 hours of the time it is usually taken, the patient should take as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 12 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not take 2 doses at one time.

Special populations

Elderly

No dose adjustment of doravirine is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease and has not been studied in dialysis patients (see section 5.2).

Hepatic impairment

No dose adjustment of doravirine is 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). It is not known whether the exposure to doravirine will increase in patients with severe hepatic impairment. Therefore, caution is advised when doravirine is administered to patients with severe hepatic impairment (see section 5.2).

Paediatric population

Safety and efficacy of Pifeltro in children aged less than 12 years or weighing less than 35 kg have not been established. No data are available.

Method of administration

Pifeltro must be taken orally, once daily with or without food and swallowed whole (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with medicinal products that are strong cytochrome P450 CYP3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of Pifeltro (see sections 4.4 and 4.5). These medicinal products include, but are not limited, to the following:

• carbamazepine, oxcarbazepine, phenobarbital, phenytoin

• rifampicin, rifapentine

• St. John's wort (Hypericum perforatum)

• mitotane

• enzalutamide

• lumacaftor

4.4. Special warnings and precautions for use

NNRTI substitutions and use of doravirine

Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase 2b/3-studies. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established (see section 5.1). There is not sufficient clinical evidence to support the use of doravirine in patients infected with HIV‑1 with evidence of resistance to the NNRTI class.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, doravirine-containing regimens should be withdrawn immediately and an alternative treatment considered (as appropriate). Clinical status should be closely monitored, and appropriate therapy should be initiated. If the patient has developed a serious reaction such as TEN, with the use of doravirine-containing regimens, treatment with doravirine-containing regimens must not be restarted in this patient at any time.

Use with CYP3A inducers

Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine (see sections 4.3 and 4.5).

Immune reactivation syndrome

Immune reactivation syndrome has been reported in patients treated with 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 necessitate further evaluation and treatment.

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

Lactose

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on doravirine

Doravirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine (see section 5.2). Doravirine should not be co-administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine (see sections 4.3 and 5.2).

Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2).

Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2).

Co-administration of doravirine and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors.

Effects of doravirine on other medicinal products

Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolised by CYP enzymes.

However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer. Therefore caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus and sirolimus).

Interactions table

Table 1 shows the established and other potential medicinal product interactions with doravirine but is not all inclusive (increase is indicated as ↑, decrease is indicated as ↓, and no change as ↔).

Table 1: Interactions of doravirine with other medicinal products

Medicinal product by therapeutic area

Effects on medicinal product levels geometric mean ratio (90 % CI)*

Recommendation concerning co-administration with doravirine

Acid-reducing agents

antacid (aluminium and magnesium hydroxide oral suspension)

(20 mL SD, doravirine 100 mg SD)

↔ doravirine

AUC 1.01 (0.92, 1.11)

Cmax 0.86 (0.74, 1.01)

C24 1.03 (0.94, 1.12)

No dose adjustment is required.

pantoprazole

(40 mg QD, doravirine 100 mg SD)

↓ doravirine

AUC 0.83 (0.76, 0.91)

Cmax 0.88 (0.76, 1.01)

C24 0.84 (0.77, 0.92)

No dose adjustment is required.

omeprazole

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

Angiotensin converting enzyme inhibitors

lisinopril

Interaction not studied.

Expected:

↔ lisinopril

No dose adjustment is required.

Antiandrogens

enzalutamide

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antibiotics

nafcillin

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Anticonvulsants

carbamazepine

oxcarbazepine

phenobarbital

phenytoin

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antidiabetics

metformin

(1 000 mg SD, doravirine 100 mg QD)

↔ metformin

AUC 0.94 (0.88, 1.00)

Cmax 0.94 (0.86, 1.03)

No dose adjustment is required.

canagliflozin

liraglutide

sitagliptin

Interaction not studied.

Expected:

↔ canagliflozin

↔ liraglutide

↔ sitagliptin

No dose adjustment is required.

Antidiarrhoeals

telotristat ethyl

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Antigout and uricosuric agents

lesinurad

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Antimycobacterials

Single dose rifampicin

(600 mg SD, doravirine 100 mg SD)

Multiple dose rifampicin

(600 mg QD, doravirine 100 mg SD)

↔ doravirine

AUC 0.91 (0.78, 1.06)

Cmax 1.40 (1.21, 1.63)

C24 0.90 (0.80, 1.01)

↓ doravirine

AUC 0.12 (0.10, 0.15)

Cmax 0.43 (0.35, 0.52)

C24 0.03 (0.02, 0.04)

(Induction of CYP3A)

Co-administration is contraindicated.

rifapentine

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

rifabutin

(300 mg QD, doravirine 100 mg SD)

↓ doravirine

AUC 0.50 (0.45, 0.55)

Cmax 0.99 (0.85, 1.15)

C24 0.32 (0.28, 0.35)

(Induction of CYP3A)

If doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (approximately 12 hours apart).

Antineoplastics

mitotane

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antipsychotics

thioridazine

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Azole antifungal agents

ketoconazole

(400 mg QD, doravirine 100 mg SD)

↑ doravirine

AUC 3.06 (2.85, 3.29)

Cmax 1.25 (1.05, 1.49)

C24 2.75 (2.54, 2.98)

(Inhibition of CYP3A)

No dose adjustment is required.

fluconazole

itraconazole

posaconazole

voriconazole

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A4)

No dose adjustment is required.

Calcium channel blockers

diltiazem

verapamil

Interaction not studied.

Expected:

↑ doravirine

(CYP3A inhibition)

No dose adjustment is required.

Cystic fibrosis treatment

lumacaftor

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Endothelin receptor antagonists

bosentan

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Hepatitis C antiviral agents

elbasvir + grazoprevir

(50 mg elbasvir QD + 200 mg grazoprevir QD, doravirine 100 mg QD)

↑ doravirine

AUC 1.56 (1.45, 1.68)

Cmax 1.41 (1.25, 1.58)

C24 1.61 (1.45, 1.79)

(Inhibition of CYP3A)

↔ elbasvir

AUC 0.96 (0.90, 1.02)

Cmax 0.96 (0.91, 1.01)

C24 0.96 (0.89, 1.04)

↔ grazoprevir

AUC 1.07 (0.94, 1.23)

Cmax 1.22 (1.01, 1.47)

C24 0.90 (0.83, 0.96)

No dose adjustment is required.

ledipasvir + sofosbuvir

(90 mg ledipasvir SD + 400 mg sofosbuvir SD, doravirine 100 mg SD)

↑ doravirine

AUC 1.15 (1.07, 1.24)

Cmax 1.11 (0.97, 1.27)

C24 1.24 (1.13, 1.36)

↔ ledipasvir

AUC 0.92 (0.80, 1.06)

Cmax 0.91 (0.80, 1.02)

↔ sofosbuvir

AUC 1.04 (0.91, 1.18)

Cmax 0.89 (0.79, 1.00)

↔ GS-331007

AUC 1.03 (0.98, 1.09)

Cmax 1.03 (0.97, 1.09)

No dose adjustment is required.

sofosbuvir/velpatasvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

sofosbuvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

daclatasvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

ombitasvir/ paritaprevir/ritonavir and dasabuvir+/-ritonavir

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A due to ritonavir)

No dose adjustment is required.

dasabuvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

glecaprevir, pibrentasvir

Interaction not studied.

Expected:

↑ doravirine

(inhibition of CYP3A)

No dose adjustment is required.

ribavirin

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

Herbal supplements

St. John's wort

(Hypericum perforatum)

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

HIV antiviral agents

Fusion and entry inhibitors

enfuvirtide

Interaction not studied.

Expected:

↔ doravirine

↔ enfuviritide

No dose adjustment is required.

maraviroc

Interaction not studied.

Expected:

↔ doravirine

↔ maraviroc

No dose adjustment is required.

Protease inhibitors

ritonavir†- boosted PIs

(atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir, tipranavir)

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A)

↔ boosted PIs

No dose adjustment is required.

cobicistat-boosted PIs

(darunavir, atazanavir)

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A)

↔ boosted PIs

No dose adjustment is required.

Integrase strand transfer inhibitors

dolutegravir

(50 mg QD, doravirine 200 mg QD)

↔ doravirine

AUC 1.00 (0.89, 1.12)

Cmax 1.06 (0.88, 1.28)

C24 0.98 (0.88, 1.09)

↑ dolutegravir

AUC 1.36 (1.15, 1.62)

Cmax 1.43 (1.20, 1.71)

C24 1.27 (1.06, 1.53)

(Inhibition of BCRP)

No dose adjustment is required.

raltegravir

Interaction not studied.

Expected:

↔ doravirine

↔ raltegravir

No dose adjustment is required.

ritonavir†-boosted elvitegravir

Interaction not studied.

Expected:

↑ doravirine

(CYP3A inhibition)

↔ elvitegravir

No dose adjustment is required.

cobicistat-boosted elvitegravir

Interaction not studied.

Expected:

↑ doravirine

(CYP3A inhibition)

↔ elvitegravir

No dose adjustment is required.

Nucleoside reverse transcriptase inhibitors (NRTI)

tenofovir disoproxil

(245 mg QD, doravirine 100 mg SD)

↔ doravirine

AUC 0.95 (0.80, 1.12)

Cmax 0.80 (0.64, 1.01)

C24 0.94 (0.78, 1.12)

No dose adjustment is required.

lamivudine + tenofovir disoproxil

(300 mg lamivudine SD + 245 mg tenofovir disoproxil SD, doravirine 100 mg SD)

↔ doravirine

AUC 0.96 (0.87, 1.06)

Cmax 0.97 (0.88, 1.07)

C24 0.94 (0.83, 1.06)

↔ lamivudine

AUC 0.94 (0.88, 1.00)

Cmax 0.92 (0.81, 1.05)

↔ tenofovir

AUC 1.11 (0.97, 1.28)

Cmax 1.17 (0.96, 1.42)

No dose adjustment is required.

abacavir

Interaction not studied.

Expected:

↔ doravirine

↔ abacavir

No dose adjustment is required.

emtricitabine

Interaction not studied.

Expected:

↔ doravirine

↔ emtricitabine

No dose adjustment is required.

tenofovir alafenamide

Interaction not studied.

Expected:

↔ doravirine

↔ tenofovir alafenamide

No dose adjustment is required.

Immunosuppressants

tacrolimus

sirolimus

Interaction not studied.

Expected:

↔ doravirine

↓ tacrolimus, sirolimus

(Induction of CYP3A)

Monitor blood concentrations of tacrolimus and sirolimus as the dose of these agents may need to be adjusted.

Kinase inhibitors

dabrafenib

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Opioid analgesics

methadone

20-200 mg QD individualised dose, doravirine 100 mg QD

↓ doravirine

AUC 0.74 (0.61, 0.90)

Cmax 0.76 (0.63, 0.91)

C24 0.80 (0.63, 1.03)

↔ R-methadone

AUC 0.95 (0.90, 1.01)

Cmax 0.98 (0.93, 1.03)

C24 0.95 (0.88, 1.03)

↔ S-methadone

AUC 0.98 (0.90, 1.06)

Cmax 0.97 (0.91, 1.04)

C24 0.97 (0.86, 1.10)

No dose adjustment is required.

buprenorphine

naloxone

Interaction not studied.

Expected:

↔ buprenorphine

↔ naloxone

No dose adjustment is required.

Oral contraceptives

0.03 mg ethinyl oestradiol/ 0.15 mg levonorgestrel SD, doravirine 100 mg QD

↔ ethinyl oestradiol

AUC 0.98 (0.94, 1.03)

Cmax 0.83 (0.80, 0.87)

↑ levonorgestrel

AUC 1.21 (1.14, 1.28)

Cmax 0.96 (0.88, 1.05)

No dose adjustment is required.

norgestimate/ethinyl oestradiol

Interaction not studied.

Expected:

↔ norgestimate/ethinyl oestradiol

No dose adjustment is required.

Pharmacokinetic enhancers

ritonavir

(100 mg BID, doravirine 50 mg SD)

↑ doravirine

AUC 3.54 (3.04, 4.11)

Cmax 1.31 (1.17, 1.46)

C24 2.91 (2.33, 3.62)

(Inhibition of CYP3A)

No dose adjustment is required.

cobicistat

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A)

No dose adjustment is required.

Psychostimulants

modafinil

Interaction not studied.

Expected:

↓doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Sedatives/hypnotics

midazolam

(2 mg SD, doravirine 120 mg QD)

↓ midazolam

AUC 0.82 (0.70, 0.97)

Cmax 1.02 (0.81, 1.28)

No dose adjustment is required.

Statins

atorvastatin

(20 mg SD, doravirine 100 mg QD)

↔ atorvastatin

AUC 0.98 (0.90, 1.06)

Cmax 0.67 (0.52, 0.85)

No dose adjustment is required.

rosuvastatin

simvastatin

Interaction not studied.

Expected:

↔ rosuvastatin

↔ simvastatin

No dose adjustment is required.

↑ = increase, ↓ = decrease, ↔ = no change

CI = Confidence Interval; SD = Single Dose; QD = Once Daily; BID = Twice Daily

*AUC0-∞ for single dose, AUC0-24 for once daily.

† The interaction was evaluated with ritonavir only.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of doravirine in pregnant women.

Antiretroviral pregnancy registry

To monitor maternal-foetal outcomes in patients exposed to antiretroviral medicinal products while pregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Animal studies with doravirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of doravirine during pregnancy.

Breast-feeding

It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (see section 5.3).

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

Fertility

No human data on the effect of doravirine on fertility are available. Animal studies do not indicate harmful effects of doravirine on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose (see section 5.3).

4.7. Effects on ability to drive and use machines

Pifeltro has a minor influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness, and somnolence have been reported during treatment with doravirine (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery.

4.8. Undesirable effects

Summary of the safety profile

In phase 3 clinical trials with doravirine plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), the most frequently reported adverse reactions were nausea (4 %) and headache (3 %).

Tabulated summary of adverse reactions

The adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE FORWARD, DRIVE SHIFT and DRIVE AHEAD) and postmarketing experience are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as 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 not known (cannot be estimated from the available data).

Table 2: Tabulated summary of adverse reactions associated with doravirine used in combination with other antiretrovirals

Frequency

Adverse reactions

Infections and infestations

Rare

rash pustular

Metabolism and nutrition disorders

Uncommon

hypophosphataemia

Rare

hypomagnesaemia

Psychiatric disorders

Common

abnormal dreams, insomnia1

Uncommon

nightmare, depression2, anxiety3, irritability, confusional state, suicidal ideation

Rare

aggression, hallucination, adjustment disorder, mood altered, somnambulism

Nervous system disorders

Common

headache, dizziness, somnolence

Uncommon

disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep

Vascular disorders

Uncommon

hypertension

Respiratory, thoracic and mediastinal disorders

Rare

dyspnoea, tonsillar hypertrophy

Gastrointestinal disorders

Common

nausea, diarrhoea, flatulence, abdominal pain4, vomiting

Uncommon

constipation, abdominal discomfort5, abdominal distension, dyspepsia, faeces soft6, gastrointestinal motility disorder7

Rare

rectal tenesmus

Hepatobiliary disorders

Not known

hepatitis

Skin and subcutaneous tissue disorders

Common

rash8

Uncommon

pruritus

Rare

dermatitis allergic, rosacea

Not known

toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Uncommon

myalgia, arthralgia

Rare

musculoskeletal pain

Renal and urinary disorders

Rare

acute kidney injury, renal disorder, calculus urinary, nephrolithiasis

General disorders and administration site conditions

Common

fatigue

Uncommon

asthenia, malaise

Rare

chest pain, chills, pain, thirst

Investigations

Common

alanine aminotransferase increased9

Uncommon

lipase increased, aspartate aminotransferase increased, amylase increased, haemoglobin decreased

Rare

blood creatine phosphokinase increased

1insomnia includes: insomnia, initial insomnia and sleep disorder

2depression includes: depression, depressed mood, major depression, and persistent depressive disorder

3anxiety includes: anxiety and generalised anxiety disorder

4abdominal pain includes: abdominal pain, and abdominal pain upper

5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort

6faeces soft includes: faeces soft and abnormal faeces

7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements

8rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, and urticarial

9alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury

Description of selected adverse reactions

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), such as toxic epidermal necrolysis (TEN), have been reported in association with doravirine-containing treatment regimens (see section 4.4).

Paediatric population

The safety of doravirine as a component of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically suppressed or treatment-naïve paediatric patients 12 to less than 18 years of age through Week 48 in an open-label trial (IMPAACT 2014 (Protocol 027)). The safety profile in paediatric subjects was similar to that in adults.

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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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