Applies to doravirine / lamivudine / tenofovir: oral tablet.

Serious side effects

Along with its needed effects, doravirine / lamivudine / tenofovir may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking doravirine / lamivudine / tenofovir:

Incidence not known

• Bloating
• bloody urine
• blurred vision
• bone fractures, especially of the femur bone
• chest tightness
• chills
• cloudy urine
• constipation
• cough
• dark urine
• decreased appetite
• decreased frequency or amount of urine
• diarrhea
• difficult or labored breathing
• difficulty swallowing
• dizziness
• dry mouth
• fast heartbeat
• fast, shallow breathing
• fever
• flushed, dry skin
• fruit-like breath odor
• general feeling of discomfort
• hives, itching, skin rash
• increased hunger
• increased thirst
• increased urination
• indigestion
• irregular heartbeat
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• light-colored stools
• loss of appetite
• lower back or side pain
• mood changes
• muscle cramps, spasms, pain, or stiffness
• nausea
• numbness or tingling in the hands, feet, or lips
• pain
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• seizures
• sleepiness
• stomach pain or discomfort
• swelling of the face, fingers, lower legs
• trouble breathing
• unexplained weight loss
• unusual bleeding or bruising
• unusual tiredness or weakness
• upper right abdominal or stomach pain
• vomiting
• weight gain
• yellow eyes or skin

Other side effects

Some side effects of doravirine / lamivudine / tenofovir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Trouble sleeping

Less common

• Abnormal dreams

Incidence not known

• Accumulation of body fat
• lack or loss of strength
• thinning or loss of hair

For Healthcare Professionals

Applies to doravirine / lamivudine / tenofovir: oral tablet.

General

The safety of this drug in patients with no antiretroviral treatment history was assessed in 2 phase 3 trials; patients received doravirine either as a single component in combination with other antiretroviral drugs as background regimens or as a component of this combination drug. Most (66%) side effects associated with this combination drug were of mild severity (grade 1).

The safety of this combination drug in virologically-suppressed patients was assessed in a trial where virologically-suppressed patients were switched from a baseline regimen to this combination drug; overall, the safety profile in virologically-suppressed patients was similar to the safety profile in patients with no antiretroviral treatment history.

Unless otherwise specified, the side effects provided below were reported during the trial using this combination drug.^[Ref]

Psychiatric

Most patients reported neuropsychiatric side effects as mild to moderate in severity; such events were mostly reported in the first 4 weeks of therapy. The prevalence of neuropsychiatric side effects through week 4, at week 48, and at week 96 was 17%, 12%, and 13%, respectively. This drug was discontinued due to neuropsychiatric side effects in 1% of patients.^[Ref]

Very common (10% or more): Neuropsychiatric side effects (up to 24%), sleep disorders and disturbances (included abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism; 12%)

Common (1% to 10%): Abnormal dreams, insomnia (included insomnia, initial insomnia, sleep disorder), depression, suicide/self-injury

Uncommon (0.1% to 1%): Nightmare, depression (included depression, depressed mood, major depression, persistent depressive disorder), anxiety (included anxiety, generalized anxiety disorder), irritability, confusional state, suicidal ideation

Rare (0.01% to 0.1%): Aggression, hallucination, adjustment disorder, altered mood, somnambulism^[Ref]

Hepatic

Increased total bilirubin (1.1 to less than 1.6 times the upper limit of normal [1.1 to less than 1.6 x ULN]: 5%; 1.6 to less than 2.6 x ULN: 2%; at least 2.6 x ULN: 1%), ALT (2.5 to less than 5 x ULN: 4%; at least 5 x ULN: 1%), and AST (2.5 to less than 5 x ULN: 3%; at least 5 x ULN: 1%) have been reported.

In virologically-suppressed patients, 22% and 16% of patients in the immediate switch group had ALT and AST elevations greater than 1.25 x ULN, respectively, through 48 weeks on this combination drug; 1% of patients had ALT or AST elevations greater than 5 x ULN through 48 weeks. No apparent patterns were observed regarding time to onset of these elevations relative to switch. In general, the ALT and AST elevations were asymptomatic and not associated with elevated bilirubin.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Severe acute exacerbations of hepatitis B (e.g., liver decompensated, liver failure) have been reported in patients coinfected with HIV-1 and hepatitis B virus after discontinuation of products containing lamivudine and/or tenofovir DF.^[Ref]

Very common (10% or more): Increased ALT (included increased ALT, hepatocellular injury; up to 22%), increased AST (up to 16%)

Common (1% to 10%): Increased total bilirubin

Lamivudine and/or tenofovir disoproxil fumarate (DF):

-Rare (0.01% to 0.1%): Hepatic steatosis, hepatitis

Lamivudine:

-Postmarketing reports: Hepatic steatosis, posttreatment exacerbations of hepatitis B (e.g., liver decompensated, liver failure)

Tenofovir DF:

-Frequency not reported: Posttreatment exacerbation of hepatitis B

-Postmarketing reports: Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, GGT)^[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache, altered sensorium (included altered state of consciousness, lethargy, somnolence, syncope), somnolence

Uncommon (0.1% to 1%): Disturbance in attention, memory impairment, paresthesia, hypertonia, poor quality sleep

Lamivudine and/or tenofovir DF:

-Very rare (less than 0.01%): Peripheral neuropathy/paresthesia^[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, diarrhea, increased lipase, abdominal pain (included abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, epigastric discomfort), vomiting, flatulence

Uncommon (0.1% to 1%): Constipation, abdominal discomfort (included abdominal discomfort, epigastric discomfort), abdominal distension, dyspepsia, soft feces (included soft feces, abnormal feces), gastrointestinal motility disorder (included gastrointestinal motility disorder, frequent bowel movements), increased amylase

Rare (0.01% to 0.1%): Rectal tenesmus

Lamivudine and/or tenofovir DF:

-Uncommon (0.1% to 1%): Pancreatitis

Tenofovir DF:

-Postmarketing reports: Pancreatitis, increased amylase, abdominal pain^[Ref]

Increased lipase (1.5 to less than 3 x ULN: 6%; at least 3 x ULN: 2%) has been reported.^[Ref]

Other

Increased alkaline phosphatase (2.5 to less than 5 x ULN: less than 1%), fasted cholesterol (at least 300 mg/dL: 1%), fasted LDL cholesterol (at least 190 mg/dL: less than 1%), and fasted triglycerides (greater than 500 mg/dL: 1%) have been reported.

Fasting lipids changed from baseline to week 48 in patients with no antiretroviral treatment history; changes included increased HDL cholesterol and reduced LDL cholesterol, non-HDL cholesterol, total cholesterol, and triglycerides. Changes from baseline to week 96 were similar to changes seen at week 48.

Fasting lipids changed from baseline to week 24 in virologically-suppressed patients who switched to this combination drug; changes included decreased LDL cholesterol, non-HDL cholesterol, total cholesterol, triglycerides, and HDL cholesterol.^[Ref]

Common (1% to 10%): Fatigue (included fatigue, asthenia, malaise)

Uncommon (0.1% to 1%): Asthenia, malaise

Rare (0.01% to 0.1%): Chest pain, chills, pain

Frequency not reported: Increased alkaline phosphatase, increased fasted cholesterol, increased fasted low-density lipoprotein (LDL) cholesterol, increased fasted triglycerides, fasting lipids changed from baseline (including LDL cholesterol, non-high-density lipoprotein [HDL] cholesterol, total cholesterol, triglycerides, HDL cholesterol)

Lamivudine and/or tenofovir DF:

-Common (1% to 10%): Fever

Lamivudine:

-Postmarketing reports: Weakness

Tenofovir DF:

-Postmarketing reports: Asthenia^[Ref]

Renal

Increased creatinine (greater than 1.3 to 1.8 x ULN or increased greater than 0.3 mg/dL above baseline: 3%; greater than 1.8 x ULN or increased at least 1.5 x above baseline: 3%) has been reported.

Rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, and hypophosphatemia have occurred as a result of proximal renal tubulopathy.^[Ref]

Common (1% to 10%): Increased creatinine

Rare (0.01% to 0.1%): Acute kidney injury, renal disorder, nephrolithiasis

Lamivudine and/or tenofovir DF:

-Uncommon (0.1% to 1%): Increased creatinine, proximal renal tubulopathy (including Fanconi syndrome)

-Rare (0.01% to 0.1%): Acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial), nephrogenic diabetes insipidus

Tenofovir DF:

-Postmarketing reports: Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine^[Ref]

Musculoskeletal

Increased creatine kinase (6 to less than 10 x ULN: 3%; at least 10 x ULN: 4%) has been reported.

Rhabdomyolysis, osteomalacia, muscular weakness, and myopathy have occurred as a result of proximal renal tubulopathy.^[Ref]

Common (1% to 10%): Increased creatine kinase

Uncommon (0.1% to 1%): Myalgia, arthralgia

Rare (0.01% to 0.1%): Musculoskeletal pain

Lamivudine and/or tenofovir DF:

-Common (1% to 10%): Muscle disorders

-Uncommon (0.1% to 1%): Rhabdomyolysis, muscular weakness

-Rare (0.01% to 0.1%): Osteomalacia (manifested as bone pain and infrequently contributing to fractures), myopathy

Lamivudine:

-Postmarketing reports: Muscle weakness, elevated creatine phosphokinase, rhabdomyolysis

Tenofovir DF:

-Frequency not reported: Decreased bone mineral density, increased biochemical markers of bone metabolism

-Postmarketing reports: Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy^[Ref]

Dermatologic

Common (1% to 10%): Rash (included rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, urticarial)

Uncommon (0.1% to 1%): Pruritus

Rare (0.01% to 0.1%): Pustular rash, allergic dermatitis, rosacea

Lamivudine and/or tenofovir DF:

-Common (1% to 10%): Alopecia

-Rare (0.01% to 0.1%): Angioedema

Lamivudine:

-Postmarketing reports: Urticaria, alopecia, pruritus

Tenofovir DF:

-Postmarketing reports: Rash^[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Hypertension^[Ref]

Hematologic

Uncommon (0.1% to 1%): Decreased hemoglobin

Lamivudine and/or tenofovir DF:

-Uncommon (0.1% to 1%): Neutropenia, anemia, thrombocytopenia

-Very rare (less than 0.01%): Pure red cell aplasia

Lamivudine:

-Postmarketing reports: Anemia (including pure red cell aplasia and severe anemias progressing on therapy)^[Ref]

Metabolic

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Hypokalemia and hypophosphatemia have occurred as a result of proximal renal tubulopathy.^[Ref]

Uncommon (0.1% to 1%): Hypophosphatemia

Rare (0.01% to 0.1%): Hypomagnesemia, thirst

Lamivudine and/or tenofovir DF:

-Uncommon (0.1% to 1%): Hypokalemia

-Rare (0.01% to 0.1%): Lactic acidosis

Lamivudine:

-Postmarketing reports: Redistribution/accumulation of body fat, hyperglycemia, lactic acidosis

Tenofovir DF:

-Frequency not reported: Higher 1,25 vitamin D levels

-Postmarketing reports: Lactic acidosis, hypokalemia, hypophosphatemia^[Ref]

Respiratory

Rare (0.01% to 0.1%): Dyspnea, tonsillar hypertrophy

Lamivudine and/or tenofovir DF:

-Common (1% to 10%): Cough, nasal symptoms

Tenofovir DF:

-Postmarketing reports: Dyspnea^[Ref]

Genitourinary

Rare (0.01% to 0.1%): Urinary calculus

Tenofovir DF:

-Postmarketing reports: Proteinuria, polyuria^[Ref]

Hypersensitivity

Lamivudine:

-Postmarketing reports: Anaphylaxis

Tenofovir DF:

-Postmarketing reports: Allergic reaction (including angioedema)^[Ref]

Endocrine

Tenofovir DF:

-Frequency not reported: Higher serum parathyroid hormone levels^[Ref]

Immunologic

Combination antiretroviral therapy:

-Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome, autoimmune hepatitis)^[Ref]