Applies to dolutegravir / lamivudine: oral tablet.

Serious side effects

Along with its needed effects, dolutegravir / lamivudine 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 dolutegravir / lamivudine:

Less common

• Black, tarry stools
• bleeding gums
• bloody urine
• chills
• cough
• dark urine
• decreased frequency or amount of urine
• fast heartbeat
• fever
• hives, itching, skin rash
• hoarseness
• increased blood pressure
• increased thirst
• irritation
• joint pain, stiffness, or swelling
• light-colored stools
• loss of appetite
• lower back or side pain
• nausea
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• redness of the skin
• sore throat
• stomach discomfort or pain
• swelling of the eyelids, face, lips, hands, or feet
• tightness in the chest
• trouble breathing or swallowing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• upper right abdominal or stomach pain
• vomiting
• weight gain
• yellow eyes and skin

Incidence not known

• Blurred vision
• diarrhea
• dry mouth
• fast, shallow breathing
• flushed, dry skin
• fruit-like breath odor
• headache
• increased hunger
• increased urination
• light-colored stools
• muscle cramps, pain, stiffness, or spasms
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• sleepiness
• stomach pain, continuing
• sweating
• unexplained weight loss
• unsteadiness or awkwardness
• weakness in the arms, hands, legs, or feet

Other side effects

Some side effects of dolutegravir / lamivudine 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:

Less common

• Abnormal dreams
• anxiety
• bloated or full feeling
• discouragement
• dizziness
• excess air or gas in the stomach or bowels
• feeling sad or empty
• headache
• loss of interest or pleasure
• passing gas
• thoughts or attempts at killing oneself
• trouble concentrating
• trouble sleeping

Incidence not known

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• difficulty in moving
• hair loss or thinning of hair
• redistribution of body fat

For Healthcare Professionals

Applies to dolutegravir / lamivudine: oral tablet.

Nervous system

Very common (10% or more): Headache (up to 11%)

Common (1% to 10%): Dizziness, somnolence

Dolutegravir:

-Very common (10% or more): Headache

-Common (1% to 10%): Dizziness

Lamivudine:

-Common (1% to 10%): Headache

-Postmarketing reports: Paresthesia, peripheral neuropathy^[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 12%)

Common (1% to 10%): Elevated lipase, nausea, hemorrhoids, abdominal pain, gastroenteritis

Dolutegravir:

-Very common (10% or more): Nausea, diarrhea

-Common (1% to 10%): Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting

Lamivudine:

-Common (1% to 10%): Nausea, vomiting, upper abdominal pain, diarrhea

-Postmarketing reports: Pancreatitis, elevated serum amylase^[Ref]

Grade 2 (greater than 1.5 to 3 times the upper limit of normal [1.5 to 3 x ULN]) and grade 3 to 4 (greater than 3 x ULN) elevated lipase have been reported in 6% and 2% of patients, respectively.^[Ref]

Respiratory

Common (1% to 10%): Nasopharyngitis, upper respiratory tract infection, pharyngitis, bronchitis, influenza, tonsillitis, sinusitis, oropharyngeal pain, cough

Metabolic

Common (1% to 10%): Hyperglycemia, hypophosphatemia, vitamin D deficiency

Dolutegravir or lamivudine:

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

Lamivudine:

-Postmarketing reports: Hyperlactatemia, lactic acidosis

Antiretroviral therapy:

-Frequency not reported: Increased glucose levels^[Ref]

Grade 2 (glucose 126 to 250 mg/dL [6.95 to 13.89 mmol/L]) and grade 3 to 4 (glucose greater than 250 mg/dL [greater than 13.89 mmol/L]) hyperglycemia have been reported in up to 9% and up to 1% of patients, respectively. Grade 2 (phosphate 1.4 to less than 2 mg/dL [0.65 to 0.81 mmol/L]) and grade 3 to 4 (phosphate less than 1.4 mg/dL [less than 0.65 mmol/L]) hypophosphatemia have been reported in up to 9% and up to 1% of patients, respectively.

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

Musculoskeletal

Common (1% to 10%): Elevated creatine phosphokinase (CPK), back pain, arthralgia

Frequency not reported: Myositis

Dolutegravir or lamivudine:

-Postmarketing reports: Arthralgia, elevated CPK, muscle weakness, myalgia, rhabdomyolysis

Dolutegravir:

-Frequency not reported: Asymptomatic CPK elevations (mainly associated with exercise)

-Postmarketing reports: Arthralgia, myalgia

Lamivudine:

-Postmarketing reports: Arthralgia, muscle disorders, rhabdomyolysis

Combination antiretroviral therapy:

-Frequency not reported: Osteonecrosis^[Ref]

Grade 2 (6 to less than 10 x ULN) and grade 3 to 4 (at least 10 x ULN) elevated CPK have been reported in 4% and up to 6% of patients, respectively.^[Ref]

Psychiatric

Suicidal ideation, attempt, behavior, or completion were reported primarily in patients with history of depression or other psychiatric illness.^[Ref]

Common (1% to 10%): Insomnia, depression, anxiety

Frequency not reported: Suicidal ideation/attempt/behavior/completion

Dolutegravir:

-Common (1% to 10%): Abnormal dreams, suicidal ideation, depression, anxiety, insomnia

-Uncommon (0.1% to 1%): Suicide attempt^[Ref]

Other

Common (1% to 10%): Fatigue (includes fatigue, asthenia, malaise), syphilis, gonorrhea, influenza-like illness, pyrexia/fever, anogenital warts

Frequency not reported: Fasted lipid values increased (including cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides), total cholesterol/HDL cholesterol ratio decreased

Dolutegravir or lamivudine:

-Postmarketing reports: Weakness, weight increased

Dolutegravir:

-Common (1% to 10%): Fatigue

-Postmarketing reports: Weight increased

Lamivudine:

-Common (1% to 10%): Fatigue, malaise, fever

Antiretroviral therapy:

-Frequency not reported: Increased weight, increased blood lipid levels^[Ref]

Hepatic

Common (1% to 10%): Elevated ALT, elevated AST, elevated total bilirubin

Rare (0.01% to 0.1%): Increased bilirubin (in combination with increased transaminases)

Dolutegravir or lamivudine:

-Postmarketing reports: Hepatic steatosis, posttreatment exacerbations of hepatitis B virus (HBV), acute liver failure, hepatotoxicity

Dolutegravir:

-Uncommon (0.1% to 1%): Hepatitis

-Frequency not reported: Transaminase/liver chemistry elevations (consistent with immune reconstitution syndrome or hepatitis B reactivation), hepatic toxicity (including elevated serum liver biochemistries, hepatitis, acute liver failure)

-Postmarketing reports: Acute hepatic failure

Lamivudine:

-Uncommon (0.1% to 1%): Transient elevated liver enzymes (AST, ALT)

-Postmarketing reports: Acute hepatic failure^[Ref]

Grade 2 (2.5 to less than 5 x ULN) and grade 3 to 4 (at least 5 x ULN) elevated ALT have been reported in up to 3% and 3% of patients, respectively. Grade 2 (2.5 to less than 5 x ULN) and grade 3 to 4 (at least 5 x ULN) elevated AST have been reported in up to 4% and up to 3% of patients, respectively. Grade 2 (1.6 to less than 2.6 x ULN) and grade 3 to 4 (at least 2.6 x ULN) elevated total bilirubin have been reported in up to 2% and up to 1% of patients, respectively.

Small elevations in total bilirubin (without clinical jaundice) were reported; such changes were not considered clinically relevant.

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

Severe acute exacerbations of HBV have been reported in patients coinfected with HBV and HIV-1 after discontinuation of lamivudine-containing products.

Transaminase/liver chemistry elevations were consistent with immune reconstitution syndrome or hepatitis B reactivation in some patients with underlying hepatitis B and/or C, especially when antihepatitis therapy was stopped.^[Ref]

Dermatologic

Common (1% to 10%): Rash, pruritus, alopecia, herpes zoster

Rare (0.01% to 0.1%): Angioedema

Dolutegravir or lamivudine:

-Postmarketing reports: Urticaria, alopecia

Dolutegravir:

-Common (1% to 10%): Pruritus, rash

Lamivudine:

-Common (1% to 10%): Rash

-Postmarketing reports: Alopecia^[Ref]

Immunologic

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

Dolutegravir:

-Uncommon (0.1% to 1%): Immune reconstitution syndrome^[Ref]

Hematologic

Dolutegravir or lamivudine:

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

Lamivudine:

-Uncommon (0.1% to 1%): Anemia, neutropenia, thrombocytopenia

-Postmarketing reports: Pure red cell aplasia^[Ref]

Hypersensitivity

Dolutegravir or lamivudine:

-Postmarketing reports: Anaphylaxis

Dolutegravir:

-Uncommon (0.1% to 1%): Hypersensitivity/hypersensitivity reactions (characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury)^[Ref]

Renal

Dolutegravir was shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increased serum creatinine was reported within the first 4 weeks of therapy and remained stable through 96 weeks. A mean change from baseline of 10.3 mcmol/L (range: -36.3 mcmol/L to 55.7 mcmol/L) was reported after 48 weeks of therapy with dolutegravir plus lamivudine; a mean change from baseline of 0.138 mg/dL was reported after 96 weeks of therapy with dolutegravir plus lamivudine. These changes were not considered clinically relevant.^[Ref]

Frequency not reported: Renal impairment, increased serum creatinine (due to inhibition of tubular secretion of creatinine)^[Ref]