Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Treatment of HIV infected adults and adolescents (aged 12 years and older weighing at least 35kg) without known mutations associated with resistance to atazanavir.

Contraindications

Children under 12 years
Children weighing less than 35kg
Breastfeeding
Haemodialysis
Long QT syndrome
Moderate hepatic impairment
Pregnancy
Torsade de pointes

Precautions and Warnings

Family history of long QT syndrome
Females of childbearing potential
Bradycardia
Electrolyte imbalance
Haemophilia
Hepatitis B
Hepatitis C
History of hepatic disorder
History of torsade de pointes
Mild hepatic impairment

Correct electrolyte disorders before treatment
Switch to more suitable alternative before planned pregnancy
Treatment does not prevent risk of transmission of HIV
Advise patient dizziness may affect ability to drive or operate machinery
Combination therapy: refer to information for concomitant agent
HIV therapy: Must be used in combination with other antiretrovirals
Perform viral resistance testing before initiating therapy
Treatment should be initiated by doctor experienced in HIV management
Advise patient to take with or after food
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Consider monitoring ECG in patients at risk of QT prolongation
Monitor for signs of osteonecrosis
Monitor renal function regularly
Monitor serum electrolytes
Advise patient to report skin reaction, pain, erythema, pruritus
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Consider discontinuation if symptoms of cholelithiasis occur
Discontinue or interrupt therapy if nephrolithiasis occurs
Inflammatory symptoms should be evaluated and treated appropriately
May cause hyperbilirubinaemia
May develop immune reactivation syndrome
Risk of developing opportunistic infections
Advise patient to seek advice at first indications of pregnancy
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Advise patient not to take St John's wort concurrently
Advise patient to avoid antacids 1 hour before and 2 hours after dose
Advise patient grapefruit products may increase plasma level
Female: Barrier or non-hormonal contraception advised during treatment
Female: Oral contraception may not be adequate during treatment

The choice of therapy should be based on individual viral resistance testing and the treatment history of the patient.

Hepatitis

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted. If hepatic disease worsens in these patients, interruption or discontinuation of therapy should be considered.

Haemophiliac patients

Increased bleeding, including spontaneous skin haematomas and haemarthroses, have been reported in type A and B haemophiliac patients treated with protease inhibitors. Additional factor VIII was required in some patients. In more than half of all reported cases, treatment was continued or reintroduced after discontinuation. Haemophiliac patients should be made aware of the possibility of increased bleeding.

Weight and metabolic parameters

Weight, blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

Hyperbilirubinaemia

Reversible elevations of indirect bilirubin have occurred in patients receiving atazanavir, any rise in hepatic transaminase that occurs with bilirubin elevations should be evaluated for alternative causes.
Alternative antiretroviral therapy should be considered if the patient views jaundice or scleral icterus as unacceptable.

Immune reactivation syndrome

An inflammatory reaction to asymptomatic or residual opportunistic pathogens, causing serious clinical conditions or aggravation of symptoms, could be expected in HIV-infected patients with severe immune deficiency at the time of the initiation of combination antiretroviral therapy (CART). Such reactions have been usually observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders, such as Graves' disease and autoimmune hepatitis, have also been observed. The reported time to onset is more variable in theses cases and can occur many months after initiation of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported especially in patients with advance HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, join stiffness or difficulty in movement.

Rash and associated syndromes

Mild to moderate maculopapular skin eruptions can occur usually within the first 3 weeks of starting therapy with atazanavir. Patients should be monitored closely and advised of the signs and symptoms of more serious rashes. Atazanavir should be discontinued if severe rash develops. If the patient develops Stevens-Johnson syndrome or DRESS due to atazanavir with cobicistat, atazanavir with cobicistat may not be restarted. Patients should be advised of the signs and symptoms to watch out for and be monitored closely for skin reactions, the best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines.

Pregnancy and Lactation

Pregnancy

Atazanavir with cobicistat is contraindicated during pregnancy.

At the time of writing, there are limited data from the use of atazanavir with cobicistat in pregnant women.

The manufacturer advises that treatment with atazanavir with cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with this agent should be switched to an alternative regime.

Animal studies with atazanavir with cobicistat are insufficient with respect to reproductive toxicity.

Because pregnancy is a risk factor for hyperglycaemia, there is a concern that antiviral agents would exacerbate this risk.

Since some reviews conclude that the expected benefit of the treatment to the HIV-positive mother outweighs the unknown risk to the fetus, it is suggested (Briggs 2015) that protease inhibitors should not be withheld.

Known effects of atazanavir during pregnancy

Treatment with atazanavir and cobicistat during the second and third trimester has been shown to result in low atazanavir exposure, compared to postpartum.

Animal data suggest low risk to the developing fetus.

It is not known if administration of atazanavir to pregnant women will exacerbate physiological hyperbilirubinaemia, which may lead to kernicterus in neonates and infants.

Known effects of cobicistat during pregnancy

As plasma levels of cobicistat and consequently of atazanavir (lower exposures of co-administered antiretroviral agents) may decrease significantly during pregnancy, which may result in virological failure and increase the risk of transmission of HIV from the mother to infant.

Lactation

Atazanavir with cobicistat is contraindicated in breastfeeding.

The manufacturer does not recommend breastfeeding whilst taking atazanavir with cobicistat because of both the potential for HIV transmission and the risk of serious adverse reactions in the nursing infant.

Atazanavir is excreted into human breast milk. The effect on a nursing infant from this exposure is unknown. It is not known also, if metabolites of cobicistat are excreted in human milk. Animal studies have shown excretion of cobicistat/metabolites in milk.

Side Effects

Abdominal distension
Abdominal pain
Alanine aminotransferase increased
Alopecia
Amnesia
Angioedema
Anorexia
Anxiety
Arthralgia
Aspartate aminotransferase increased
Asthenia
Autoimmune hepatitis
Blood lipid changes
Chest pain
Cholecystitis
Cholelithiasis
Cholestasis
Chronic kidney disease
Creatine kinase increased
Decrease in creatinine clearance
Depression
Diarrhoea
Disorientation
Dizziness
Dream abnormalities
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dry mouth
Dysgeusia
Dyslipidaemia
Dyspepsia
Dyspnoea
Eczema
Elevated serum lipase
Erythema multiforme
Fatigue
Flatulence
Gait abnormality
Gastritis
Graves' disease
Gynaecomastia
Haematuria
Headache
Hepatitis
Hepatosplenomegaly
Hyperbilirubinaemia
Hyperglycaemia
Hypersensitivity reactions
Hypertension
Increased appetite
Insomnia
Interstitial nephritis
Jaundice
Low neutrophil count
Malaise
Muscular atrophy
Myalgia
Myopathy
Nausea
Nephrolithiasis
Oedema
Osteonecrosis
Palpitations
Pancreatitis
Peripheral neuropathy
Pollakiuria
Prolongation of QT interval
Proteinuria
Pruritus
Pyrexia
Rash
Renal disorders
Renal pain
Scleral icterus
Skin eruption
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Stomatitis
Syncope
Torsades de pointes
Urticaria
Vasodilatation
Vesiculo-bullous reactions
Vomiting
Weight changes

Presentation

Oral formulations of atazanavir (as sulfate) with cobicistat.

Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Treatment of HIV infected adults and adolescents (aged 12 years and older weighing at least 35kg) without known mutations associated with resistance to atazanavir.

Dosage

Atazanavir with cobicistat is used in combination with other antiretrovirals, therefore the product information of any other co-administered products should be consulted.

Adults

Children

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Children under 12 years
Children weighing less than 35kg
Breastfeeding
Haemodialysis
Long QT syndrome
Moderate hepatic impairment
Pregnancy
Torsade de pointes

Precautions and Warnings

Family history of long QT syndrome
Females of childbearing potential
Bradycardia
Electrolyte imbalance
Haemophilia
Hepatitis B
Hepatitis C
History of hepatic disorder
History of torsade de pointes
Mild hepatic impairment

Correct electrolyte disorders before treatment
Switch to more suitable alternative before planned pregnancy
Treatment does not prevent risk of transmission of HIV
Advise patient dizziness may affect ability to drive or operate machinery
Combination therapy: refer to information for concomitant agent
HIV therapy: Must be used in combination with other antiretrovirals
Perform viral resistance testing before initiating therapy
Treatment should be initiated by doctor experienced in HIV management
Advise patient to take with or after food
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Consider monitoring ECG in patients at risk of QT prolongation
Monitor for signs of osteonecrosis
Monitor renal function regularly
Monitor serum electrolytes
Advise patient to report skin reaction, pain, erythema, pruritus
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Consider discontinuation if symptoms of cholelithiasis occur
Discontinue or interrupt therapy if nephrolithiasis occurs
Inflammatory symptoms should be evaluated and treated appropriately
May cause hyperbilirubinaemia
May develop immune reactivation syndrome
Risk of developing opportunistic infections
Advise patient to seek advice at first indications of pregnancy
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Advise patient not to take St John's wort concurrently
Advise patient to avoid antacids 1 hour before and 2 hours after dose
Advise patient grapefruit products may increase plasma level
Female: Barrier or non-hormonal contraception advised during treatment
Female: Oral contraception may not be adequate during treatment

The choice of therapy should be based on individual viral resistance testing and the treatment history of the patient.

Hepatitis

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted. If hepatic disease worsens in these patients, interruption or discontinuation of therapy should be considered.

Haemophiliac patients

Increased bleeding, including spontaneous skin haematomas and haemarthroses, have been reported in type A and B haemophiliac patients treated with protease inhibitors. Additional factor VIII was required in some patients. In more than half of all reported cases, treatment was continued or reintroduced after discontinuation. Haemophiliac patients should be made aware of the possibility of increased bleeding.

Weight and metabolic parameters

Weight, blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

Hyperbilirubinaemia

Reversible elevations of indirect bilirubin have occurred in patients receiving atazanavir, any rise in hepatic transaminase that occurs with bilirubin elevations should be evaluated for alternative causes.
Alternative antiretroviral therapy should be considered if the patient views jaundice or scleral icterus as unacceptable.

Immune reactivation syndrome

An inflammatory reaction to asymptomatic or residual opportunistic pathogens, causing serious clinical conditions or aggravation of symptoms, could be expected in HIV-infected patients with severe immune deficiency at the time of the initiation of combination antiretroviral therapy (CART). Such reactions have been usually observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders, such as Graves' disease and autoimmune hepatitis, have also been observed. The reported time to onset is more variable in theses cases and can occur many months after initiation of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported especially in patients with advance HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, join stiffness or difficulty in movement.

Rash and associated syndromes

Mild to moderate maculopapular skin eruptions can occur usually within the first 3 weeks of starting therapy with atazanavir. Patients should be monitored closely and advised of the signs and symptoms of more serious rashes. Atazanavir should be discontinued if severe rash develops. If the patient develops Stevens-Johnson syndrome or DRESS due to atazanavir with cobicistat, atazanavir with cobicistat may not be restarted. Patients should be advised of the signs and symptoms to watch out for and be monitored closely for skin reactions, the best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines.

Pregnancy and Lactation

Pregnancy

Atazanavir with cobicistat is contraindicated during pregnancy.

At the time of writing, there are limited data from the use of atazanavir with cobicistat in pregnant women.

The manufacturer advises that treatment with atazanavir with cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with this agent should be switched to an alternative regime.

Animal studies with atazanavir with cobicistat are insufficient with respect to reproductive toxicity.

Because pregnancy is a risk factor for hyperglycaemia, there is a concern that antiviral agents would exacerbate this risk.

Since some reviews conclude that the expected benefit of the treatment to the HIV-positive mother outweighs the unknown risk to the fetus, it is suggested (Briggs 2015) that protease inhibitors should not be withheld.

Known effects of atazanavir during pregnancy

Treatment with atazanavir and cobicistat during the second and third trimester has been shown to result in low atazanavir exposure, compared to postpartum.

Animal data suggest low risk to the developing fetus.

It is not known if administration of atazanavir to pregnant women will exacerbate physiological hyperbilirubinaemia, which may lead to kernicterus in neonates and infants.

Known effects of cobicistat during pregnancy

As plasma levels of cobicistat and consequently of atazanavir (lower exposures of co-administered antiretroviral agents) may decrease significantly during pregnancy, which may result in virological failure and increase the risk of transmission of HIV from the mother to infant.

Lactation

Atazanavir with cobicistat is contraindicated in breastfeeding.

The manufacturer does not recommend breastfeeding whilst taking atazanavir with cobicistat because of both the potential for HIV transmission and the risk of serious adverse reactions in the nursing infant.

Atazanavir is excreted into human breast milk. The effect on a nursing infant from this exposure is unknown. It is not known also, if metabolites of cobicistat are excreted in human milk. Animal studies have shown excretion of cobicistat/metabolites in milk.

Counselling

Advise patient to take tablet with food. Swallow tablet whole, it must not be chewed, broken or crushed.

Advise patient to avoid antacids 1 hour before and 2 hours after dose.

Advise patient to avoid taking St John's wort concurrently.

Advise patient to avoid grapefruit products.

Advise patient to seek medical advice if movement becomes difficult or joint aches or pains occur.

Advise patient to report any rashes that occur during treatment for assessment.

Advise patient dizziness may affect ability to drive or operate machinery.

Advise the patient to seek advice at first indications of pregnancy.

Side Effects

Abdominal distension
Abdominal pain
Alanine aminotransferase increased
Alopecia
Amnesia
Angioedema
Anorexia
Anxiety
Arthralgia
Aspartate aminotransferase increased
Asthenia
Autoimmune hepatitis
Blood lipid changes
Chest pain
Cholecystitis
Cholelithiasis
Cholestasis
Chronic kidney disease
Creatine kinase increased
Decrease in creatinine clearance
Depression
Diarrhoea
Disorientation
Dizziness
Dream abnormalities
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dry mouth
Dysgeusia
Dyslipidaemia
Dyspepsia
Dyspnoea
Eczema
Elevated serum lipase
Erythema multiforme
Fatigue
Flatulence
Gait abnormality
Gastritis
Graves' disease
Gynaecomastia
Haematuria
Headache
Hepatitis
Hepatosplenomegaly
Hyperbilirubinaemia
Hyperglycaemia
Hypersensitivity reactions
Hypertension
Increased appetite
Insomnia
Interstitial nephritis
Jaundice
Low neutrophil count
Malaise
Muscular atrophy
Myalgia
Myopathy
Nausea
Nephrolithiasis
Oedema
Osteonecrosis
Palpitations
Pancreatitis
Peripheral neuropathy
Pollakiuria
Prolongation of QT interval
Proteinuria
Pruritus
Pyrexia
Rash
Renal disorders
Renal pain
Scleral icterus
Skin eruption
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Stomatitis
Syncope
Torsades de pointes
Urticaria
Vasodilatation
Vesiculo-bullous reactions
Vomiting
Weight changes

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: March 2020.

Reference Sources

Summary of Product Characteristics: Evotaz 300mg/150mg tablets. Bristol-Myers Squibb Pharmaceuticals Ltd. Revised July 2021.

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.