Atazanavir/ Ritonavir

Registered South African indications:

• HIV infection

Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment
• Elderly
• Co-administration with anti-tuberculosis regimens containing rifampicin
• Co-administration with medicines highly dependent on CYP3A4 for clearance and for which elevated plasma
  concentrations are associated with serious or life-threatening diseases
• Coadministration with anti-dysrhythmics (e.g. digoxin,
  amiodarone, bepridil, flecainide, encainide, propafenone and quinidine)
• Coadministration with ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, ergonovine, methylergonovine)
• Coadministration with gastro-intestinal prokinetics (e.g. cisapride)
• Coadministration with antipsychotics (e.g. pimozide)
• Coadministration with sedatives and hypnotics (e.g. triazolam and midazolam)
• Coadministration with antifungals (e.g. ketoconazole,
  itraconazole and voriconazole)
• Coadministration with statins (e.g. lovastatin and simvastatin)
• Coadministration with anti-histamines
• Co-administration with products containing St. John's wort (Hypericum perforatum)

Cautions

Atazanavir/ Ritonavir

• Mild hepatic impairment
• Hepatitis (including hepatitis B and/or hepatitis C)
• Liver enzyme abnormalities (increased transaminases)
• Liver disease
• Hyperbilirubinaemia (bilirubin > 5 times the upper limit of normal (ULN))
• Underlying opportunistic diseases (and development of Immune Reconstitution Inflammatory Syndrome (IRIS))
• Long-term exposure to combination antiretroviral therapy
• Haemophilia type A and B
• Pre-existing conduction disorders
• Continued administration following loss of viral suppression
• Resistance/cross-resistance among protease inhibitors
• Lipid disorders
• Patients that smoke tobacco products
• Galactose intolerance e.g. galactosaemia
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Fructose intolerance
• May impair the ability to drive and operate heavy machinery

Atazanavir

• Diabetes mellitus
• Hyperglycaemia
• Diabetic ketoacidosis

Ritonavir

• Hepatitis
• Hepatic dysfunction
• Elevated transaminases
• Liver disease
• Hypertriglyceridemia
• Pancreatitis
• Coadministration of multiple medicines
• Patients with advanced HIV/AIDS

Forms avail. in SA and covered in this monograph: tab

HIV infection

Atazanavir/ Ritonavir

• Oral (tab): 300mg/100mg, dly

---

Not for use as monotherapy

---

Use recommended for treatment-naive or treatment-experienced patients with prior virologic failure

---

Each tablet must be taken with food

Forms avail. in SA and covered in this monograph: tab

HIV infection

Atazanavir/ Ritonavir

According to the Southern African HIV Clinicians Society's Antiretroviral Drug Dosing Chart for Children 2019

• Oral (tab): 300mg/100mg, dly (≥40 kg)

---

Target dose must be calculated based on weight band and given once daily

---

Not for use as monotherapy

---

Use recommended for treatment-naive or treatment-experienced patients with prior virologic failure

---

Each tablet must be taken with food

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Pregnancy

• Contraindicated
• Safety in pregnancy has not been established
• Patients should inform the healthcare professional if they are pregnant or are planning a pregnancy

Breastfeeding

• Contraindicated
• It is not known whether atazanavir/ ritonavir is secreted in human milk
• Because of both the potential for HIV transmission and the potential for serious adverse reactions in breastfed infants, mothers should be instructed not to breastfeed when taking atazanavir/ ritonavir
• It is not known whether atazanavir/ ritonavir given to mothers will exacerbate physiologic hyperbilirubinaemia and lead to kernicterus in neonates and young infants

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Mild: Caution; no dose adjustment recommended
  As the liver is the main organ of elimination of ritonavir, caution should be exercised when administering this medicine to patients with impaired liver function. Monitor liver enzyme values
• Moderate to severe: Contraindicated

Elderly

• Contraindicated
  The safety and efficacy in elderly patients has not been established

Porphyria Information

• Ritonavir: Porphyrinogenic (P)
• Atazanavir: Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Atazanavir/ Ritonavir

Cardiovascular Disorders

• PR interval prolongation
• First-degree atrioventricular block

Hepatobiliary Disorders

• Elevated transaminases
• Hyperbilirubinaemia

Genitourinary Disorders

• Nephrolithiasis

Musculoskeletal Disorders

• Oesteonecrosis
• Joint aches and stiffness
• Difficulty in joint movement

Skin and Subcutaneous Tissue disorders

• Rash
• Mild to moderate maculopapular skin eruptions
• Lipodystrophy
• Dorso-cervical fat enlargement

Immune, Blood and Lymphatic System Disorders

• Elevated total triglycerides and chlolestrol
• Elevated blood glucose
• Immune Reconstitution Inflammatory Syndrome (IRIS)
• Opportunistic infections

Others

• Peripheral wasting
• Breast enlargement
• Central obesity

Atazanavir

Central Nervous System Disorders

• Dizziness
• Headache
• Insomnia
• Sleep disorder
• Peripheral neurologic symptoms
• Abnormal dreams
• Amnesia
• Confusion and somnolence
• Abnormal gait
• Anxiety
• Depression 
• Asthenia
• Fatigue

Cardiovascular Disorders

• Hypertension
• Syncope
• Oedema
• Palpitation
• Vasodilation

Respiratory Disorders

• Pharyngitis

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Dyspepsia
• Nausea and vomiting
• Dry mouth
• Dysgeusia
• Flatulence
• Gastritis
• Pancreatitis
• Elevated lipase
• Elevated amylase
• Stomatitis aphthous
• Abdominal distension

Hepatobiliary Disorders

• Jaundice
• Hepatitis
• Hepatosplenomegaly
• Elevated total bilirubin
• Elevated ALT/SGPT
• Elevated AST/SGOT

Genitourinary Disorders

• Haematuria
• Pollakiuria
• Proteinuria
• Kidney pain
• Nephrolithiasis

Endocrine and Metabolic Disorders

• Anorexia
• Appetite increased
• Weight gain
• Weight decreased
• Diabetes melitus

Musculoskeletal Disorders

• Arthralgia
• Muscle atrophy
• Myalgia
• Myopathy

Skin and Subcutaneous Tissue Disorders

• Rash
• Lipodystrophy
• Alopecia
• Eczema
• Pruritus
• Urticaria
• Vesiculobullous rash
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Erythema mutiforme

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Low neutrophils
• Ecchymosis
• Leukopenia
• Lymphadenopathy
• Lymphocytosis
• Thrombocytopenia
• Allergic reaction
• Fever

Sensory Disorders

• Scleral icterus

Other

• Gynaecomastia
• Chest pain
• Elevated creatinine kinase (CK)

Ritonavir

Central Nervous System Disorders

• Headache
• Anxiety
• Insomnia
• Agitation
• Confusion
• Depression
• Emotional lability
• Euphoria
• Hallucinations
• Decreased libido
• Nervousness
• Personality disorder and abnormal thinking
• Circumoral paresthesia
• Peripheral paresthesia
• Hyperesthesia
• Dizziness
• Somnolence
• Abnormal dreams
• Amnesia
• Aphasia
• Ataxia
• Convulsion
• Grand mal convulsion
• Incoordination
• Neuralgia
• Neuropathy
• Paralysis
• Parosmia
• Peripheral neuropathy
• Tremor
• Asthenia
• Migraine
• Abnormal gait

Cardiovascular Disorders

• Orthostatic hypotension
• Palpitation
• Syncope
• Haemorrhage
• Hypotension
• Peripheral vascular disorder
• Tachycardia
• Myocardial infarction

Respiratory Disorders

• Increased cough
• Asthma
• Dyspnoea
• Epistaxis
• Hiccup
• Hypoventilation
• Interstitial pneumonia
• Lung disorder
• Rhinitis
• Bronchospasm

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Bloody diarrhoea
• Abnormal stool
• Anorexia
• Abdominal pain
• Dry mouth
• Dyspepsia
• Eructation
• Flatulence
• Local throat irritation
• Mouth ulcer
• Enlarged abdomen
• Cheilitis
• Colitis
• Constipation
• Dysphagia
• Pharyngitis
• Oesophagitis
• Gastritis
• Gastroenteritis
• Gastrointesinal disorder
• Gastrointestinal haemorrhage
• Gingivitis
• Ileitis
• Oral moniliasis
• Pancreatitis
• Periodontal abscess
• Rectal disorder
• Tenesmus
• Thirst

Hepatobiliary Disorders

• Cholangitis
• Hepatitis
• Hepatomegaly
• Liver damage
• Liver dysfunction
• Abnormal liver function test
• Elevated ALT/AST
• Elevated GGT

Genitourinary Disorders

• Dysuria
• Haematuria
• Kidney calculus
• Kidney failure
• Kidney pain
• Nocturia
• Polyuria
• Pyelonephritis
• Urethritis
• Urinary retention
• Impotence
• Penis disorder
• Menorrhagia

Endocrine and Metabolic Disorders

• Diabetes mellitus
• Anorexia
• Hyperlipemia
• Hypertriglyceridemia
• Weight loss
• Avitaminosis
• Cachexia
• Dehydration
• Oedema
• Glycosuria
• Gout
• Peripheral oedema
• Dehydration
• Altered hormone level

Musculoskeletal Disorders

• Myalgia
• Arthalgia
• Arthrosis
• Back pain
• Facial pain
• Joint disorder
• Muscle cramps
• Muscle weakness
• Myositis
• Neck pain
• Neck rigidity
• Rhabdomyolysis
• Twitching

Skin and Subcutaneous Tissue Disorders

• Rash
• Maculopapular rash
• Pruritus
• Sweating
• Acne
• Contact dermatitis
• Dry skin
• Eczema
• Facial oedema
• Folliculitis
• Molluscum contagiosum
• Photosensitivity reaction
• Psoriasis
• Seborrhoea
• Urticaria
• Skin eruptions
• Vesiculobullous rash
• Stevens-Johnson Syndrome
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Allergic reaction
• Anaphylaxis
• Fever
• Vasodilation
• Ecchymosis
• Lymphadenopathy
• Lymphocytosis
• Anaemia
• Leukopenia
• Thrombocytopenia

Sensory Disorders

• Peripheral sensory neuropathy
• Taste loss
• Taste perversion
• Visual field defect
• Abnormal vision
• Amblyopia/blurred vision
• Blephartis
• Diplopia
• Eye pain
• Iritis
• Photophobia
• Uveitis
• Abnormal electroretinogram
• Abnormal electro-oculogram
• Ear pain
• Hearing impairment
• Increased cerumen
• Tinnitus
• Vertigo

Other

• Chest pain
• Substernal chest pain
• Flu syndrome
• Chills
• Hypothermia
• Redistribution/accumulation of body fat
• Elevated CPK
• Elevated uric acid

Atazanavir/ Ritonavir

• CYP3A4 inducers
• Rifampicin
• CYP3A4 substates 
• CYP3A4 inhibitors
• Calcium channel blockers
• HMG-CoA reductase inhibitors
• Immunosuppressants
• PDE5 inhibitors
• Agents that induce PR interval prolongation
• Atenolol
• Diltiazem
• Verapamil

Atazanavir

• Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
• Didanosine
• Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
• Tenofovir
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Efavirenz
• Nevirapine
• Protease Inhibitors
• Saquinavir
• Ritonavir
• Indinavir
• Antidysrhythmics
• Lidocaine
• Amiodarone
• Quinine
• Antimycobacterials
• Rifampicin
• Rifabutin
• Antineoplastics
• Irinotecan
• Calcium channel blockers
• Bepridil
• Diltiazem
• Felodipine
• Nifedipine
• Nicardipine
• Verapamil
• Ergot derivatives
• Dihydroergotamine
• Ergotamine
• Ergonovine
• Methylergonovine
• Gastrointestinal motility agents
• Cisapride
• HMG-CoA reductase inhibitors
• Lovastatin
• Simvastatin
• Atorvastatin
• Neuroleptics
• Pimozide
• Proton-pump inhibitors
• Sedative hypnotics
• Midazolam
• Triazolam
• St John's Wort (Hypericum perforatum)
• Antacids and buffered medicines
• Anticoagulants
• Warfarin
• Antidepressants
• Tricyclic antidepressants
• Trazodone
• Antifungals
• Ketoconazole
• Itraconazole
• PDE5 inhibitors
• Sildenafil
• Tadalafil
• Vardenafil
• H-receptor antagonists
• Immunosuppressants
• Ciclosporin
• Tacrolimu
• Sirolimus
• Macrolide antibiotics
• Clarithromycin
• Oral contraceptives
• Ethinyloestradiol and norethindrone
• Ethinyloestradiol and a progestin

Ritonavir

• CYP3A4 inducers
• Phenobarbitone
• Carbamazepine
• Dexamethasone
• Phenytoin
• Rifampicin
• Rifabutin
• CYP3A4 substrates
• CYP2D6 substrates
• CYP2C9 substrates
• CYP2C19 substrates
• Glucuronidated medicines
• Inhaled/intranasal corticosteroids
• Fluticasone propionate
• HMG-CoA reductase inhibitors
• Simvastatin
• Lovastatin
• Atorvastatin
• PDE5 inhibitors
• Sildenafil
• Tadalafil
• Vardenafil
• Protease inhibitors
• Amprenavir
• Indinavir
• Oral or patch contraceptive
• Ethinyl estradiol
• St. John's Wort (Hypericum perforatum)
• Disopyramide
• Mexiletine
• Fluoxetine
• Alprazolam
• Desipramine
• Trazodone
• Buspirone
• Methadone
• Clarithromycin
• Ketoconazole
• Voriconazole
• Sulfamethoxazole/ trimethoprim
• Fusidic acid
• Delavirdine
• Didanosine
• Efavirenz
• Zidovudine
• Theophylline
• Digoxin
• Warfarin
• Tobacco

• Viral load
• CD4 count

Specific cases may require

• Liver function
• Elevated total bilirubin
• Serum lipase or amylase
• Total triglycerides and cholesterol
• Physical signs of fat redistribution
• Tenofovir-associated adverse events

Dosing

• Atazanavir should be given with food. Bioavailability of atazanavir sulphate (with or without the ritonavir boosted regimen) is enhanced if given with food and pharmacokinetic variability is reduced

Interaction profile

• When ritonavir-boosted atazanavir is given, the medicine interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir

Resistance/Cross-resistance to other protease inhibitors

• Varying degrees of cross-resistance among protease inhibitors may occur. Continued administration of atazanavir/ ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors
• The potential for HIV cross-resistance between protease inhibitors has not been fully explored. Therefore, it is unknown what effect atazanavir/ ritonavir therapy will have on the activity of concordantly or subsequently administered protease inhibitors
• Ritonavir is used as a pharmacokinetic enhancer (CYP3A4 inhibitor) and the low doses used for this purpose are not known to induce ritonavir resistance mutations

The risk of HIV transmission to others

• Patients should be advised that current antiretroviral therapy, including atazanavir/ ritonavir, does not necessarily prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed

Atazanavir

Atazanavir sulphate is an azapeptide HIV-1 protease inhibitor, with a C2-symmetrical chemical structure that is active against HIV-1 and HIV-2.

Ritonavir 

Ritonavir is a peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.

Tablet FCT 300mg/100mg 

• Riatem (Emcure Pharmaceuticals)
• Ritoataz (Emcure Pharmaceuticals) originator
• Tarito (Cipla Medpro)
• Zatonav (Mylan)