INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ASPEN ATAZANAVIR 150 mg (capsules)
ASPEN ATAZANAVIR 200 mg (capsules)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ASPEN ATAZANAVIR 150 mg (capsules)
ASPEN ATAZANAVIR 200 mg (capsules)

COMPOSITION:
Each ASPEN ATAZANAVIR 150 mg capsule contains the equivalent of 150 mg
atazanaviras atazanavir sulphate.
Each ASPEN ATAZANAVIR 200 mg capsule contains the equivalent of200 mg atazanavir as atazanavir sulphate.

PHARMACOLOGICAL CLASSIFICATION:
A 20.2.8 Antimicrobial (chemotherapeutic) agents. Antiviral agents.

PHARMACOLOGICAL ACTION:
Pharmacodynamic properties:
Mechanism of action:
Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI), which selectively inhibits the virus-specific proteolytic cleavage of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells thereby preventing formation of mature infectiousvirus particles.
Antiviral Activity In Vitro:
Atazanavir exhibits anti-HIV
-1activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells and MT-2 cells.
Atazanavir has activity against HIV-1 group M subtype viruses A, B, C, D, AE, AG, F, G and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9 to 32 nM), with EC
50values above the EC50values of failure isolates.
Resistance:
In vitro: HIV-1 isolates that were 93- to 183-fold resistant to atazanavir from three different viral strains were selected. The mutations in these viruses that contributed to atazanavir resistance included I50L, N88S, I84V, A71V and M46I. Recombinant viruses containing the I50L mutation were growth impaired and displayed increased in vitro susceptibility to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir).
Clinical Studies of Treatment-Naive Patients:
Atazanavir resistant clinical isolates from treatment-naive patients who experienced virologic failure developed an I50L mutation (after an average of 50 weeks of atazanavir therapy), often in combination with an A71V mutation.
Clinical studies of Treatment-Experienced patients:
Most atazanavir-resistant isolates from patients who experienced virologic failure developed mutations that were associated with resistance to multiple protease inhibitors and displayed decreased susceptibility to multiple protease inhibitors.
Cross-Resistance:
Cross-resistance among protease inhibitors has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of protease inhibitor-experienced patients demonstrated that isolates cross-resistant to multiple protease inhibitors were crossresistant to atazanavir. Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir/ritonavir therapy.
Pharmacokinetic properties:
The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily.
Absorption:
Atazanavir is rapidly absorbed with a Tmax of approximately 2,5 hours.
Atazanavir demonstrates non-linear pharmacokinetics with greater than dose-proportional increases in AUC and C
maxvalues over the dose range of 200 - 800 mg once daily. Steady-state is achieved between days 4 and 8, with an accumulation of approximately 2.3-fold.
Food Effect:
Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose of atazanavir with a light meal resulted in a 70% increase in AUC and 57% increase in C
maxrelative to the fasting state. Administration with a high fat meal resulted in a mean increase in AUC of 35% with no change in Cmaxrelative to the fasting state.
Distribution:
Atazanavir is 86% bound to human serum proteins (both alpha-1-acid glycoprotein (AAG) and albumin, to a similar extent). Protein binding is independent of concentration. In a multiple-dose study in HIV-infected patients dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.
Metabolism:
Atazanavir is extensively metabolised in the liver by CYP3A in humans. The major biotransformation pathways in humans are mono-oxygenation and di-oxygenation. Two minor metabolites of atazanavir in plasma have been characterised, but neither demonstrated in vitro antiviral activity.
Elimination:
Following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers and HIV-infected adult patients was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
Special Populations:
Age/Gender:
In a study of the pharmacokinetics of atazanavir in young andelderly healthy subjects, there were no clinically important pharmacokinetic differences observed due to age or gender.
Paediatrics:
There are insufficient data at this time to recommend a dose. ASPEN ATAZANAVIR should not be administered to paediatric patients below the age of 3 months due to the risk of kernicterus.
Impaired Renal Function:
The renal elimination of unchanged atazanavir was approximately 7% of the administered dose in healthy subjects. There are no pharmacokinetic data available on patients with impaired renal function.
Impaired Hepatic Function:
Atazanavir is primarily metabolised and eliminated by the liver. Atazanavir has been studied in adult subjects with moderate to severe hepatic impairment (Child-Pugh B and C grades) after a single 400 mg dose.
The mean AUC(0) - was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12,1 hours compared to 6,4 hours in healthy volunteers. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function. The pharmacokinetics of atazanavir in combination with ritonavir have not been studied in subjects with hepatic impairment.

INDICATIONS:
ASPEN ATAZANAVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The efficacy of ASPEN ATAZANAVIR has been demonstrated in antiretroviral-naive and treatment-experienced patients.

CONTRA-INDICATIONS:
Hypersensitivityto atazanavir or any of its excipients.

WARNINGS:
Co-administration of ASPEN ATAZANAVIR is contra-indicated with medicines that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/ or life-threatening events. These medicines include midazolam, triazolam, dihydroergotamine, ergotamine, ergonovine, methylergonovine, pimozide and cisapride (see "INTERACTIONS").
Severe hepatic impairment (Child-Pugh C) (SEE DOSAGE AND DIRECTIONS).

INTERACTIONS:
ASPEN ATAZANAVIR is an inhibitor of CYP3A, CYP2C8, and UGT1A1 and should therefore not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A, CYP2C8 or UGT1A1.
ASPEN ATAZANAVIR has been shown in vivonot to induce its own metabolism, nor to increase the biotransformation of some medicines metabolised by CYP3A.
Medicines that induce CYP3A activity may increase the clearance of atazanavir, resulting in lowered plasma concentrations. Co-administration of ASPEN ATAZANAVIR and other medicines that inhibit CYP3A may increase atazanavir plasma concentrations.
Co-administration of ASPEN ATAZANAVIR is contra-indicated with medicines that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (SEE CONTRA-INDICATIONS). These medicines include:
? Benzodiazepines: midazolam, triazolam: potential for prolonged or increased sedation or respiratory depression.
? Ergot Derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine: potential for acute ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
? Neuroleptic: pimozide: potential for cardiac arrhythmias.
? GI Motility Agent: cisapride: potential for cardiac arrhythmias.
The extent of CYP3A-mediated drug interactions may change when coadministered with ritonavir, a potent CYP3A inhibitor (refer to prescribing information for ritonavir).
Rifampicin is a potent inducer of CYP450 metabolism and when coadministered, substantially decreases plasma concentrations of ASPEN ATAZANAVIR. This may result in the loss of therapeutic efficacy and the development of resistance.
Concomitant use of ASPEN ATAZANAVIR and St. John's Wort (Hypericum perforatum) or products containing St. John's Wort is not recommended.
Co-administration is expected to substantially decrease concentrations of ASPEN ATAZANAVIR, resulting in suboptimal levels of ASPEN ATAZANAVIR thereby potentially leading to a resultant loss of virologic response and possible resistance to ASPEN ATAZANAVIR or to other protease inhibitors. ASPEN ATAZANAVIR inhibits UGT and as a result may interfere with the metabolism of irinotecan thereby resulting in increased irinotecan adverse effects.
HIV-protease inhibitors such as ASPEN ATAZANAVIR may themselves induce metabolism and may reduce plasma concentrations of theophylline.
Antiretroviral medicinal products:
Nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs):
Didanosine:
The co-administration of ASPEN ATAZANAVIR and didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that ASPEN ATAZANAVIR be taken with food 2 hours before or 1 hour after didanosine buffered formulations to avoid a decrease in ASPEN ATAZANAVIR and didanosine concentrations. Simultaneous administration of didanosine enteric coated formulation and ASPEN ATAZANAVIR with food results in a decrease in didanosine exposure. Therefore these medicines should be administered at different times.
Tenofovir:
Tenofovir may decrease the AUC and Cmin of ASPEN ATAZANAVIR and ASPEN ATAZANAVIR may increase tenofovir concentrations. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving ASPEN ATAZANAVIR and tenofovir should be monitored for tenofovir-associated adverse events. When co-administering these medicines, it is recommended that ASPEN ATAZANAVIR 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all with a single daily dose with food). ASPEN ATAZANAVIR alone, without ritonavir should not be co-administered with tenofovir.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs):
Efavirenz:
Co-administration may result in a reduced ASPEN ATAZANAVIR concentration. In treatment-naive patients receiving efavirenz and ASPEN ATAZANAVIR, the recommended dose is ASPEN ATAZANAVIR 300 mg with ritonavir 100 mg and efavirenz 600 mg (all once daily), as this combination results in ASPEN ATAZANAVIR exposure that approximates the mean exposure to atazanavir produced by 400 mg of ASPEN ATAZANAVIR alone. Dosing recommendations for efavirenz and ASPEN ATAZANAVIR in treatment-experienced patients have not yet been established. (SEE DOSAGE AND DIRECTIONS FOR USE).
Nevirapine:
Nevirapine is an inducer of CYP3A and is expected to decrease ASPEN ATAZANAVIR exposure. In the absence of data, co-administration is not recommended.
Protease inhibitors (PI's):
Ritonavir:
When co-administering ASPEN ATAZANAVIR with ritonavir, it is recommended that ASPEN ATAZANAVIR 300 mg once daily be given with ritonavir 100 mg once daily with food (refer to the prescribing information of ritonavir for information on drug interactions with ritonavir). Although not studied, the co-administration of ASPEN ATAZANAVIR/ritonavir and other protease inhibitors would be expected to increase exposure tothe other protease inhibitor. Such co-administration is not recommended as it may lead to a increased ASPEN ATAZANAVIR concentration.
Saquinavir:
Co-administration may lead to an increased saquinavir concentration. Appropriate dosing recommendations with respect to efficacy and safety for this combination, with or without ritonavir, have not been established. In a clinical study, saquinavir 1200 mg co-administered with ASPEN ATAZANAVIR 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy.
Indinavir
Co-administration of ASPEN ATAZANAVIR and indinavir is not recommended as both ASPEN ATAZANAVIR and indinavir are associated with indirect (unconjugated) hyperbillirubinemia.A combination of these drugs has not been studied.
Other medicinal products:
Antiarrhythmics (amiodarone, bepridil, systemic lidocaine and quinidine):
The co-administration of antiarrhythmics (amiodarone, bepridil, systemic lidocaine and quinidine) with ASPEN ATAZANAVIR has the potential to produce serious and/or life-threatening adverse events as a result of increased concentrations of antiarrhythmics. Caution is advised and therapeutic concentration monitoring is recommended.
Anticoagulants:
The co-administration of warfarin with ASPEN ATAZANAVIR may potentially produce serious and/or life-threatening bleeding as a result of an increase in the warfarin plasma concentration. It is recommended that international normalised ratio (INR) be monitored.
Anticonvulsants (carbamazepine, phenobarbital and phenytoin):
Enzyme inducers such as carbamazepine, phenobarbital and phenytoin may reduce the plasma concentrations of HIV-protease inhibitors including ASPEN ATAZANAVIR.
Calcium channel blockers:
Caution is advised. Co-administration with ASPEN ATAZANAVIR may lead to increased plasma concentrations of diltiazem and desacetyldiltiazem.
A 50% dose reduction of diltiazem should be considered and ECG monitoring is recommended. Co-administration of ASPEN ATAZANAVIR/ ritonavir with diltiazem has not been studied.
Co-administration of ASPEN ATAZANAVIR with felodipine, nifedipine, nicardipine, and verapamil may lead to increased calcium channel blocker plasma concentrations. Dose titration of the calcium channel blocker should be considered and ECG monitoring is recommended.
Macrolide antibiotics:
Clarithromycin:
Exposure to clarithromycin is increased when co-administration with ASPEN ATAZANAVIR. As increased concentrations of clarithromycin may cause QTc prolongations, a 50% dose reduction of clarithromycin should be considered when co-administered with ASPEN ATAZANAVIR.
Inhaled/nasal corticosteroid:
Fluticasone propionate
Concomitant use of fluticasone propionate and ASPEN ATAZANAVIR (without ritonavir) may increase fluticasone propionate plasma concentrations; therefore caution is advised when using this combination.
Alternatives to fluticasone propionate, particularly for long-term use should be considered.
A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations.
Concomitant use of ASPEN ATAZANAVIR with ritonavir and fluticasone propionate is expected to produce similar effects. Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate.
Therefore, co-administrationof fluticasone propionate and ASPEN ATAZANAVIR/ritonavir is not recommended. These effects can also occur with other corticosteroids metabolised with the CYP 3A pathway, e.g. budesonides.
HMG-CoA reductase inhibitors:
Concomitant use of ASPEN ATAZANAVIR with lovastatin or simvastatin is not recommended due to potential serious reactions such as myopathy, including rhabdomyolysis.
Caution should be exercised if HIV protease inhibitors, including ASPEN ATAZANAVIR, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolised by the CYP3A pathway (e.g. atorvastatin). The concomitant use may lead to an increase in atorvastatin levels. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including ASPEN ATAZANAVIR, are used in combination with atorvastatin.
H2-receptor antagonists and proton-pump inhibitors:
Reduced plasma concentrations of ASPEN ATAZANAVIR are expected if proton-pump inhibitors, antacids, buffered medications or H2-receptor antagonists are administered with ASPEN ATAZANAVIR, which may result in loss of therapeutic effect and development of resistance. ASPEN ATAZANAVIR should therefore be administered 2 hours before or 1 hour after these medicines.
In treatment-naive patients taking an H2-receptor antagonist, either of the following regimens may be considered: ASPEN ATAZANAVIR 400 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist OR ASPEN ATAZANAVIR 300 mg with ritonavir 100 mg once daily with food, without the need for separation from the H2-receptor antagonist.
In treatment-experienced patients, the following regimen should be used: ASPEN ATAZANAVIR 300 mg with ritonavir 100 mg once daily with food at least 2 hours before and atleast 10 hours after the H2-receptor antagonist.
Omeprazole substantially decreases plasma concentrations of ASPEN ATAZANAVIR, and as a result, concomitant use of proton-pump inhibitors and ASPEN ATAZANAVIR may result in loss of therapeutic effect and development of resistance.
Immunosuppressants (cyclosporine, sirolimus, tacrolimus):
Therapeutic concentration monitoring is recommended for immunosuppressant agents (e.g. cyclosporine, sirolimus, tacrolimus) when co-administered with ASPEN ATAZANAVIR the plasma concentrations of the immunosuppressants may be increased.
Antifungals:
Ketoconazole and itraconazole
Co-administration of ketoconazole has been studied with ASPEN ATAZANAVIR without ritonavir (negligible increase in atazanavir AUC and C
max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used with caution with ASPEN ATAZANAVIR/ritonavir. Concomitant use may increase the plasma concentration of ketoconazole and itraconazole.
Voriconazole:
Co-administration of voriconazole with ASPEN ATAZANAVIR, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steadystate AUC by an average of 39%.
Voriconazole should not be administered to patients receiving ASPEN ATAZANAVIR/ritonavir. Co-administration of voriconazole with ASPEN ATAZANAVIR (without ritonavir) may increase concentrations of atazanavir.
Hormonal contraceptives:
Oestrogen-based contraception:
Co-administration of ASPEN ATAZANAVIR/ritonavir with hormonal contraceptives has not been studied. Higher doses of ritonavir, without ASPEN ATAZANAVIR decrease contraceptive steroid concentrations.
As contraceptive steroid concentrations may be altered when coadministering ASPEN ATAZANAVIR or ASPEN ATAZANAVIR/ritonavir with oral contraceptives or with the contraceptive patch, alternate methods of nonhormonal contraception should be considered. Co-administration may reduce levels of ethinyl oestradiol and norethindrone.
PDE5 inhibitors:
Caution should be used when prescribing PDE5 inhibitors for erectile dysfunction (e.g. sildenafil, tadalafil, or vardenafil) for patients receiving protease inhibitors, including ASPEN ATAZANAVIR. Co-administration with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and potentially result in an increase in PDE5 inhibitor-associated adverse events, which include hypotension, visual changes and priapism.
Antimycobacterials:
Rifabutin:
A rifabutin dose reduction of up to 75% (e.g. 150 mg every other day or 3 times per week) is recommended as co-administration with ASPEN ATAZANAVIR may increase rifabutin plasma concentrations.
Antidepressants:
Tricyclic antidepressants:
The co-administration of tricyclic antidepressants with ASPEN ATAZANAVIR may potentially produce serious and/or life-threatening adverse events as a result of an increase in the tricyclic antidepressants concentration.
Trazodone
Concomitant use of trazodone and ASPEN ATAZANAVIR with or without ritonavir may increase plasma concentrations of trazodone, thereby resulting in increased trazodone adverse events e.g. nausea, dizziness, hypotension and syncope. If trazodone is used with a CYP3A4 inhibitor such as ASPEN ATAZANAVIR, the combination should be used with caution and a lower dose of trazodone should be considered.

PREGNANCY AND LACTATION:
Safety in pregnancy and lactation has not been established.
Pregnancy:
ASPEN ATAZANAVIR should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus. Hyperbilirubinemia occurred frequently during treatment with ASPEN ATAZANAVIR. It is not known whether ASPEN ATAZANAVIR administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and young infants. In the prepartum period, additional monitoring and alternative therapy to ASPEN ATAZANAVIR should be considered.
Lactation:
It is not known whether ASPEN ATAZANAVIR is secreted in breast milk. A study in lactating rats has demonstrated that atazanavir is secreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ASPEN ATAZANAVIR.
Fertility:
At the systemic drug exposure levels in rats, equal to those at a human clinical dose of 400 mg once daily, ASPEN ATAZANAVIR did not produce significant effects on mating, fertility or early embryonic development.

DOSAGE AND DIRECTIONS FOR USE:
The recommended dose of ASPEN ATAZANAVIR is 400 mg all at once daily taken with food. When coadministered with ritonavir, it is recommended that ASPEN ATAZANAVIR 300 mg once daily be taken with ritonavir 100 mg one daily, with food.
ASPEN ATAZANAVIR without ritonavir is not recommended for treatment experienced patients with prior virologic failure.
Concomitant therapy:
Efavirenz:
In treatment naive patients who receive efavirenz and ASPEN ATAZANAVIR, the recommended dose is ASPEN ATAZANAVIR 300 mg with ritonavir 100 mg and efavirenz 600 mg (all once daily). Dosing recommendations for efavirenz and ASPEN ATAZANAVIR in treatment-experienced patients with prior virologic failure have not been established.
Didanosine:
When co-administered with didanosine buffered or enteric-coated formulations, ASPEN ATAZANAVIR should be given (with food) 2 hours before or 1 hour after didanosine.
Tenofovir disoproxil fumarate: When co-administered with tenofovir, it is recommended that ASPEN ATAZANAVIR300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food).
ASPEN ATAZANAVIR without ritonavir should not be co-administered with tenofovir. H2-receptor antagonists:
Treatment-naive patients: ASPEN ATAZANAVIR 400 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist or ASPEN ATAZANAVIR 300 mg with ritonavir 100 mg once daily with food, without the need for separation from the H2-receptor antagonist.
Treatment-experienced patients: ASPEN ATAZANAVIR 300 mg with ritonavir 100 mg once daily with food at least 2 hours before and at least 10 hours after the H2-receptor antagonist.
Patients with Renal Impairment:
In patients with renal impairment no dosage adjustment is recommended. Adequate hydration is however recommended to reduce the risk of nephrolithiasis and monitoring should be advised. Treatment may need to be temporarily interrupted or discontinued completely in patients developing nephrolithiasis.
Patients with hepatic impairment:
ASPEN ATAZANAVIR should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be considered. ASPEN ATAZANAVIR should not be used in patients with severe hepatic impairment (Child-Pugh Class C). Combination treatment with ritonavir has not been studied in subjects with hepatic impairment and is not recommended.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Adult Patients
The following adverse reactions have been reported. The frequency of adverse reactions listed below is defined using the following convention: very common (>1/1) common (>1/100 <1/10), uncommon (>1/1 000 to <1/100), rare (>1/10 000 to 1/1 000, or very rare (<1/10 000.)
Body as a whole:
Common: Headache
Digestive System
Common: Nausea
Jaundice/scleral icterus
Vomiting
Diarrhoea
Abdominal pain
Nervous system:
Common: Dizziness
Insomnia
Peripheralneurologic symptoms
Skin and Appendages:
Common: Rash
Treatment-Emergent Adverse Events in Treatment-Experienced patients:
Selected drug-related clinical adverse events of moderate-severe intensity in >2% of treatment-experienced patients receiving ASPEN ATAZANAVIR/ritonavir therapy are presented below:
Body as a whole:
Fever
Digestive System:
Jaundice/scleral icterus
Diarrhoea
Nausea
Nervous System:
Depression
Musculoskeletal System:
Myalgia
Postmarketing Experience:
The following events were identified during post-approval use of ASPEN ATAZANAVIR. Since these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.
Adverse Event: Frequent
Nervous system disorders
: dizziness, headache, insomnia, peripheral neurologic symptoms
Eye disorders: scleral icterus
Gastrointestinal disorders: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting
Hepatobiliary disorders: jaundice
Skin and Subcutaneous disorders: rash
General disorders and administration site condition: asthenia, fatigue
Adverse Event: Less Frequent and rare
Immune system disorders: Less frequent
: allergic reaction
Metabolism and nutrition disorders: Less frequent: anorexia, appetite increased, weight decreased, weight gain
Psychiatric disorders: less frequent: anxiety, depression, sleep disorder
Nervous system disorders: Less frequent: abnormal dream, amnesia, confusion, somnolence; Rare: abnormal gait
Cardiac disorders Vascular disorders: Less Frequent: hypertension,
syncope, Rare: Oedema, palpitations
Respiratory, thoracic, and mediastinal disorders: Less Frequent: dyspnoea
Gastrointestinal disorders: less frequent: dry mouth, dysgeusia,
flatulence, gastritis, pancreatitis, stomatitis, aphthous; Rare: abdominal
distension
Hepatobiliary system: less frequent: hepatitis; Rare: hepatosplenomegaly.
Skin and subcutaneous tissue disorders: Less Frequent: alopecia,
eczema, pruritus, urticaria; Rare: vasodilation, vesiculobullous rash
Musculoskeletal and connective tissue disorders: Less Frequent: arthralgia, muscle atrophy, myalgia; Rare: myopathy
Renal and urinary disorders: Less Frequent: hematuria, pollakiuria, proteinuria; Rare: kidney pain, nephrolithiasis
Reproductive systemand disorders: Less Frequent: gynaecomastia
General disorders and administration site conditions: Less Frequent: chest pain, fever, malaise
Body as a whole:
Headache, fever, oedema, taste disturbances, asthenia, fatigue, alopecia, lipodystrophy, in growing toenails and paronychia of the great toes, dry mouth.
Cardiovascular system:
Second-degree AV block.
Gastrointestinal disorders:
Nausea, vomiting, diarrhoea.
Jaundice/scleral icterus, abdominal pain, pancreatitis, anorexia, increased appetite, flatulence, acid regurgitation, dyspepsia.
Hepatobiliary disorders:
Unconjugated hyperbilirubinaemia.
Hepatic function abnormalities.
Renal and urinary disorders:
Renal insufficiency, nephrolithiasis (often with flank pain) may occur with or without haematuria, dysuria.
Metabolic system and Nutrition disorders:
Hyperglycaemia, diabetes mellitus.
Musculoskeletal and connective tissue disorders:
Myalgia, arthralgia, myositis, rhabdomyolysis.
Skin and subcutaneous tissue disorders:
Pruritus, alopecia, maculopapular rash, dry skin, hyperpigmentation. Rash (a possible association with Stevens-Johnson syndrome and erythema multiforme has been reported).
Nervous system disorders:
Dizziness, insomnia, peripheral neurologic systems, depression, sleep disturbances, paraesthesia, hypoaesthesia.
Immune system disorders:
Vasculitis, anaphylaxis.
Blood and lymphatic system disorders:
Anaemia (including haemolytic anaemia), thrombocytopenia, reduced neutrophil counts.
Laboratory Investigations:
Patients Co-infected with Hepatitis B and/or C virus:
Liver function tests should be monitored in patients with a history of hepatitis B or C.
Raised liver enzymes and bilirubin (jaundice and hepatitis have occurred), raised creatinine phosphokinase and raised blood lipids (with rare cases of pancreatitis).
Treatment emergent clinical laboratory abnormalities (Grade 3 or 4), reported in >2% of the treatment-naive patients were changes in SGOT/AST, SGPT/ALT, total bilirubin, amylase, lipase, creatine kinase, total cholesterol, triglycerides, haemoglobin and neutrophils.
Treatment emergent clinical laboratory abnormalities (Grade 3 or 4), reported in >2% of the treatment-experienced patients were changes in SGOT/AST, SGPT/ALT, total bilirubin, lipase, creatine kinase, total cholesterol, triglycerides, glucose, platelets and neutrophils.
Changes from baseline for their lipid profiles were also observed.
Special precautions:
Hyperbilirubinaemia:
The majority of patients receiving ASPEN ATAZANAVIR experience asymptomatic elevations in indirect (unconjugated) bilirubin related to the inhibition of UDP-glucuronosyl transferase (UGT). Hepatic transaminase elevations that occur simultaneously with hyperbilirubinaemia should be evaluated for alternative etiologies. Long-term safety data are not available for patients experiencing persistent elevations in total bilirubin >5 times ULN. Alternative antiretroviral therapy to ASPEN ATAZANAVIR may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of ASPEN ATAZANAVIR is not recommended as long-term efficacy of reduced doses has not been established.
In general, appropriate caution should be exercised in the administration and monitoring of ASPEN ATAZANAVIR in elderly patients due to the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.
Rash:
In controlled clinical trials, rash (all grades, regardless of causality) occurred in 21% of patients treated with ASPEN ATAZANAVIR. The median time to onset of rash was 8 weeks after initiation of therapy and the median duration of rash was 1,3 weeks. Rashes were mostly mid-to-moderate maculopapular skin eruptions. Dosing with ASPEN ATAZANAVIR was often continued without interruption in patients who developed a rash. The discontinuation rate for rash in clinical trials was 0,4%. ASPEN ATAZANAVIR should be discontinued if a severe rash develops. Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving ASPEN ATAZANAVIR.
Hepatic Impairment and Toxicity:
As atazanavir is principally metabolised by the liver, ASPEN ATAZANAVIR should be administered with caution to patients with hepatic impairment as atazanavir concentrations may be increased. Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to initiation of treatment, may be at an increased risk for developing further transaminase elevations or hepatic decompensation. There are no clinical trialdata on the use of ASPEN ATAZANAVIR/ritonavir in patients with any degree of hepatic impairment.
Nephrolithiasis:
Cases of nephrolithiasis were reported during postmarketing surveillance. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy should be advised.
Resistance/Cross-Resistance:
Various degrees of cross-resistance have been observed among protease inhibitors. Resistance to ASPEN ATAZANAVIR may not preclude the subsequent use of other protease inhibitors.
Haemophilia:
Cases of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors have been reported. In some cases, additional factor VII was given. In the majority of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Fat Redistribution:
Redistribution/accumulation of body fat which includes central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown.
Immune Reconstitution Syndrome:
Immune reconstitution syndrome was reported in patients treated with combination antiretroviral therapy, including ASPEN ATAZANAVIR. During the initial phase of combination antiretroviral treatment, patients may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may result in the need for further evaluation and treatment.
Effects on Electrocardiogram (PR Interval Prolongation)
Asymptomatic concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving ASPEN ATAZANAVIR.
ASPEN ATAZANAVIR has also been shown to prolong the PR interval of the electrocardiogram in some patients. In both healthy volunteers and patients, asymptomatic abnormalities in atrioventricular (AV) conduction were mostly limited to first-degree AV block. Cases of second-degree AV block and other conduction abnormalities have been reported. As there is limited clinical experience, ASPEN ATAZANAVIR should be used with caution in patients with pre-existing conduction system disease (e.g. marked first-degree AV block or second- or third- degree AV block).
In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval was seen. A 50% dose reduction of diltiazem should be considered and ECG monitoring is recommended when used in combination with ASPEN ATAZANAVIR. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily,no substantial additive effect of atazanavir and atenolol on the PR interval was seen. This combination therefore requires no dose adjustment of atenolol.
Pharmacokinetic studies between ASPEN ATAZANAVIR and other medicines that may prolong the PR interval including beta blockers (other than atenolol), verapamil, and digoxin, have not been conducted. As an additive effect of ASPEN ATAZANAVIR and these medicines cannot be excluded; caution is advised when ASPEN ATAZANAVIR is given concurrently with these medicines.
No concentration dependent effect of atazanavir on the QTc interval (using Fridericia's correction) was seen when electrocardiographic effects of ASPEN ATAZANAVIR were determined in a clinical pharmacology study, where oral doses of 400 mg and 800 mg were compared with placebo. In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject of HIV-infected patient had a QTc interval >500 msec.
Diabetes Mellitus/Hyperglycaemia
New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycaemia were reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy.
Some patients required initiation - or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases diabetic ketoacidosis occurred. In some patients who discontinued protease inhibitor therapy, hyperglycaemia persisted. These events were reported voluntarily during clinical practice, hence estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy including ASPEN ATAZANAVIR and these events has not been established.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Human experience of acute overdosage with ASPEN ATAZANAVIR is limited. No symptomatic untoward effects have been seen after single doses up to 1200 mg were taken by healthy volunteers. A single self-administered overdose of 29,2 g of ASPEN ATAZANAVIR in an HIV-infected patient (73 times the 400 mg recommended dose) was associated with asymptomatic bifascicular block accompanied by PR interval prolongation.
At high drug exposure doses, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongation may be seen.
Treatment of overdosage requires general supportive measures including monitoring of vital signs and ECG, and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir can be achieved by emesis or gastric lavage. Activated charcoal may also be administered to aid removal of unabsorbed medicine. There is no specific antidote for overdose with ASPEN ATAZANAVIR. Dialysis is unlikely to be beneficial in significant removal of atazanavir, as it is extensively metabolised by the liver and is highly protein bound.

IDENTIFICATION:
ASPEN ATAZANAVIR 150 mg capsules: white No. 1 capsules imprinted as follows: 150 mg printed in circular orientation in blue on the cap and A38 printed in circular orientation in blue on the body.
ASPEN ATAZANAVIR 200 mg capsules: white No 0 capsules imprinted as follows: 200 mg printed in circular orientation in blue on the cap and A37 printed in circular orientation in blue on the body.
CAPSULE CONTENTS: Capsules contain white to light yellow granules which may appear as powder.

PRESENTATION:
ASPEN ATAZANAVIR capsules are available in HDPE bottles with a child-proof screw cap, packaged together with a package insert in a unit carton.
Pack sizes are as follows:
ASPEN ATAZANAVIR 150 mg capsules: 60's
ASPEN ATAZANAVIR 200 mg capsules: 60's

STORAGE INSTRUCTIONS:
ASPEN ATAZANAVIR capsules should be stored at 25°C in a tightly closed container. Protect from moisture.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER:
ASPEN ATAZANAVIR 150 mg: 42/20.2.8/0838
ASPEN ATAZANAVIR 200 mg: 42/20.2.8/0839

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
PHARMACARE LIMITED
Building 12, Healthcare Park
Woodlands Drive
Woodmead
2191

DATE OF PUBLICATION OF THE PACKAGE INSERT:
10 December 2009
03

New addition to this site: May 2011
Source
: Pharmaceutical Industry

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