Saquinavir

Herbal preparations containing St. John’s wort must not be used concomitantly with saquinavir. If a patient is already taking St. John’s wort, stop St. John’s wort, check viral levels and if possible saquinavir levels. Saquinavir levels may increase on stopping St. John’s wort, and the dose of saquinavir may need adjusting. The inducing effect of St. John’s wort may persist for at least 2 weeks after cessation of treatment.

Plasma levels of unboosted saquinavir can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or transport proteins by St. John’s wort.

The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, in vitro studies have shown that saquinavir is a substrate and an inhibitor for P-glycoprotein (P-gp). Therefore, medicinal products that either share this metabolic pathway or modify CYP3A4 and/or P-gp activity may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other medicinal products that are substrates for CYP3A4 or P-gp.

Interaction:

Grapefruit juice (single dose) (unboosted saquinavir):

• Saquinavir
  • ↑50% (normal strength grapefruit juice)
  • ↑100% (double strength grapefruit juice)

Recommendations concerning coadministration: Increase not thought to be clinically relevant. No dose adjustment required.

Caution should be exercised in patients with severe renal impairment.

Combination not recommended. No data are available on the concomitant administration of saquinavir/ritonavir and other proton pump inhibitors.

Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended.

Interaction with saquinavir/ritonavir not studied. Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4. Saquinavir concentrations may be increased.

Careful monitoring of patients with regard to sedative effects is warranted. A decrease in the dose of the benzodiazepine may be required.

Concentrations of these medicinal products may be increased when coadministered with saquinavir/ritonavir.

Interaction:

Atazanavir 300 mg qd (saquinavir/ritonavir 1,600/100 mg qd):

Atazanavir ↔

No clinical data available for the combination of saquinavir/ritonavir 1,000/100 mg bid and atazanavir.

Recommendations concerning coadministration: Contraindicated in combination with saquinavir/ritonavir due to the potential for life threatening cardiac arrhythmia.

When used with saquinavir/ritonavir, the lowest possible dose of atorvastatin should be administered and the patient should be carefully monitored for signs/symptoms of myopathy (muscle weakness, muscle pain, rising plasma creatinine kinase).

Atorvastatin is less dependent on CYP3A4 for metabolism.

Dose adjustment of bosentan may be required. When bosentan is administered concomitantly with saquinavir/ritonavir, the patient’s tolerability of bosentan should be monitored. Monitoring of the patient’s HIV therapy is also recommended.

Not studied. Concomitant use of bosentan and saquinavir/ritonavir may increase plasma levels of bosentan and may decrease plasma levels of saquinavir/ritonavir.

Use with caution. Monitoring of saquinavir plasma concentration is recommended.

Interaction with saquinavir/ritonavir not studied. These medicinal products will induce CYP3A4 and may therefore decrease saquinavir concentrations.

Careful therapeutic drug monitoring is necessary for these immunosuppressants when coadministered with saquinavir/ritonavir.

Concentrations of these medicinal products increase several fold when co-administered with saquinavir/ritonavir.

It is not recommended to coadminister saquinavir/ritonavir with cobicistat containing products.

Interaction with saquinavir/ritonavir not studied. Cobicistat is not recommended in combination with regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Because of a potential increase of colchicine-related toxicity (neuromuscular events including rhabdomyolysis), its concomitant use with saquinavir/ritonavir is not recommended, especially in the case of renal or hepatic impairment.

Concomitant use of colchicine and saquinavir/ritonavir is expected to increase plasma levels of colchicine due to P-gp and/or CYP3A4 inhibition by the protease inhibitor.

Interaction:

Delavirdine (unboosted saquinavir)

Saquinavir AUC: ↑348%

There are limited safety and no efficacy data available from the use of this combination. In a small, preliminary study, hepatocellular enzyme elevations occurred in 13% of subjects during the first several weeks of the delavirdine and saquinavir combination (6% Grade 3 or 4).

Recommendations concerning coadministration: Hepatocellular changes should be monitored frequently if this combination is prescribed.

Interaction:

Dexamethasone (saquinavir/ritonavir): Interaction with invirase/ritonavir not studied. Dexamethasone induces CYP3A4 and may decrease saquinavir concentrations.

Recommendations concerning coadministration: Use with caution. Monitoring of saquinavir plasma concentration is recommended.

Interaction:

Digoxin 0.5 mg single dose (saquinavir/ritonavir 1,000/100 mg bid):

• Digoxin
  • AUC_0-72: ↑49%
  • C_max: ↑27%

Digoxin levels may differ over time. Large increments of digoxin may be expected when saquinavir/ritonavir is introduced in patients already treated with digoxin.

Recommendations concerning coadministration: Caution should be exercised when saquinavir/ritonavir and digoxin are coadministered. The serum concentration of digoxin should be monitored and a dose reduction of digoxin should be considered if necessary.

The combination of saquinavir and ritonavir with efavirenz has been shown to be associated with an increased risk of liver toxicity; liver function should be monitored when saquinavir and ritonavir are co-administered with efavirenz. No clinically significant alterations of either saquinavir or efavirenz concentration were noted in studies in healthy volunteers or in HIV infected patient.

Alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered.

Concentration of ethinyl estradiol may be decreased when coadministered with saquinavir/ritonavir.

Caution is warranted and clinical monitoring of patients is recommended.

Concentrations of these medicinal products may be increased when coadministered with saquinavir/ritonavir.

Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended.

Interaction with saquinavir/ritonavir not studied. Both drugs are CYP3A4 inhibitors and may increase the plasma concentration of saquinavir.

Interaction:

Fluticasone propionate 50 mcg qid, intranasal (ritonavir 100 mg bid):

• Fluticasone propionate: ↑
• Intrinsic cortisol: ↓86% (90% CI 82%-89%)

Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide.

Effects of high fluticasone systemic exposure on ritonavir plasma levels yet unknown.

Recommendations concerning coadministration:

Concomitant administration of boosted saquinavir and fluticasone propionate and other corticosteroids metabolised via the P450 3A pathway (e.g. budesonide) is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects.

Dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). In case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.

Not studied. Co-administration of fusidic acid and saquinavir/ritonavir can cause increased plasma concentration of both fusidic acid and saquinavir/ritonavir.

Interaction:

Indinavir (saquinavir/ritonavir): Low dose ritonavir increases the concentration of indinavir.

Indinavir 800 mg tid (saquinavir 600-1,200 mg single dose):

• Saquinavir AUC: ↑4.6-7.2 fold
• Indinavir ↔

No safety and efficacy data available for this combination. Appropriate doses of combination not established.

Recommendations concerning coadministration: Increased concentrations of indinavir may result in nephrolithiasis [indinavir (saquinavir/ritonavir)].

Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended.

Interaction with saquinavir/ritonavir not studied. Itraconazole is a moderately potent inhibitor of CYP3A4. An interaction is possible.

Interaction:

Ketoconazole 200 mg qd (saquinavir/ritonavir 1,000/100 mg bid):

Recommendations concerning coadministration: No dose adjustment required when saquinavir/ritonavir combined with ≤200 mg/day ketoconazole. High doses of ketoconazole (>200 mg/day) are not recommended.

Interaction:

Maraviroc 100 mg bid (saquinavir/ritonavir 1,000/100 mg bid):

• Maraviroc
  • AUC₁₂: ↑8.77
  • C_max: ↑3.78

Saquinavir/ritonavir concentrations not measured, no effect is expected.

Recommendations concerning coadministration: No dose adjustment of saquinavir/ritonavir is required. Dose of maraviroc should be decreased to 150 mg bid with monitoring.

Combination not recommended. Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended.

Interaction with saquinavir/ritonavir not evaluated. Nefazodone inhibits CYP3A4. Saquinavir concentrations may be increased.

Interaction:

Nelfinavir 1,250 mg bid (saquinavir/ritonavir 1,000/100 mg bid):

Recommendations concerning coadministration: Combination not recommended.

Interaction:

Omeprazole 40 mg qd (saquinavir/ritonavir 1,000/100 mg bid):

• Saquinavir
  • AUC: ↑82% (90% CI 44-131%)
  • C_max: ↑75% (90% CI 38-123%)
• Ritonavir ↔

Recommendations concerning coadministration: Combination not recommended.

Interaction unknown. If no alternative treatment is available, use with careful monitoring.

Interaction not studied. Metabolism of pravastatin and fluvastatin is not dependent on CYP3A4. Interaction via effects on transport proteins cannot be excluded.

Interaction:

Rifabutin 150 mg q3d (saquinavir/ritonavir 1,000/100 mg bid) in healthy volunteers:

* Sum of rifabutin + 25-O-desacetyl rifabutin metabolite

Recommendations concerning coadministration:

To prevent possible development of rifabutin resistance in TB and HIV co-infected patients, the recommended dose of rifabutin is 150 mg every other day or three times per week, with the dose of saquinavir/ritonavir unchanged (1,000/100 mg bid).

Monitoring of neutropenia and liver enzyme levels is recommended due to an expected increase in exposure to rifabutin.

Combination not recommended as may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Concomitant use of salmeterol and saquinavir/ritonavir is expected to increase plasma levels of salmeterol.

Interaction:

Tipranavir/ritonavir (saquinavir/ritonavir):

Saquinavir C_min: ↓78%

Dual-boosted protease inhibitor combination therapy in multipletreatment experienced HIV-positive adults.

Recommendations concerning coadministration: Concomitant administration of tipranavir, co-administered with low dose ritonavir, with saquinavir/ritonavir, is not recommended. If the combination is considered necessary, monitoring of the saquinavir plasma levels is strongly encouraged.

Concentrations of warfarin may be affected when co-administered with saquinavir/ritonavir.

INR (international normalised ratio) monitoring recommended.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced 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, joint stiffness or difficulty in movement.

The safety and efficacy of saquinavir/ritonavir has not been established in patients with significant underlying liver disorders, therefore saquinavir/ritonavir should be used cautiously in this patient population. Saquinavir/ritonavir is contraindicated in patients with decompensated liver disease. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

No dosage adjustment seems warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to increased variability of the exposure in this population. There have been reports of exacerbation of chronic liver dysfunction, including portal hypertension, in patients with underlying hepatitis B or C, cirrhosis and other underlying liver abnormalities.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been 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 carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Interaction:

Garlic capsules (dose approx. equivalent to two 4 g cloves of garlic daily) (unboosted saquinavir 1,200 mg tid):

• Saquinavir
  • AUC: ↓51%
  • C_trough: ↓49% (8 hours post dose)
  • C_max: ↓54%

Recommendations concerning coadministration: Patients on saquinavir treatment must not take garlic capsules due to the risk of decreased plasma concentrations and loss of virological response and possible resistance to one or more components of the antiretroviral regimen.

Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo or foetus, the course of gestation and peri- and post-natal development. Clinical experience in pregnant women is limited: Congenital malformations, birth defects and other disorders (without a congenital malformation) have been reported rarely in pregnant women who had received saquinavir in combination with other antiretroviral agents.

However, so far the available data are insufficient and do not identify specific risks for the unborn child. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

There are no laboratory animal or human data available on secretion of saquinavir in breast milk. The potential for adverse reactions to saquinavir in nursing infants cannot be assessed, and therefore, breast-feeding should be discontinued prior to receiving saquinavir. It is recommended that HIV-infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

Saquinavir may have a minor influence on the ability to drive and use machines. Dizziness, fatigue and visual impairment have been reported during treatment with saquinavir. No studies on the effects on the ability to drive and use machines have been performed.

a. Summary of the safety profile

Limited data is available from two clinical studies where the safety of saquinavir soft capsule (1,000 mg twice daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks was studied in 311 patients.

The following adverse events with an at least possible relationship to ritonavir boosted saquinavir (i.e. adverse reactions) were reported most frequently: nausea, diarrhoea, fatigue, vomiting, flatulence, and abdominal pain.

The following adverse events were reported with the highest severity (grades 3 and 4): anaemia, diabetes mellitus, diarrhoea, nausea, vomiting and fatigue.

For comprehensive dose adjustment recommendations and drug-associated adverse reactions for ritonavir and other medicinal products used in combination with saquinavir, physicians should refer to the Summary of Product Characteristics for each of these medicinal products.

b. List of adverse reactions

Adverse reactions from two pivotal studies of saquinavir soft capsule (1,000 mg twice daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks are summarised in below. Also included are serious and non-serious adverse reactions from post-marketing spontaneous reports for which a causal relationship to saquinavir cannot be excluded. Adverse reactions are presented according to the MedDRA system organ classification. The frequency groupings according to MedDRA convention are: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).

Blood and the lymphatic system disorders

Very common: Decreased platelet count

Common: Anaemia, decreased haemoglobin, decreased lymphocyte count, decreased white blood cell count

Uncommon: Neutropenia

Eye Disorders

Uncommon: Visual impairment

Immune System Disorders

Common: Hypersensitivity

Metabolism and nutrition disorders

Very common: Increased blood cholesterol, increased blood triglycerides

Common: Diabetes mellitus, anorexia, increased appetite

Uncommon: Decreased appetite

Psychiatric Disorders

Common: Decreased libido, sleep disorder

Nervous System Disorder

Common: Paraesthesia, peripheral neuropathy, dizziness, dysgeusia, headache

Uncommon: Somnolence, convulsions

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea

Gastrointestinal disorders

Very common: Diarrhoea, nausea

Common: Vomiting, abdominal distension, abdominal pain, upper abdominal pain, constipation, dry mouth, dyspepsia, eructation, flatulence, lip dry, loose stools

Uncommon: Pancreatitis

Hepato-biliary disorders

Very common: Increased alanine aminotransferase, increased aspartate aminotransferase, increased low density lipoprotein

Common: Increased blood bilirubin, increased blood amylase

Uncommon: Hepatitis, jaundice

Renal and urinary disorders

Common: Increased blood creatinine

Uncommon: Renal impairment

Skin and subcutaneous tissue disorders

Common: Alopecia, dry skin, eczema, lipoatrophy, pruritus, rash

Uncommon: Stevens Johnson syndrome, dermatitis bullous

Musculoskeletal and connective tissue disorders

Common: Muscle spasms

General disorders and administration site conditions

Common: Asthenia, fatigue, increased fat tissue, malaise

Uncommon: Mucosal ulceration

c. Description of selected adverse reactions

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophilic patients type A and B treated with protease inhibitors.

Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside analogues. Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

d. Paediatric population

Limited safety data are available from a paediatric study (NV20911, n=18) in which the safety of saquinavir hard capsules (50 mg/kg bid, not to exceed 1,000 mg bid) used in combination with low dose ritonavir oral solution (3 mg/kg bid for body weight from 5 to <15 kg, 2.5 mg/kg bid for body weight from 15 to 40 kg and 100 mg bid for body weight >40 kg) has been studied in paediatric patients aged 4 months to 6 years old.

Four patients in the study experienced five adverse events that were considered related to trial treatment. These events were vomiting (3 patients), abdominal pain (1 patient) and diarrhoea (1 patient). No unexpected adverse events were observed in this study.