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Invirase
Overview
What is Invirase?
INVIRASE brand of saquinavir mesylate is an inhibitor of the human immunodeficiency virus (HIV) protease. INVIRASE is available as light brown and green, opaque hard gelatin capsules for oral administration in a 200-mg strength (as saquinavir free base). Each capsule also contains the inactive ingredients lactose, microcrystalline cellulose, povidone K30, sodium starch glycolate, talc, and magnesium stearate. Each capsule shell contains gelatin and water with the following dye systems: red iron oxide, yellow iron oxide, black iron oxide, FD&C Blue #2, and titanium dioxide.
INVIRASE is also available as a light orange to greyish- or brownish-orange, oval cylindrical, biconvex film-coated tablet for oral administration in a 500-mg strength (as saquinavir free base). Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, and magnesium stearate. Each film coat contains hypromellose, titanium dioxide, talc, iron oxide yellow, iron oxide red, and triacetin.
The chemical name for saquinavir mesylate is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulfonate with a molecular formula CHNO•CHOS and a molecular weight of 766.96. The molecular weight of the free base is 670.86. Saquinavir mesylate has the following structural formula:
Saquinavir mesylate is a white to off-white, very fine powder with an aqueous solubility of 2.22 mg/mL at 25°C.
What does Invirase look like?
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What are the available doses of Invirase?
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What should I talk to my health care provider before I take Invirase?
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How should I use Invirase?
INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV infection. The twice daily administration of INVIRASE in combination with ritonavir is supported by safety data from the MaxCmin 1 study (see ) and pharmacokinetic data (see ). The efficacy of INVIRASE with ritonavir has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.
INVIRASE must be used in combination with ritonavir, because it significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.
What interacts with Invirase?
INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g. anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients including ritonavir.
INVIRASE/ritonavir should not be administered concurrently with rifampin, terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir and ritonavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation (see ).
INVIRASE/ritonavir should not be given together with rifampin, due to the risk of severe hepatocellular toxicity if the three drugs are given together (see .
INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.
INVIRASE/ritonavir should not be administered concurrently with drugs listed in .
What are the warnings of Invirase?
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Interaction with HMG-CoA Reductase Inhibitors
INVIRASE should not be used with lovastatin or simvastatin (see . Caution should be exercised if HIV protease inhibitors, including INVIRASE, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin). Since increased concentrations of statins can, in rare cases, cause severe adverse events such as myopathy including rhabdomyolysis, this risk may be increased when HIV protease inhibitors, including saquinavir, are used in combination with these drugs (see ).
Interaction with St. John's Wort (hypericum perforatum)
Concomitant use of INVIRASE and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of protease inhibitors, including INVIRASE, with St. John's wort is expected to substantially decrease protease-inhibitor concentrations and may result in sub-optimal levels of INVIRASE and lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see ).
Interaction with Digoxin
Caution should be exercised when INVIRASE and digoxin are coadministered; serum concentration of digoxin should be monitored and the dose of digoxin may need to be reduced (see).
Interaction with Fluticasone
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 INVIRASE with ritonavir and fluticasone propionate is expected to produce the same 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, coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see ).
Diabetes Mellitus and Hyperglycemia
New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease-inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease-inhibitor therapy and these events has not been established.
What are the precautions of Invirase?
General
If a serious or severe toxicity occurs during treatment with INVIRASE, INVIRASE should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose INVIRASE may be considered. For antiretroviral agents used in combination with INVIRASE, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.
Hepatic Effects
The use of INVIRASE (in combination with ritonavir) by patients with hepatic impairment has not been studied. In the absence of such studies, caution should be exercised, as increases in saquinavir levels and/or increases in liver enzymes may occur. In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease.
Renal Effects
Renal clearance is only a minor elimination pathway; the principal route of metabolism and excretion for saquinavir is by the liver. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment have not been studied, and caution should be exercised when prescribing saquinavir in this population.
Hemophilia
There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients additional factor VIII was required. In the majority of reported cases treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.
Hyperlipidemia
Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of INVIRASE with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.
Lactose Intolerance
Each capsule contains lactose (anhydrous) 63.3 mg. This quantity should not induce specific symptoms of intolerance.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), facial wasting, peripheral wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. A causal relationship between protease-inhibitor therapy and these events has not been established and the long-term consequences are currently unknown.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INVIRASE. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection, cytomegalovirus, pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Resistance/Cross-resistance
Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of INVIRASE therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors (see ).
Information for Patients
A statement to patients and health care providers is included on the product's bottle label:
INVIRASE may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort.
Patients should be informed that INVIRASE is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections. Patients should be advised that
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
Patients should be told that the long-term effects of INVIRASE are unknown at this time. They should be informed that INVIRASE therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
Patients should be advised that INVIRASE administered with ritonavir should be taken within 2 hours after a full meal (see ). When INVIRASE is taken without food, concentrations of saquinavir in the blood are substantially reduced and may result in no antiviral activity. Patients should be advised of the importance of taking their medication every day, as prescribed, to achieve maximum benefit. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose as soon as possible. However, the patient should not double the next dose.
Laboratory Tests
Clinical chemistry tests, viral load, and CD4 count should be performed prior to initiating INVIRASE therapy and at appropriate intervals thereafter. Elevated nonfasting triglyceride levels have been observed in patients in saquinavir trials. Triglyceride levels should be periodically monitored during therapy. For comprehensive information concerning laboratory test alterations associated with use of other antiretroviral therapies, physicians should refer to the complete product information for these drugs.
Drug Interactions
Drug interaction studies have been completed with INVIRASE and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for INVIRASE/ritonavir.
The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp.
Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in under . These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in , which summarizes the effect of saquinavir, administered as saquinavir soft gel capsules or INVIRASE, on the geometric mean AUC and C of coadministered drugs and , which summarizes the effect of coadministered drugs on the geometric mean AUC and C of saquinavir. Clinical dose recommendations can be found in . The magnitude of the interactions may be different when INVIRASE is given with ritonavir (see ).
When coadministering INVIRASE/ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations. Examples and clinical dose recommendations can be found in .
| Concomitant Drug Class:Drug Name | Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment | HIV-Antiviral Agents |
|---|---|---|---|
| Non-nucleoside reverse transcriptase inhibitor: | INVIRASE/ritonavir interaction has not been evaluated. | ↑ Saquinavir Effect on delavirdine is not well established | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Non-nucleoside reverse transcriptase inhibitor: | See , and for magnitude of interactions. | ↓ Saquinavir↔ Efavirenz | Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established. |
| HIV protease inhibitor: | INVIRASE/ritonavir | Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased. | |
| HIV protease inhibitor: | ↑ Saquinavir Effect on indinavir is not well established | Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. | |
| HIV protease inhibitor: | ↔ Saquinavir↔ Lopinavir↓ Ritonavir | Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. | |
| HIV protease inhibitor: | ↓ Saquinavir | Combining saquinavir with tipranavir/ritonavir is not recommended. | |
| HIV fusion inhibitor: | Saquinavir soft gel capsules/ritonavir↔ enfuvirtide | No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required. | Other Agents |
| Antiarrhythmics: | ↑ Antiarrhythmics | Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir. | |
| Anticoagulant: | ↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: | ↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established | Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. | |
| Anti-infective: | ↑ Saquinavir↑ Clarithromycin | Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended: For patients with renal impairment, the following dosage adjustments should be considered: No dose adjustment for patients with normal renal function is necessary. | |
| Antifungal: | ↔ Saquinavir↔ Ritonavir↑ Ketoconazole | Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see ). Hence, doses of ketoconazole > 200 mg/day are not recommended. | |
| Antimycobacterial: | ↓ Saquinavir↑ Rifabutin | Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. | |
| Benzodiazepines: | ↑ Benzodiazepines | Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed. | |
| ↑ Midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see ]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. | ||
| ↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. | ||
| Corticosteroid: | ↓ Saquinavir | Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. | |
| Digitalis Glycosides: | ↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir. | Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see ). | |
| Inhaled/nasal steroid: | INVIRASE/ritonavir | Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see ). | |
| ↑ Atorvastatin↑ Rosuvastatin | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see ). | ||
| ↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir. | ||
| Narcotic analgesic: | ↓ Methadone | Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. | |
| Oral contraceptives: | ↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered. | |
| ↑ Sildenafil↔ Saquinavir ↑ Vardenafil ↑ Tadalafil | Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. | ||
| Antidepressant: | ↑ Trazodone | Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered. | |
| ↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir. | ||
| Proton pump inhibitors: | ↑ Saquinavir | When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis. | |
| Herbal Products: | ↓ Saquinavir | Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see ). | |
| Garlic Capsules | ↓ Saquinavir | Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations. |
Drugs That Are Mainly Metabolized by CYP3A4
Although specific studies have not been performed, coadministration with drugs that are mainly metabolized by CYP3A4 (e.g., calcium channel blockers, dapsone, disopyramide, quinine, amiodarone, quinidine, warfarin, tacrolimus, cyclosporine, ergot derivatives, pimozide, carbamazepine, fentanyl, alfentanyl, alprazolam, and triazolam) may result in elevated plasma concentrations of these drugs when coadministered with saquinavir; therefore, these combinations should be used with caution. Since INVIRASE is coadministered with ritonavir, the ritonavir label should be reviewed for additional drugs that should not be coadministered.
Inducers of CYP3A4
Coadministration with compounds that are potent inducers of CYP3A4 (e.g., phenobarbital, phenytoin, dexamethasone, carbamazepine) may result in decreased plasma levels of saquinavir.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administered saquinavir for approximately 2 years. Because of limited bioavailability of saquinavir in animals, the plasma exposures (AUC values) in the respective species were approximately 29% (using rat) and 65% (using mouse) of those obtained in humans at the recommended clinical dose boosted with ritonavir.
Mutagenesis
Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes, and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test.
Impairment of Fertility
No adverse effects were reported in fertility and reproductive performance study conducted in rats. Because of limited bioavailability of saquinavir in animals, the maximal plasma exposures achieved in rats were approximately 26% of those obtained in humans at the recommended clinical dose boosted with ritonavir.
Pregnancy
Teratogenic Effects: Category B
Reproduction studies conducted with saquinavir have shown no embryotoxicity or teratogenicity in both rats and rabbits. Because of limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir. Clinical experience in pregnant women is limited. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including INVIRASE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV
infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
mothers should be instructed not to breast-feed if they are receiving antiretroviral medications, including INVIRASE.
Pediatric Use
Safety and effectiveness of INVIRASE in HIV-infected pediatric patients younger than 16 years of age have not been established.
Geriatric Use
Clinical studies of INVIRASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be taken when dosing INVIRASE in elderly patients due to the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
What are the side effects of Invirase?
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Concomitant Therapy with Ritonavir Adverse Reactions
In combination with ritonavir the recommended dose of INVIRASE is 1000 mg two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. lists grade 2, 3 and 4 adverse events that occurred in ≥2% of patients receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).
Limited experience is available from three studies investigating the pharmacokinetics of the INVIRASE 500 mg film-coated tablet compared to the INVIRASE 200 mg capsule in healthy volunteers (n=140). In two of these studies saquinavir was boosted with ritonavir; in the other study, saquinavir was administered as single drug. The INVIRASE tablet and the capsule formulations were similarly tolerated. The most common adverse events were gastrointestinal disorders (such as diarrhea). Similar bioavailability was demonstrated and no clinically significant differences in saquinavir exposures were seen. Thus, similar safety profiles are expected between the two INVIRASE formulations.
In a study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted INVIRASE) involving 28 healthy volunteers, 11 of 17 healthy volunteers (65%) exposed concomitantly to rifampin and ritonavir-boosted INVIRASE developed severe hepatocellular toxicity which presented as increased hepatic transaminases. In some subjects, transaminases increased up to >20-fold the upper limit of normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical symptoms abated and the increased hepatic transaminases normalized (see ).
| Adverse Events | Saquinavir soft gel capsules 1000 mg plus Ritonavir 100 mg bid (48 weeks)N=148n (%=n/N) |
|---|---|
| Endocrine Disorders | |
| Diabetes mellitus/hyperglycemia | 4 (2.7) |
| Lipodystrophy | 8 (5.4) |
| Gastrointestinal Disorders | |
| Nausea | 16 (10.8) |
| Vomiting | 11 (7.4) |
| Diarrhea | 12 (8.1) |
| Abdominal Pain | 9 (6.1) |
| Constipation | 3 (2.0) |
| General Disorders and Administration Site Conditions | |
| Fatigue | 9 (6.1) |
| Fever | 5 (3.4) |
| Musculoskeletal Disorders | |
| Back Pain | 3 (2.0) |
| Respiratory Disorders | |
| Pneumonia | 8 (5.4) |
| Bronchitis | 4 (2.7) |
| Influenza | 4 (2.7) |
| Sinusitis | 4 (2.7) |
| Dermatological Disorders | |
| Rash | 5 (3.4) |
| Pruritus | 5 (3.4) |
| Dry lips/skin | 3 (2.0) |
| Eczema | 3 (2.0) |
Additional Adverse Reactions Reported with Saquinavir
Additionally, adverse experiences of any intensity, at least remotely related to saquinavir, that were reported from clinical trials using INVIRASE or saquinavir soft gel capsules with or without ritonavir, are listed below by body system:
Body as a Whole: allergic reaction, anorexia, asthenia, chest pain, drug fever, edema, fatigue, fever, intoxication, mucosa damage, parasites external, retrosternal pain, shivering, wasting syndrome, weakness generalized, weight decrease, redistribution/accumulation of body fat (see )
Cardiovascular: cyanosis, heart murmur, heart valve disorder, hypertension, hypotension, peripheral vasoconstriction, syncope, thrombophlebitis, vein distended
Endocrine/Metabolic: appetite decrease, appetite disturbance, dehydration, diabetes mellitus, dry eye syndrome, hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hyperphosphatemia, hypertriglyceridemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, weight increase, xerophthalmia
Gastrointestinal: ascites, abdominal discomfort, buccal mucosa ulceration, cheilitis, colic abdominal, constipation, dyspepsia, dysphagia, esophagitis, eructation, exacerbation of chronic liver disease with grade 4 LFT, feces bloodstained, feces discolored, flatulence, gastralgia, gastritis, gastrointestinal inflammation, intestinal obstruction, gingivitis, glossitis, hemorrhage rectum, hemorrhoids, hepatitis, hepatomegaly, hepatosplenomegaly, hyperbilirubinemia, infectious diarrhea, jaundice, liver enzyme disorder, melena, pain pelvic, painful defecation, pancreatitis, parotid disorder, portal hypertension, right and left upper quadrant abdominal pain, salivary glands disorder, stomach upset, stomatitis, toothache, tooth disorder, vomiting, frequent bowel movements
Hematologic: anemia, bleeding dermal, hemolytic anemia, leukopenia, microhemorrhages, neutropenia, pancytopenia, splenomegaly, thrombocytopenia, lymphadenopathy
Infections and Infestations: abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, influenza, moniliasis
Investigations: ALT increase, AST increase, GGT increase, increased alkaline phosphatase, increased creatine phosphokinase, increased gamma GT, isolated increase in transaminase, raised amylase, raised LDH, TSH increase
Musculoskeletal: arthralgia, arthritis, back pain, cramps leg, cramps muscle, creatine phosphokinase increased, musculoskeletal disorders, musculoskeletal pain, myalgia, stiffness, tissue changes, trauma
Neoplasms benign, malignant and unspecified: acute myeloblastic leukemia
Neurological: ataxia, confusion, convulsions, dizziness, dysarthria, dysesthesia, extremity numbness, headache, heart rate disorder, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, mouth dry, myelopolyradiculoneuritis, numbness face, pain facial, paresis, paresthesia, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, seizures, spasms, intracranial hemorrhage leading to death, tremor, unconsciousness
Psychological: agitation, amnesia, anxiety, anxiety attack, depression, dreaming excessive, euphoria, hallucination, insomnia, intellectual ability reduced, irritability, lethargy, libido disorder, overdose effect, psychic disorder, psychosis, somnolence, speech disorder, suicide attempt
Reproductive System: impotence, prostate enlarged, vaginal discharge
Respiratory: bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection
Skin and Appendages: acne, alopecia, bullous skin eruption and polyarthritis, chalazion, dermatitis, dermatitis seborrheic, eczema, erythema, folliculitis, furunculosis, hair changes, hot flushes, nail disorder, night sweats, papillomatosis, photosensitivity reaction, pigment changes skin, rash maculopapular, severe cutaneous reaction associated with increased liver function tests, skin disorder, skin nodule, skin ulceration, Stevens-Johnson syndrome, sweating increased, urticaria, verruca, xeroderma
Special Senses: blepharitis, earache, ear pressure, eye irritation, hearing decreased, otitis, taste alteration, tinnitus, visual disturbance
Urinary System: micturition disorder, nephrolithiasis, renal calculus, urinary tract bleeding, urinary tract infection
Postmarketing Experience
Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with INVIRASE and saquinavir soft gel capsules alone or in combination with ritonavir.
What should I look out for while using Invirase?
INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g. anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients including ritonavir.
INVIRASE/ritonavir should not be administered concurrently with rifampin, terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir and ritonavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation (see ).
INVIRASE/ritonavir should not be given together with rifampin, due to the risk of severe hepatocellular toxicity if the three drugs are given together (see .
INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.
INVIRASE/ritonavir should not be administered concurrently with drugs listed in .
INVIRASE must be used in combination with ritonavir.
What might happen if I take too much Invirase?
There is limited experience of overdose with saquinavir.
No acute toxicities or sequelae were noted in 1 patient who ingested 8 grams of INVIRASE as a single dose. The patient was treated with induction of emesis within 2 to 4 hours after ingestion. A second patient ingested 2.4 grams of INVIRASE in combination with 600 mg of ritonavir and experienced pain in the throat that lasted for 6 hours and then resolved. In an exploratory Phase II study of oral dosing with INVIRASE at 7200 mg/day (1200 mg q4h), there were no serious toxicities reported through the first 25 weeks of treatment.
Treatment of overdose with saquinavir should consist of general supportive measures including monitoring of vital signs and ECG and observations of the patient's clinical status. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
How should I store and handle Invirase?
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.INVIRASE 200-mg capsules are light brown and green opaque capsules with ROCHE and 0245 imprinted on the capsule .INVIRASE 500-mg film-coated tablets are light orange to greyish- or brownish-orange, oval cylindrical, biconvex tablets with ROCHE and SQV 500 imprinted on the tablet face.They are supplied by as follows:INVIRASE 200-mg capsules are light brown and green opaque capsules with ROCHE and 0245 imprinted on the capsule .INVIRASE 500-mg film-coated tablets are light orange to greyish- or brownish-orange, oval cylindrical, biconvex tablets with ROCHE and SQV 500 imprinted on the tablet face.They are supplied by as follows:INVIRASE 200-mg capsules are light brown and green opaque capsules with ROCHE and 0245 imprinted on the capsule .INVIRASE 500-mg film-coated tablets are light orange to greyish- or brownish-orange, oval cylindrical, biconvex tablets with ROCHE and SQV 500 imprinted on the tablet face.They are supplied by as follows:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The pharmacokinetic properties of INVIRASE have been evaluated in healthy volunteers (n=351) and HIV-infected patients (n=270) after single- and multiple-oral doses of 25, 75, 200, and 600 mg three times daily and in healthy volunteers after intravenous doses of 6, 12, 36 or 72 mg (n=21). The pharmacokinetics of INVIRASE/ritonavir 1000/100 mg twice daily have also been evaluated in HIV-infected patients.
Similar bioavailability was demonstrated when INVIRASE 500 mg film-coated tablet (2 × 500 mg) and INVIRASE 200 mg capsule (5 × 200 mg) were administered with low-dose ritonavir (100 mg) under fed conditions. The ratio of mean exposures (90% confidence intervals) of tablets vs capsules were 1.10 (1.04-1.16) for AUC and 1.19 (1.14-1.25) for C.
Non-Clinical Toxicology
INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g. anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients including ritonavir.INVIRASE/ritonavir should not be administered concurrently with rifampin, terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir and ritonavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation (see ).
INVIRASE/ritonavir should not be given together with rifampin, due to the risk of severe hepatocellular toxicity if the three drugs are given together (see .
INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.
INVIRASE/ritonavir should not be administered concurrently with drugs listed in .
INVIRASE must be used in combination with ritonavir.
Drug interaction studies have been completed with INVIRASE and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for INVIRASE/ritonavir.
The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp.
Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in under . These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in , which summarizes the effect of saquinavir, administered as saquinavir soft gel capsules or INVIRASE, on the geometric mean AUC and C of coadministered drugs and , which summarizes the effect of coadministered drugs on the geometric mean AUC and C of saquinavir. Clinical dose recommendations can be found in . The magnitude of the interactions may be different when INVIRASE is given with ritonavir (see ).
When coadministering INVIRASE/ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations. Examples and clinical dose recommendations can be found in .
If a serious or severe toxicity occurs during treatment with INVIRASE, INVIRASE should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose INVIRASE may be considered. For antiretroviral agents used in combination with INVIRASE, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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