Drug information of saquinavir

محل تبلیغ - صفحه داخلی بالا

saquinavir

فارسی

An HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases.

Mechanism of effect

Saquinavir inhibits the HIV viral proteinase by binding to the site of HIV-1 protease activity and inhibiting cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV. This results in the formation of immature, non-infectious viral particles.

Pharmacodynamic

Saquinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1.
Saquinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

Pharmacokinetics

  • Absorption: Poor absorption; increased with high fat meal
  • Protein Bound: ~98%
  • Distribution: Does not distribute into CSF, partition into tissue
  • Vd: 700 L
  • Metabolism: Extensively metabolized via hepatic CYP3A4; extensive first-pass effect
  • Elimination: Excretes into Feces: 81-88%; urine: 1-3%

Dosage

Usual Adult Dose for HIV Infection:

Standard dose: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day
Therapy-naive patients (starting therapy with saquinavir/ritonavir):
-The first 7 days: Saquinavir 500 mg plus ritonavir 100 mg orally twice a day
-After 7 days: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day
Patients switching immediately (no washout period) from another ritonavir-containing regimen (excluding delavirdine, rilpivirine): Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day

Patients switching from a regimen containing delavirdine or rilpivirine:
-The first 7 days: Saquinavir 500 mg plus ritonavir 100 mg orally twice a day
-After 7 days: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day

Usual Adult Dose for Non-occupational Exposure

US CDC recommendations: Saquinavir 1000 mg plus ritonavir 100 mg (or saquinavir 400 mg plus ritonavir 400 mg) orally twice a day
Duration of therapy: 28 days
-Prophylaxis should be started as soon as possible, within 72 hours of exposure.

Usual Adult Dose for Occupational Exposure

US Public Health Service working group recommendations: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day
Duration of therapy: 28 days, if tolerated
-Prophylaxis should be started as soon as possible, preferably within hours after exposure.

Usual Pediatric Dose for HIV Infection

16 years or older:

5 kg to <15 kg: Saquinavir 50 mg/kg/dose twice daily plus ritonavir 3 mg/kg/dose twice daily

15 kg to <40 kg: Saquinavir 50 mg/kg/dose (maximum dose: 1,000 mg/dose) twice daily plus ritonavir 2.5 mg/kg/dose twice daily

Standard dose: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day

Therapy-naive patients (starting therapy with saquinavir/ritonavir):

-The first 7 days: Saquinavir 500 mg plus ritonavir 100 mg orally twice a day
-After 7 days: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day
Patients switching immediately (no washout period) from another ritonavir-containing regimen (excluding delavirdine, rilpivirine): Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day

Patients switching from a regimen containing delavirdine or rilpivirine:

-The first 7 days: Saquinavir 500 mg plus ritonavir 100 mg orally twice a day
-After 7 days: Saquinavir 1000 mg plus ritonavir 100 mg orally twice a day

Renal Dose Adjustments

Mild or moderate renal dysfunction: No adjustment recommended. Severe renal dysfunction or end-stage renal disease: No adjustment recommended; caution recommended. Significant removal via dialysis is not likely (highly protein bound).

Liver Dose Adjustments

Mild or moderate liver dysfunction: No adjustment recommended.

When used with ritonavir:

-Severe liver dysfunction: Contraindicated

Alerts

Concerns related to adverse effects:

  • Altered cardiac conduction: Saquinavir/ritonavir prolongs the QT interval, potentially leading to torsade de pointes, and prolongs the PR interval, potentially leading to heart block. Second- or third-degree AV block has been reported (rare). An ECG should be performed for all patients prior to starting saquinavir/ritonavir therapy; do not initiate therapy in patients with a baseline QT interval ≥450 msec or diagnosed with long QT syndrome. If baseline QT interval <450 msec, may initiate saquinavir/ritonavir, but a subsequent ECG is recommended after ~10 days of therapy. For patients already receiving saquinavir/ritonavir that require concomitant therapy with another medication with the potential to prolong the QT interval, may initiate the concomitant therapy if baseline QT interval <450 msec, but a subsequent ECG is recommended after 3 to 4 days of therapy. If subsequent QT interval is >480 msec or is prolonged over baseline by >20 msec, therapy should be discontinued. Patients who may be at increased risk for QT- or PR-interval prolongation include those with heart failure, brady arrhythmias, hepatic impairment, electrolyte abnormalities, ischemic heart disease, cardiomyopathy, structural heart disease, or those with pre-existing cardiac conduction abnormalities; ECG monitoring is recommended for these patients.
  • Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).
  • Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
  • Increased cholesterol: Increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.
  • Photosensitivity reactions: May cause photosensitivity reactions (eg, exposure to sunlight may cause severe sunburn, skin rash, redness, or itching); advise patient to avoid exposure to sunlight and artificial light sources (eg, sunlamps, tanning bed/booth) and to wear protective clothing, wide-brimmed hats, sunglasses, and lip sunscreen (SPF ≥15). Sunscreen should be used (broad-spectrum sunscreen or physical sunscreen [preferred] or sunblock with SPF ≥15).

Disease-related concerns:

  • Diabetes: Changes in glucose tolerance, hyperglycemia, exacerbation of diabetes, DKA, and new-onset diabetes mellitus have been reported in patients receiving protease inhibitors.
  • Electrolyte imbalances: Correct electrolyte abnormalities prior to treatment and monitor potassium and magnesium levels during therapy.
  • Hemophilia A or B: Use with caution in patients with hemophilia A or B; increased bleeding during protease inhibitor therapy has been reported.
  • Hepatic impairment: May cause hepatitis and/or exacerbate preexisting hepatic dysfunction; use with caution in patients with underlying mild-to-moderate hepatic disease, including hepatitis B or C, cirrhosis, or chronic alcoholism; contraindicated in severe hepatic impairment.

Other warnings/precautions:

  • Appropriate use: Must be used in combination with ritonavir. Ritonavir significantly inhibits metabolism of this drug, increasing plasma saquinavir levels.
  • Cross-resistance to other HIV drugs: Continued administration after loss of viral suppression efficacy may increase the likelihood of cross-resistance to other protease inhibitors. Promptly discontinue therapy if viral suppression response is lost.

Monitoring Parameters

Monitor ECG [prior to therapy and after 3 to 4 days of therapy (patients already receiving saquinavir/ritonavir and initiating concomitant QT prolonging therapy) or after ~10 days of therapy (patients initiating saquinavir/ritonavir); serum potassium and magnesium levels, triglycerides and cholesterol (prior to initiation and periodically during therapy); viral load, CD4 count; glucose

Points of recommendation

Tell all of your health care providers that you take this medicine (saquinavir tablets). This includes your doctors, nurses, pharmacists, and dentists.

  • If you have an allergy to saquinavir or any other part of this medicine (saquinavir tablets).
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Heart block without a working pacemaker, liver disease, or low blood magnesium or potassium levels.
  • If you have ever had a long QT on ECG.
  • If you are not taking ritonavir.
  • If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine, like certain drugs that are used for high cholesterol, migraines, or mood problems. There are many drugs that must not be taken with this medicine (saquinavir tablets).
  • If you are breast-feeding. Do not breast-feed while you take this medicine.
  • This medicine interacts with many other drugs. The chance of this medicine's side effects may be raised or how well this medicine (saquinavir tablets) works may be lowered. The chance of the other drugs' side effects may also be raised. This may include very bad, life-threatening, or deadly side effects. Check with your doctor and pharmacist to make sure that it is safe for you to take this medicine with all of your other drugs (prescription or OTC, natural products, vitamins).
  • You may have some heart tests before starting this medicine.
  • A type of abnormal heartbeat (prolonged QT interval) can happen with this medicine. Call your doctor right away if you have a fast heartbeat, a heartbeat that does not feel normal, or if you pass out.
  • If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
  • Some people with hemophilia have had times of more bleeding when taking drugs like this one. If you have hemophilia, talk with your doctor.
  • This medicine may cause high cholesterol and triglyceride levels. Talk with the doctor.
  • This medicine is not a cure for HIV. This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
  • When taking saquinavir tablets, birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Take your dose of saquinavir and ritonavir by mouth at the same times, as directed by your doctor, with a meal or up to 2 hours after a meal, usually 2 times daily.
  • Keep taking this medicine (saquinavir tablets) as you have been told by your doctor or other health care provider, even if you feel well.
  • To reduce your risk of side effects, your doctor may direct you to start saquinavir at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.
  • This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at the same times each day.
  • It is important that you do not miss or skip a dose of this medicine during treatment. but if you miss a dose: Take a missed dose as soon as you think about it. If it is close to the time for your next dose, skip the missed dose and go back to your normal time. Do not take 2 doses at the same time or extra doses.
  • Administer saquinavir and ritonavir at the same time and within 2 hours after a full meal. Patients unable to swallow capsules may open capsules and mix contents with 15 mL of syrup (or sorbitol if diabetic or glucose intolerant) or with 3 teaspoons of jam. Mixture should be stirred for 30 to 60 seconds and then administered entirely. Suspension should be at room temperature prior to administration.

Pregnancy level

B

Adverse events were not observed in animal reproduction studies. Saquinavir has a low level of transfer across the human placenta. Data collected by the antiretroviral pregnancy registry are insufficient to evaluate human teratogenic risk.
A small increased risk of preterm birth has been associated with maternal use of protease inhibitor-based combination antiretroviral therapy during pregnancy; however, the benefits of use generally outweigh this risk and protease inhibitors (PIs) should not be withheld if otherwise recommended. Information related to stillbirth, low birth weight, and small for gestational age infants is limited. Long-term follow-up is recommended for all infants exposed to antiretroviral medications;
children who develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction. Hyperglycemia, new onset of diabetes mellitus, or diabetic ketoacidosis have been reported with PIs; it is not clear if pregnancy increases this risk.

Combination antiretroviral (cART) therapy is recommended for all HIV-infected pregnant women to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should begin as soon as possible after diagnosis.
The Health and Human Services (HHS) Perinatal HIV Guidelines do not recommend ritonavir-boosted saquinavir for initial use in antiretroviral-naive pregnant women due to potential toxicity, twice-daily dosing requirements, and limited data in pregnancy; use of saquinavir without ritonavir is not recommended in any patient. Based on available data, dose adjustments are not required in pregnant women. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated. Monitoring during pregnancy is more frequent than in non-pregnant adults; cART should be continued postpartum.

For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s) and expert consultation is recommended; modification of therapy (if needed) and optimization of the woman’s health should be done prior to conception. HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

During pregnancy, this medication should be used only when clearly needed. Treatment can lower the risk of passing HIV infection to your baby, and saquinavir may be part of that treatment. Discuss the risks and benefits with your doctor.

Breast feeding warning

In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. No published information is available on the use of saquinavir during breastfeeding.
In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through at least 12 months of life up to 24 months of life.[1] The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include:
1) zidovudine, lamivudine and efavirenz;
2) zidovudine, lamivudine and nevirapine; or
3)
tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date. It is unknown if this medication passes into breast milk. Because breast milk can transmit HIV, do not breast-feed.

Comments
    No comments yet.

Ask a Pharmacist