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Fortovase Side Effects, and Drug Interactions - Saquinavir Mesylate

Fortovase Side Effects, and Drug Interactions - Saquinavir Mesylate

SIDE EFFECTS

(see PRECAUTIONS)

INVIRASE may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with FORTOVASE. See Concomitant Therapy with Ritonavir Adverse Reactions for safety information with the recommended dosage regimen.

The safety of INVIRASE was studied in patients who received the drug either alone or in combination with zidovudine and/or HIVID (zalcitabine, ddC). The majority of adverse events were of mild intensity. The most frequently reported adverse events among patients receiving INVIRASE in clinical trials (excluding those toxicities known to be associated with zidovudine and HIVID when used in combinations) were diarrhea, abdominal discomfort, and nausea.

The following grade 2 to grade 4 adverse events, (considered at least possibly related to study drug or of unknown relationship) occurred in t2% of patients receiving INVIRASE 600 mg tid alone or in combination with zidovudine and/or HIVID: abdominal discomfort, abdominal pain, appetite disturbances, asthenia, buccal mucosa ulceration, diarrhea, dizziness, dyspepsia, extremity numbness, headache, mucosa damage, musculoskeletal pain, myalgia, nausea, paresthesia, peripheral neuropathy, pruritus, and rash.

Rare occurrences of the following serious adverse experiences have been reported during clinical trials of INVIRASE and were considered at least possibly related to use of study drugs: confusion, ataxia, and weakness; acute myeloblastic leukemia; hemolytic anemia; attempted suicide; Stevens-Johnson syndrome; seizures; severe cutaneous reaction associated with increased liver function tests; isolated elevation of transaminases; thrombophlebitis; headache; thrombocytopenia; exacerbation of chronic liver disease with Grade 4 elevated liver function tests, jaundice, ascites, and right and left upper quadrant abdominal pain; drug fever; bullous skin eruption and polyarthritis; pancreatitis leading to death; nephrolithiasis; thrombocytopenia and intracranial hemorrhage leading to death; peripheral vasoconstriction; portal hypertension; intestinal obstruction. These events were reported from a database of >6000 patients. Over 100 patients on INVIRASE therapy have been followed for >2 years.

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. Table 7 lists grades 2, 3 and 4 related adverse events that occurred in >2% of patients receiving FORTOVASE with ritonavir (1000/100 mg bid).

Table 7 : Grade 2, 3 and 4 Related Adverse Events (All Causality) Reported in >2% of Adult Patients in the MaxCmin 1 Study of FORTOVASE in Combination with Ritonavir 1000/100 mg bid
	FORTOVASE 1000 mg plus Ritonavir 100 mg bid (48 weeks) N=148 n(%=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)
Includes events with unknown relationship to study drug

Additionally, adverse events that occurred in clinical trials with FORTOVASE, which are not listed above, are listed for completeness. However, due to the higher bioavailability of FORTOVASE, these adverse events might not be predictive of the safety profile of INVIRASE.

Experience from Clinical Trials with FORTOVASE

The safety of FORTOVASE was studied in more than 500 patients who received the drug either alone or in combination with other antiretroviral agents. The most frequently reported adverse events among patients receiving FORTOVASE in combination with other antiretroviral agents were diarrhea, nausea, abdominal discomfort, and dyspepsia. Clinical adverse events of at least moderate intensity, which occurred in t2% of patients in 2 studies with FORTOVASE, which are not listed above, are listed below by body system.

Gastrointestinal Disorders: constipation, flatulence, vomiting

Body as a Whole: appetite decreased, chest pain, fatigue

Psychological: depression, insomnia, anxiety, libido disorder

Special Senses: taste alteration

Skin and Appendages: verruca, eczema

Laboratory Abnormalities with INVIRASE

Grade 3 and 4 lab abnormalities have been observed with FORTOVASE in combination with ritonavir. At 48 weeks, lab abnormalities included increased ALT, anemia, increased AST, increased GGT, hyperglycemia, hypertriglyceridemia, increased TSH, neutropenia, raised amylase, raised LDH, and thrombocytopenia.

INVIRASE may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with FORTOVASE.

In studies NV14255/ACTG 229 and NV14256, the following grade 3 or grade 4 abnormalities in laboratory tests were reported among patients receiving INVIRASE 600 mg tid alone or in combination with ZDV and/or HIVID:

Biochemistry

· Incidence between <1% and 4%-hypoglycemia, hyper- or hypocalcemia, hypophosphatemia, hyper- or hypokalemia, hyper- or hyponatremia, raised serum amylase grade 3 or 4 elevations in transaminases (SGOT [AST] SGPT [ALT]), hyperbilirubinemia

· Incidence of <5%: hyperglycemia. Incidence of between 7% and 12%: elevated creatine phosphokinase.

Hematology

· Incidence of <2%: thrombocytopenia and anemia.I Incidence of between 1% and 8%: leucopenia.

Additional marked lab abnormalities have been observed with FORTOVASE. These include: alkaline phosphatase (high), gamma GT (high), and triglycerides (high).

Monotherapy and Combination Studies

Other clinical adverse experiences of any intensity, at least remotely related to INVIRASE, including those in <2% of patients on arms containing INVIRASE in studies NV14255/ACTG229 and NV14256, and those in smaller clinical trials, are listed below by body system.

Body as a Whole: allergic reaction, anorexia, chest pain, edema, fatigue, fever, intoxication, parasites external, retrosternal pain, shivering, wasting syndrome, weakness generalized, weight decrease, redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution)

Cardiovascular: cyanosis, heart murmur, heart valve disorder, hypertension, hypotension, syncope, vein distended

Endocrine/Metabolic: dehydration, diabetes mellitus, dry eye syndrome, hyperglycemia, weight increase, xerophthalmia

Gastrointestinal: cheilitis, colic abdominal, constipation, dyspepsia, dysphagia, esophagitis, eructation, feces bloodstained, feces discolored, flatulence, gastralgia, gastritis, gastrointestinal inflammation, gingivitis, glossitis, hemorrhage rectum, hemorrhoids, hepatitis, hepatomegaly, hepatosplenomegaly, infectious diarrhea, jaundice, liver enzyme disorder, melena, pain pelvic, painful defecation, pancreatitis, parotid disorder, salivary glands disorder, stomach upset, stomatitis, toothache, tooth disorder, vomiting

Hematologic: anemia, bleeding dermal, microhemorrhages, neutropenia, pancytopenia, splenomegaly, thrombocytopenia

Musculoskeletal: arthralgia, arthritis, back pain, cramps leg, cramps muscle, creatine phosphokinase increased, musculoskeletal disorders, stiffness, tissue changes, trauma

Neurological: ataxia, bowel movements frequent, confusion, convulsions, dysarthria, dysesthesia, heart rate disorder, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, mouth dry, myelopolyradiculoneuritis, numbness face, pain facial, paresis, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, spasms, 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

Resistance Mechanism: abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, influenza, lymphadenopathy, moniliasis, tumor

Respiratory: bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection

Skin and Appendages: acne, alopecia, chalazion, dermatitis, dermatitis seborrheic, eczema, erythema, folliculitis, furunculosis, hair changes, hot flushes, nail disorder, night sweats, papillomatosis, photosensitivity reaction, pigment changes skin, rash maculopapular, skin disorder, skin nodule, skin ulceration, 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, renal calculus, urinary tract bleeding, urinary tract infection

Postmarketing Experience with INVIRASE and FORTOVASE

Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with INVIRASE and FORTOVASE and administration of INVIRASE and FORTOVASE in combination with ritonavir.

DRUG INTERACTIONS

Several drug interaction studies have been completed with both INVIRASE and FORTOVASE. Observations from drug interaction studies with FORTOVASE may not be predictive for INVIRASE. Because ritonavir is coadministered, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.

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 Table 4 under CONTRAINDICATIONS. Additional drugs that are not recommended for coadministration with INVIRASE and ritonavir are included in Table 5. 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 Table 2, which summarizes the effect of saquinavir, administered as FORTOVASE or INVIRASE, on the geometric mean AUC and C_max of coadministered drugs and Table 3, which summarizes the effect of coadministered drugs on the geometric mean AUC and C_max of saquinavir. Clinical dose recommendations can be found in Table 6. The magnitude of the interactions may be different when INVIRASE or FORTOVASE are given with ritonavir.

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 Table 6.

Table 5 Drugs That Should Not Be Coadministered With INVIRASE/Ritonavir
Drug Class: Drug Name	Clinical Comment
Antiarrhythmics: Amiodarone, bepridil, flecainide, propafenone, quinidine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions.
Antihistamines: astemizole*, terfenadine*	CONTRAINDICATED due to potential for serious and/or life-threatening cardiac arrhythmias.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Antimycobacterial Agents: rifampin	CONTRAINDICATED since the coadministration of this product with saquinavir in an antiretroviral regimen reduces the plasma concentrations of saquinavir.
Garlic Capsules	Garlic capsules should not be used while taking saquinavir (FORTOVASE) as the sole protease inhibitor due to the risk of decreased saquinavir plasma concentrations.
	No data are available for the coadministration of INVIRASE/ritonavir or FORTOVASE/ritonavir and garlic capsules.
GI Motility Agent: cisapride*	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort (hypericum perforatum)	WARNING coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	WARNING potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Sedatives/Hypnotics: triazolam, midazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
* No longer marketed in the US.

 

Table 6 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (Information in the table applies to INVIRASE/ritonavir)
Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
	HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Delavirdine	­ Saquinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
	Effect on delavirdine is not well established
	INVIRASE/ritonavir Interaction has not been evaluated
Non-nucleoside reverse transcriptase inhibitor: Efavirenz*, nevirapine	¯ Saquinavir ¯ Efavirenz	INVIRASE should not be given as the sole protease inhibitor to patients.
	INVIRASE/ritonavir Interaction has not been evaluated	Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV protease inhibitor: Indinavir*	­ Saquinavir	Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
	Effect on indinavir is not well established
	Interaction has not been evaluated
HIV protease inhibitor: Nelfinavir*	­ Saquinavir	Saquinavir 1200 mg bid with nelfinavir 1250 mg bid results in adequate plasma drug concentrations for both protease inhibitors.
	­ Nelfinavir
	INVIRASE/ritonavir Interaction has not been evaluated
HIV protease inhibitor: Ritonavir*	­ Saquinavir	The recommended dose regimen when ritonavir is given to increase saquinavir concentrations is 1000 mg saquinavir plus ritonavir 100 mg twice daily.
	« Ritonavir
HIV protease inhibitor: Lopinavir/ritonavir (coformulated capsule)*	­ Saquinavir	FORTOVASE (SQV) 800 mg bid + KALETRA produces ­ AUC, ­ Cmax, and ­ Cmin relative to FORTOVASE 1200 mg tid (see CLINICAL PHARMACOLOGY: Table 3)
	Effect on lopinavir is not well established
HIV fusion inhibitor: Enfuvirtide*	FORTOVASE Interaction has not been evaluated	No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with FORTOVASE/ritonavir1000/100 mg bid. No dose adjustments are required.
	FORTOVASE/ritonavir « enfuvirtide
	Other Agents
Antiarrhythmics: Lidocaine (systemic)	­ 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: Carbamazepine, phenobarbital, phenytoin	¯ Saquinavir	Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
	Effect on carbamazepine, phenobarbital, and phenytoin is not well established
	INVIRASE/ritonavir Interaction has not been evaluated
Anti-infective: Clarithromycin*	­ Saquinavir	No dose adjustment is required when the two drugs are coadministered for a limited time at the doses studied (clarithromycin500 mg bid and FORTOVASE 1200 mg tid for 7 days).
	­ Clarithromycin
	INVIRASE/ritonavir Interaction has not been evaluated
		For patients with renal impairment, the following dosage adjustments should be considered:
		· For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
		· For patients with CLCR<30 mL/min the dose of clarithromycin should be decreased by 75%.
		No dose adjustment for patients with normal renal function is necessary.
Antifungal: Ketoconazole*, itraconazole	­ Saquinavir	No dose adjustment is required when the two drugs are coadministered for a limited time at the doses studied (ketoconazole 400 mg qd and FORTOVASE 1200 mg tid). A similar increase in plasma concentrations of saquinavir could occur with itraconazole.
	« Ketoconazole
	INVIRASE/ritonavir Interaction has not been evaluated
Antimycobacterial Rifabutin*	¯ Saquinavir	INVIRASE should not be given as the sole protease inhibitor to patients.
	­ Rifabutin
		Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
Antimycobacterial Rifampin*	¯ Saquinavir	INVIRASE should not be given as the sole protease inhibitor to patients.
	­ Rifabutin
	INVIRASE/ritonavir Interaction has not been evaluated	Appropriate doses of the combination of rifampin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	­ Benzodiazepines	Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	­ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	¯ Saquinavir	Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
	INVIRASE/ritonavir Interaction has not been evaluated
Histamine H2-receptor antagonist: Ranitidine	­ Saquinavir	The increase is not thought to be clinically relevant and no dose adjustment of FORTOVASE is recommended.
	INVIRASE/ritonavir Interaction has not been evaluated
		Appropriate doses of the combination of ranitidine and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HMG-CoA reductase inhibitors: Simvastatin, lovastatin, atorvastatin	­ HMG-CoA reductase inhibitors	The combination of INVIRASE/ritonavir with simvastatin and lovastatin should be avoided. Use lowest possible dose of atorvastatin and with careful monitoring or consider other HMG-CoA reductase inhibitors such as pravastatin, fluvastatin and rosuvastatin.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	­ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic: Methadone	¯ Methadone	Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.
Oral contraceptives: Ethinyl estradiol	¯ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil*, vardenafil, tadalafil	­ Sildenafil	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.
	« Saquinavir
	­ Vardenafil
	­ Tadalafil
		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.
Tricyclic antidepressants: Amitriptyline, imipramine	­ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
*See CLINICAL PHARMACOLOGY: Pharmacokinetics, Tables 2 and 3 for magnitude of interactions

Drugs That Are Mainly Metabolized by CYP3A4

Although specific studies have not been performed, coadministration with drugs that are mainly metabolized by CYP3A4 (eg, calcium channel blockers, dapsone, disopyramide, quinine, amiodarone, quinidine, warfarin, tacrolimus, cyclosporine, ergot derivatives, pimozide, carbamazepine, fentanyl, alfentanyl, alprazolam, and triazolam) may have elevated plasma concentrations 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 (eg, phenobarbital, phenytoin, dexamethasone, carbamazepine) may result in decreased plasma levels of saquinavir.

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