Proposed Preferred Drug List with
Clinical Criteria Proposal for TennCare
November 14, 2013
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November 14, 2013 Tennessee PAC
Responsibilities of the TennCare Pharmacy Advisory Committee Source: Tennessee Code/Title 71 Welfare/Chapter 5 Programs and Services for Poor Persons/Part 24 Tennessee TennCare Pharmacy Advisory Committee/71-5-2401 through 71-52404.
Make recommendations regarding a preferred drug list (PDL) to govern all state expenditures for prescription drugs for the TennCare program. o The TennCare Pharmacy Advisory Committee shall submit to the bureau of TennCare both specific and general recommendations for drugs to be included on any state PDL adopted by the bureau. In making its recommendations, the committee shall consider factors including, but not limited to, efficacy, the use of generic drugs and therapeutic equivalent drugs, and cost information related to each drug. The committee shall also submit recommendations to the bureau regarding computerized, voice, and written prior authorization, including prior authorization criteria and step therapy. o The state TennCare pharmacy advisory committee shall include evidence-based research in making its recommendations for drugs to be included on the PDL. o The TennCare bureau shall consider the recommendations of the state TennCare pharmacy advisory committee in amending or revising any PDL adopted by the bureau to apply to pharmacy expenditures within the TennCare program. The recommendations of the committee are advisory only and the bureau may adopt or amend a PDL regardless of whether it has received any recommendations from the committee. It is the legislative intent that, insofar as practical, the TennCare bureau shall have the benefit of the committee’s recommendations prior to implementing a PDL or portions thereof. Keep minutes of all meetings including votes on all recommendations regarding drugs to be included on the state preferred drug list The chair may request that other physicians, pharmacists, faculty members of institutions of higher learning, or medical experts who participate in various subspecialties act as consultants to the committee as needed.
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PDL Decision Process The primary clinical decision that needs to be made is determining if the drugs within the therapeutic class of interest can be considered therapeutic alternatives. A Therapeutic Alternative is defined by the AMA as: “drug products with different chemical structures but which are of the same pharmacological and/or therapeutic class, and usually can be expected to have similar therapeutic effects and adverse reaction profiles when 1 administered to patients in therapeutically equivalent doses” . The Committee should not feel obligated to decide if every drug within the therapeutic class is exactly equal to all other drugs within the class, nor should they feel obligated to decide if every drug within the therapeutic class works equally well in every special patient population or in every disease. In special situations (e.g., presence of comorbid conditions) and in special populations (e.g., pediatrics) use of a non-preferred drug might be the most appropriate therapy. These cases can be handled through prior authorization (PA). PA serves as a “safety valve” in that it facilitates use of the most appropriate agent regardless of PDL status. LENGTH OF AUTHORIZATIONS: Dependent upon diagnosis and length of therapy needed to treat. (Most medications are used chronically, and thus would be approved for 1 year.) 1. Is there any reason the patient cannot be changed to a medication not requiring prior approval within the same class? Acceptable reasons include: Allergy to medications not requiring prior approval Contraindication to or drug-to-drug interaction with medications not requiring prior approval History of unacceptable/toxic side effects to medications not requiring prior approval 2. The requested medication may be approved if both of the following are true: If there has been a therapeutic failure of at least two medications within the same class not requiring prior approval (unless otherwise specified) The requested medication’s corresponding generic (if a generic is available and preferred by the State) has been attempted and failed or is contraindicated 3. The requested medication may be approved if the following is true: An indication which is unique to a non-preferred agent and is supported by peer-reviewed literature or an FDA approved indication exists. ---------------------------------------------------------------------------------------------------------------------------- ---The information provided for each drug class is organized into the following sections, when applicable: BACKGROUND: General overview Pharmacology Therapeutic effect(s) Adverse reactions Outcomes data Place in therapy according to current Treatment Guidelines RECOMMENDATION: General recommendation regarding utility and therapeutic equivalence among the agents in the class, as well as requirements for product availability (PDL placement)
1
AMA Policy H-125.991 Drug Formularies and Therapeutic Interchange
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ANTI-INFECTIVES RE-REVIEW: ORAL ANTIFUNGALS FOR SYSTEMIC INFECTIONS BACKGROUND
This review will focus on oral antifungal agents used for the treatment of systemic infections and includes fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, posaconazole, and voriconazole. Fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole are azole antifungal agents which have a broad spectrum of activity. The azole antifungals alter the fungal cell membrane by inhibiting ergosterol synthesis. Flucytosine is a pyrimidine antifungal agent which works by inhibiting fungal deoxyribonucleic acid synthesis. Griseofulvin exerts its fungistatic activity by disrupting the mitotic spindle structure of the fungal cell, which causes an arrest of metaphase of cell division. The azole antifungals have a broad spectrum of activity and a wide variety of indications including but not limited to aspergillosis, Candida infections, dermatophyte infections and cryptococcal infections. Of note, ketoconazole is now indicated only for the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients who are intolerant to, or who have failed other agents. Flucytosine is used in combination with amphotericin B for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus. It should not be used as monotherapy due to the emergence of resistance. Griseofulvin is indicated for the treatment of ringworm infections of the body, skin, hair, and nails, namely tinea corporis, tinea pedis, tinea cruris, tinea barbae, tinea capitis, and tinea unguium. For a complete listing of FDA-approved indications please refer to pages two and three of the Magellan therapeutic class review. The most common adverse reactions associated with the azole antifungals include nausea, vomiting and headache. Other common and severe adverse reactions are as follows: o Fluconazole: Severe: QT interval prolongation, Torsades de pointes, Stevens-Johnson Syndrome, Toxic epidermal necrolysis, agranulocytosis, anaphylaxis, seizure o Flucytosine: Common: abdominal pain, diarrhea, nausea, vomiting, confusion, headache, hallucinations Severe: cardiotoxicity, leukopenia, myelosupression, thrombocytopenia, renal failure o Griseofulvin: Common: photosensitivity, rash, urticarial, diarrhea, nausea, vomiting, headache Severe: acroparesthesia, elevated liver function tests, jaundice o Itraconazole: Common: rash, rhinitis, sinusitis, upper respiratory infection Severe: congestive heart failure, Stevens-Johnson syndrome, pancreatitis, hepatotoxicity, anaphylaxis, hearing loss o Ketoconazole: Severe: hepatotoxicity, anaphylaxis, hypersensitivity reaction o Posaconazole: Common: hypokalemia, diarrhea, fever Severe: prolonged QT interval, Torsades de pointes, cholestasis, liver failure o Voriconazole: Common: rash, visual disturbance, hallucinations, fever Severe: hepatitis, liver failure, optic neuritis, papilledema, prolonged QT interval, Tosades de pointes, acute renal failure, pancreatitis, exfoliative cutaneous reactions including Stevens-Johnson Syndrome, photosensivity
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ANTI-INFECTIVES o
o
o
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Contraindications: Fluconazole is associated with QT prolongation and is a moderate CYP3A4 inhibitor. Fluconazole is contraindicated with concurrent administration of drugs that prolong the QT interval and are metabolized via CYP3A4 such as quinidine and pimozide. Avoid concomitant administration of fluconazole and voriconazole, and fluconazole and erythromycin. Griseofulvin is contraindicated in patients with porphyria and hepatocellular failure. Griseofulvin is also contraindicated in pregnancy; therefore, additional contraceptive measures should be taken during treatment with griseofulvin and for one month after cessation of treatment. Males should wait at least six months after cessation of therapy to father a child. Itraconazole should not be administered to women considering pregnancy or who are pregnant. Simvastatin and lovastatin, which are metabolized by CYP 3A4, are contraindicated with itraconazole. Itraconazole is contraindicated in patients with ventricular dysfunction as evidenced by congestive heart failure (CHF) or a history of CHF. Concomitant administration of nisoldipine and itraconazole is contraindicated. Ketoconazole is a strong inhibitor of the CYP3A4 system. Due to this, use of this agent is contraindicated with other drugs that are metabolized by CYP3A4. Black Box Warnings: Flucytosine carries a black boxed warning regarding its use in patients with impaired renal function, due to potential accumulation of the drug. Itraconazole carries a black boxed warning regarding the risk of congestive heart failure, stating it should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure or a history of congestive heart failure. Itraconazole also carries a black boxed warning regarding drug interactions which may result in serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest and/or sudden death. Co-administration of cisapride, pimozide, quinidine, dofetilide or levacetylmethadol (levomethadyl) with itraconazole is contraindicated. Ketoconazole carries a black box warning regarding the risk of hepatotoxicity and fatalaties. Use in patients with hepatic disease is contraindicated. It also carries a black box warning regarding the risk drug interactions with astemizole, cisapride, terfenadine, and triazolam due to the potential for serious cardiovascular adverse events. Precautions/warnings: Fluconazole should be administered with caution in patients with liver or renal dysfunction. It has been associated with rare cases of serious hepatic toxicity including fatalities, usually in patients with serious underlying medical conditions. Flucytosine should be used with extreme caution in patients with bone marrow depression. Griseofulvin is derived from a species of penicillin which may result in cross-sensitivity. Adrenal insufficiency has also been reported with the administration of ketoconazole due to the inhibition of production of corticosteroids. Monitor adrenal function in those patients with existing adrenal concerns while they are utilizing oral ketoconazole therapy. Rare cases of torsades de pointes have been reported in patients taking posaconazole and voriconazole. These agents should be administered with caution in patients with potentially proarrhythmic conditions.
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ANTI-INFECTIVES
Photosensitivity may occur with use of griseofulvin or voriconazole. Patients should avoid intense or prolonged exposure to direct sunlight. o Numerous drug-drug interactions are associated with the oral antifungal agents. Contraindications are specified above, for a complete listing, please reference pages 12-14 of the Magellan Therapeutic Class Review. Current clinical guidelines recommend the use of various oral antifungal agents as first-or second-line treatment options for various infections. The Infectious Diseases Society of America (IDSA) recommends the use of voriconazole as initial therapy in patients with pulmonary aspergillosis. Posaconazole is recommended for aspergillus prophylaxis in hematopoietic stem cell transplant patients with graft-vs-host-disease as well as in neutropenic patients with cancer. IDSA recommends fluconazole as the treatment of choice in neutropenic and non-neutropenic patients with candidiasis. A safety alert issued by the FDA warns that ketoconazole tablets can cause severe liver injuries, adrenal gland problems and significant drug interactions. Additionally, a contraindication has been added for patients with hepatic disease. Due to these changes, ketoconazole tablets are no longer recommended as first-line treatment for any fungal infection, but should be reserved for the treatment of endemic mycoses only when alternaltive antifungal therapies have failed or are not tolerated.
RECOMMENDATION The oral antifungal agents are FDA-approved to treat a wide variety of infections, including but not limited to aspergillosis, blastomycosis and histoplasmosis, candidiasis, cryptococcal infections and dermatophyte infections. Clinical trials demonstrate efficacy within the FDA-approved indications and current clinical guidelines recommend the use of various oral antifungal agents as first- or second-line treatment options for various infections. Due to the relative safety and efficacy of fluconazole and griseofulvin in the treatment of fungal infections, it is recommended these agents should be available. Ketoconazole, itraconazole, posaconazole and voriconazole are all effective for their respective FDA-approved indications; however, these agents are associated with significant adverse events and/or have very specific FDA-approved indications; therefore, these agents should be subject to clinical criteria. Due to the emergence of resistance, flucytosine is only indicated to be given in combination with amphotericin B; therefore, this agent should be subject to clinical criteria. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ORAL ANTIFUNGALS FOR SYSTEMIC INFECTIONS PREFERRED NON-PREFERRED QL PA fluconazole (compares to DIFLUCAN) ANCOBON (flucytosine) QL griseofulvin suspension DIFLUCAN (fluconazole) PA Gris-Peg (griseofulvin) flucytosine (compares to ANCOBON) GRIFULVIN V (griseofulvin) GRISEOFULVIN ULTRAMICROSIZE (compares to GrisPeg) griseofulvin microsize PA, QL itraconazole (compares to SPORANOX) PA ketoconazole PA NOXAFIL (posaconazole) PA, QL ONMEL (itraconazole) PA, QL SPORANOX (itraconazole) PA VFEND (voriconazole) PA voriconazole (compares to VFEND) Note: PA criteria & QLs for itraconazole products previously presented and approved with agents for onychomycosis
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ANTI-INFECTIVES Prior Authorization Criteria for ketoconazole Ketoconazole will be approved for patients who meet the following criteria: Treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis or paracoccidioidomycoisis, AND Patient has tried and failed or is intolerant, refractory or resistant to other antifungals Note: If started as an inpatient hospital regimen and this is a continuation of therapy, then the drug is approvable COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for fluconazole (Diflucan) suspension
No PA required for 11 years old and younger. All others: Will be approved for patients unable to swallow tablets.
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for flucytosine/Ancobon Individuals started on flucytosine therapy in the hospital will be approved for this agent following hospital discharge in order to allow for completion of the course of therapy. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for NOXAFIL NOXAFIL will be approved if used for ANY of the following: As indicated for the prophylaxis of invasive Aspergillus and/or Candida in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoetic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD) or recipients with hematologic malignancies (leukemia, lymphoma, myelodysplastic syndromes) with prolonged neutropenia from chemotherapy Treatment of Fusariosis disease Treatment of Zygomycetes disease Treatment of other fungal infections or molds that are refractory or resistant to, or in patient who have a contraindication or intolerance to, itraconazole or voriconazole Note: If started as an inpatient hospital regimen and this is a continuation of therapy, then the drug is approvable. COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
ANTI-INFECTIVES Prior Authorization Criteria for voriconazole/Vfend VFEND will be approved for the following diagnoses: Treatment of invasive aspergillosis Serious fungal infections caused by S. apiospermum and Fusarium species including F. solani Part of standard anti‐fungal regimen in febrile neutropenic patients Other fungal infections that are refractory or resistant to other oral triazole agents (i.e., fluconazole,ketoconazole, itraconazole) Note: If started as an inpatient hospital regimen and this is a continuation of therapy, then the drug is approvable COMMITTEE VOTE: APPROVED
DISAPPROVED
Quantity Limits fluconazole (DIFLUCAN) 150 mg
APPROVED with MODIFICATION
2 per 26 days
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. 3. Magellan Medicaid Administration. Antifungals, Oral Therapeutic Class Review. August 1, 2013. 4. Freifled A, Bow E, Sepkowitz K, Boeckh M, Ito J, Mullen C, et al. Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. CID. 2011;52:e56-e93. 5. 12. Pappas P, Kauffman C, Andes D, Benjamin D, Calandra T, Edwards J,, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. CID. 2009;48:503-35. 6. FDA drug safety communication: FDA limits use of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. Available at http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed July 31 2013.
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CARDIOVASCULAR AGENTS RE-REVIEW: LIPOTROPICS MISCELLANEOUS BACKGROUND
Familial hypercholesterolemia (FH) is a rare genetic disorder leading to accumulation of LDL (low density lipoprotein) particles in plasma and premature cardiovascular disease. There are 2 major categories of familial hypercholesterolemia, homozygous and heterozygous. The more severe form, homozygous familial hypercholesterolemia (HoFH) is rare, occurring in about one out of a million people in the US. In HoFH, LDL receptor activity is nearly absent and LDL-C (low-density lipoprotein cholesterol) levels commonly range between 400-1,000 mg/dL. The less serious form, heterozygous familial hypercholesterolemia (HeFH) occurs in one in 500 persons in the US. Coronary Artery Disease (CAD) symptoms begin to manifest in the fourth and fifth decades of life, in men and women, respectively. Most patients with HoFH will form xanthelasmas (yellowish collection of cholesterol under the skin) and cutaneous xanthomas within the first few months of life. Patients with HoFH express little or no LDL-receptor activity and become resistant to diet modifications and most medications indicated for lowering cholesterol. This class review will focus on 2 agents, oral lomitapide and mipomersen sodium injectable. Lomitapide binds and inhibits microsomal triglyceride transfer protein (MTP) which resides in the lumen of the endoplasmic reticulum. Thus preventing the assembly of apolipoprotein B(apo B)containing lipoproteins in enterocytes and hepatocytes and inhibiting the synthesis of chylomicrons and very low density lipoprotein (VLDL) which leads to reduced levels of plasma LDL-C (low density lipoprotein cholesterol). Mipomersen is an antisense oligonucleotide (ASO). It inhibits the synthesis of apo B-100, the principal apolipoprotein of LDL and VLDL. Mipomersen inhibits synthesis of apo B by sequence-specific binding to its messenger ribonucleic acid (mRNA), resulting in degradation of the mRNA through enzyme-mediated pathways or disruption of mRNA function through binding alone. Lomitapide and Mipomersen are both FDA approved as an adjunct to a low-fat diet and other lipid-lowering treatments to reduce LDL-C, total cholesterol (TC), apo B, and non-HDL-C (high density lipoprotein cholesterol) in patients with HoFH. Both lomitapide and mipomersen are contraindicated in patients with moderate to severe hepatic impairment (Child Pugh category B or C) or active liver disease, including unexplained persistent abnormal liver function tests. Both agents carry a boxed warning of the risk of hepatotoxicity resulting from increases in transaminases and hepatic steatosis. As a result of the risk of hepatotoxicity, lomitapide and mipomersen are only available through restricted distribution under the risk evaluation and mitigation strategy (REMS) program. Only certified providers and pharmacies may prescribe and dispense these two agents. Providers must complete a REMS program prescriber enrollment form, complete a prescriber training module, and submit a REMS Prescription Authorization Form for each new prescription. Precaution should be utilized when lomitapide and mipomersen are taken with other medications that are known to be hepatotoxic (isotretinoin, amiodarone, high doses of APAP [>4gm/day for 3 or more days]). Patient should also limit alcohol intake to no more than one alchoholic beverage per day to prevent increased levels of hepatic fat. The most common adverse events associated with these agents includes: o lomitapide: abdominal & back pain, headache, abnormal LFTs, constipation and dyspepsia o mipomersen: injection site reactions, flu-like symptoms, increase in ALT and AST liver transaminases and nausea Lomitapide is classified as a pregnancy category X drug and is contraindicated for use during pregnancy because the drug may cause fetal harm. Females of reproductive potential should have a negative pregnancy test before starting lomitapide and should use effective contraception during therapy. In contrast, mipomersen is classified as a pregnancy category B drug. Mipomersen dos not currently have any clinically relevant drug interactions. However, lomitapide should not be given with strong CYP3A4 inhibitiors (e.g. ketoconazole, boceprevir, clarithromycin, ritonavir, etc)
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appr
CARDIOVASCULAR AGENTS
The National Lipid Association Expert Panel on Familial Hypercholesterolemia guidelines recommend: o A low-fat, low-cholesterol diet, tobacco cessation, physical activity, and maintenance of a healthy body weight. o Moderate or high doses of a high-potency statin to reduce LDL-C at least 50% from baseline o If patient is unable to meet LDL-C goal with statin, additional agents such as ezetimibe, bile acid sequestrants, or niacin may be added to statin therapy. o LDL-C apheresis is recommended for patients with HoFH who have an LDL-C level of at least 300mg/dL despite maximal drug therapy for at least 6 months.
RECOMMENDATION Familial Hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) levels associated with an increased risk of atherosclerosis. Lomitapide and mipomersen are FDA approved as an adjunct to a low-fat diet and other lipid-lowering treatments to reduce LDL-C, total cholesterol (TC), apo B, and non-HDL-C (high density lipoprotein cholesterol) in patients with HoFH. The National Lipid Association guidelines for the management of Familial Hypercholesterolemia recommend dietary and lifestyle changes in addition to pharmacological treatment. Statin agents are the first line of therapy to reduce the LDL-C by 50% from baseline. For patients whom the LDL-C goal is unable to be met, statin therapy may be intensified with ezetimibe, bile acid sequestrants or niacin. Both lomitapide and mipomersen carry black box warnings for the risk of hepatotoxicity and precautions when taking with other drugs. It is recommended that mipomersen and lomitapide are subject to prior authorization to reserve use for patients with Homozygous Familial Hypercholesterolemia (HoFH). COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ORAL ANTIFUNGALS FOR SYSTEMIC INFECTIONS PREFERRED NON-PREFERRED PA PA KYNAMRO (mipomersen sodium) JUXTAPID (lomitapide) Prior Authorization Criteria for JUXTAPID Will be Approvved if All of the following criteria is met: Diagnosis of Homozygous Familial Hypercholesterolemia(HoFH) AND Member will be concurrently taking other lipid-lowering medications AND Clinically valid reason as to why preferred agent cannot be used AND If female, documentation patient is not currently pregnant COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for KYNAMRO Will be approved if All of the following criteria is met: Diagnosis of Homozygous Familial Hypercholesterolemia(HoFH) AND Member will be concurrently taking other lipid-lowering medications COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CARDIOVASCULAR AGENTS Quantity Limits JUXTAPID
5mg/10mg: 1 capsule/day 20mg: 3 capsules/ day 200mg/ml: 4 syringes/month
KYNAMRO COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. 3. Magellan Medicaid Administration. Lipotropics, Other Therapeutic Class Review. February 12, 2013. 4. Goldberg AC, Hopkins PN, Toth PP, et al. Familial Hypercholersterolemia: Prevalence, Genetics, Diagnosis and Screening Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(Suppl 3):S33-40. RE-REVIEW: LIPOTROPICS NIACIN DERIVATIVES BACKGROUND
Familial hypercholesterolemia (FH) is a genetic disorder characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol. There are 2 major categories of familial hypercholesterolemia. The more severe form, homozygous familial hypercholesterolemia (HoFH) is rare, occurring in about one out of a million people in the US. In HoFH, LDL receptor activity is nearly absent and LDL-C (low-density lipoprotein cholesterol) levels commonly range between 400-1,000 mg/dL. Severe and widespread atherosclerosis affects all major arteries and children are at risk for early coronary events and valve abnormalities, particularly aortic stenosis.The less serious form, heterozygous familial hypercholesterolemia (HeFH) occurs in one in 500 persons in the US. Coronary Artery Disease (CAD) symptoms begin to manifest in the fourth and fifth decades of life, in men and women, respectively. Additional risk factors (e.g. genetic, metabolic and environmental) can lead to variations in the clinical manifestations and severity of atherosclerotic disease of HeFH. Accumulation of cholesterol in nonvascular tissue (cornea, skin, tendons, and joints) also commonly occurs in children with HoFH, and in adults with HeFH. Niacin (nicotinic acid) inhibits lipolysis in adipocytes and possibly inhibits hepatic triglyceride (TG) production resulting in a reduction in the synthesis of VLDL (very low-density lipoprotein) that is available for conversion to LDL-C. It may involve several actions including partial inhibition of the release of free fatty acids from adipose tissue and increased lipoprotein lipase activity. Niacin also increases high-density lipoprotein cholesterol (HDL-C) by reducing the hepatic uptake of HDL-C. Nicotinic acid increases HDL-C levels by 15 to 35 percent. ® ® This class review will focus on two agents, niacin IR (Niacor ) and niacin ER (Niaspan ). A few adverse events associated with these agents includes: abdominal pain (niacin ER), headache, abnormal liver function tests (LFTs), dyspepsia and flushing. Due to intolerance, patients often need to take aspirin prior to each dose of niacin IR to reduce the vasodilation and flushing associated with immediate-release niacin. In an effort to increase tolerance, a film-coated, extended-release niacin (Niaspan) was developed. However, flushing has been reported to occur ® in about 88% of patients who take niacin ER (Niaspan ). ® Niacin ER (Niaspan ) is contraindicated in patients with chronic liver disease, active peptic ulcer disease, or arterial bleeding. Liver function tests should be monitored in all patients during therapy at roughly 6-month intervals or when clinically indicated. If transaminase levels (i.e., ALT or AST) rise to 3 times the upper limit of normal, or clinical symptoms of hepatic dysfunction are present, niacin should be discontinued. Caution should also be used when niacin ER is used in patients with unstable angina or in the acute phase of a myocardial infarction (MI), particularly
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CARDIOVASCULAR AGENTS
when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents. Caution should be observed when niacin is administered concomitantly with anticoagulants. Both niacin IR and niacin ER have been associated with small but statistically significant increases in prothrombin time. When niacin is taken concurrently with lovastatin or simvastatin, the dose of niacin ER should not exceed 2,000 mg while lovastatin or simvastatin doses should not exceed 40mg. Additionally, caution should be taken when niacin is given to diabetic patients and patients with gout, as high doses of niacin may cause hyperglycemia and hyperuricemia. Niacin doses above the recommended daily allowance (RDA) such as levels required for treatment of hyperlipidemia classifies the niacin agents as pregancy category C. o Drug Interactions: Niacin ER: administration with cholestyramine or colestipol reduces absorption of niacin. Niacin IR and ER: concurrent use with a statin drug may increase risk of myopathy. The third report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel(ATP) III suggest that fibric acids or nicotinic acid are alternatives to statin therapy in patients with LDL-C 100 to 130 mg/dL and low HDL-C. o Based on data from the Heart Protection Study (HPS), NCEP guidance further indicates that, in patients with low HDL-C, fibric acids or nicotinic acid should be used in combination with a LDL-C lowering drug, rather than as monotherapy. o For patients with LDL-C levels >130 mg/dL, standard doses of statins may be insufficient to achieve the goal of 500 mg/dL should be started on fibrate therapy in addition to statin therapy to prevent acute pancreatitis. If treatment with a statin (including trials of higher-dose statins and higher-potency statins) does not achieve goal levels, intensification of LDL-C–lowering drug therapy with a bile acid sequestrant or niacin is reasonable. For patients who do not tolerate statins, LDL-C–lowering therapy with bile acid sequestrants and/or niacin is considered an alternative option.
RECOMMENDATION The niacin derivatives have been shown to reduce the risk of coronary heart disease (CHD) and yield a significant reduction in LDL-C as well as an increase in HDL-C when given in combination with a statin agent. The National Cholesterol Education Program (NCEP) Adult Treatment Panel(ATP) III report suggest that fibric acid or nicotinic acid are alternatives to statin therapy in patients with a LDL-C of 100 to 130 mg/dL and a low HDL-C. Clinical guidelines consider statin agents as first line drugs for lowering LDL-C levels and niacin is recommended as a second line agent or an adjunctive therapy option in the management of hypercholesterolemia. It is recommended that niacin derivative agents are subject to prior authorization. COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CARDIOVASCULAR AGENTS PREFERRED n/a
RE-REVIEW: LIPOTROPICS NIACIN DERIVATIVES NON-PREFERRED NIACIN ER (compares to Niaspan) PA NIACOR (niacin IR) PA Niaspan (niacin ER)
Prior Authorization Criteria for NIACOR & Niaspan Will be approved if ONE of the following criteria is met: Patients has a LDL-C level >130 mg/dL and will be taking concurrently with another lipid-lowering agent OR Patient has a contraindication, adverse event or allergy to a statin. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. 3. Magellan Medicaid Administration. Lipotropics, Other Therapeutic Class Review. February 12, 2013. 4. Farnier M, Bruckert E. Severe familial hypercholesterolaemia: current and future management. Arch Cardiovasc Dis. 2012; 105(12):656-65. 5. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143–3421. 6. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004; 110:227-239.
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CNS AGENTS RE-REVIEW: MAOI-Bs BACKGROUND
The MAO-Bs exert their physiological effects by irreversibly inhibiting monoamine oxidase type B activity, blocking dopamine breakdown, increasing dopaminergic activity and interfering with dopamine reuptake at the synapse. Both agents are approved for adjunctive therapy to levodopa in advanced Parkinson’s Disease (PD). Rasagiline is also approved for use as monotherapy in early PD. The most common adverse effects include confusion, dizziness, diskinesia, orthostatic complications and nausea. Selegiline seems to cause a greater incidence of confusion, dizziness and dyskinesia than rasagiline. However, rasagiline seems to cause more orthostatic complications. o MAO-Bs are contraindicated in patients with pheochromocytoma and those who are undergoing general anesthesia. MAO-Bs should never be used in conjunction with other MAOIs. o Rasagiline should be adjusted to 0.5 mg daily in patients with mild hepatic impairment, and it should be avoided in patients with moderate or severe hepatic disease. Selegiline should also be used with caution in patients with hepatic impairment. The MAO-Bs should be used with caution in renal disease as well. o Due to potentially fatal reactions that have occurred in patients receiving MAO inhibitors concomitantly with meperidine, the use of rasagiline and selegiline with meperidine is contraindicated. For similar reasons, these two drugs should not be used concurrently with methadone, propoxyphene, or tramadol; and this contraindication is often extended to other opioids. Rasagiline and selegiline are contraindicated for use with sympathomimetic amines due to the potential for severe hypertensive reactions. Other contraindications for the MAO-B inhibitors are general anesthesia, pheochromocytoma, and concurrent use with other MAO inhibitors. Concomitant use of MAO-B inhibitors with non-selective MAO inhibitors, SNRIs, SSRIs or tricyclic antidepressants is not recommended. o Selegiline undergoes extensive first-pass metabolism in the liver resulting in 5 metabolites, including pharmacologically active l-amphetamine and lmethamphetamine which can increase the risk for confusion, specifically in elder patients with underlying cognitive dysfunction. Because orally disintegrating selegiline tablets avoid the first pass effect, clinical efficacy can be achieved at lower doses resulting in lower concentrations of amphetamine metabolites. No head-to-head trials have been completed comparing the MAO-Bs to each other. Selegiline has been used historically as a neuroprotective agent. After a review of the literature, the American Academy of Neurology reported that selegiline has a mild symptomatic benefit, but clinical evidence for neuroprotective benefit is nonexistent. Although their effectiveness as neuroprotective agents has yet to be demonstrated by clinical trials, the MAO-B inhibitors are effective as adjuncts to allow lower doses of levodopa while lengthening dosage intervals. Both agents are approved for use as adjunct to levodopa in later stage disease because they can increase the percent of “on” time in advanced PD patients. Rasagiline is also approved for use as monotherapy in early PD. The 2006 guidelines from the American Academy of Neurology (AAN) recommended that entacapone be offered to patients with PD with motor fluctuations to reduce off time. Pramipexole, ropinirole, and tolcapone are recommended as alternatives to be considered, although the AAN notes that tolcapone, due to hepatotoxicity, should be used with caution and requires monitoring. For patients who continue to experience unpredictable on and off periods, a MAO-B inhibitor or amantadine may be added to the patient’s drug regimen. There is insufficient evidence to conclude that any one agent is superior to another in reducing off time.
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CNS AGENTS RECOMMENDATION The monoamine oxidase type B (MAO-B) inhibitors have been shown to cause a slight improvement in motor performance upon initiation of therapy and to delay the development of disability that requires the addition of levodopa in patients with PD. Although their effectiveness as neuroprotective agents has yet to be demonstrated by clinical trials, the MAO-B inhibitors are effective as adjuncts to allow lower doses of levodopa while lengthening dosage intervals. Current treatment guidelines recommend their use as second line therapy for the symptomatic treatment of PD, or as a first line agent in adjunctive therapy to allow lower dosages and longer dosing intervals of levodopa. It is recommended that at least one MAO-B inhibitor agents be available for the treatment of PD. COMMITTEE VOTE: APPROVED
PREFERRED selegiline
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: MAOI-Bs NON-PREFERRED AZILECt (rasalgiline) ELDEPRYL (selegiline) PA ZELAPAR (selegiline ODT)
Prior Authorization Criteria for ZELAPAR Zelapar will be approved for patients meeting one of the following criteria: Inability to swallow, OR Patients who experience adverse reactions to selegiline secondary to the active metabolites , l-amphetamine and l-methamphetamine COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. 3. Magellan Medicaid Administration. Antiparkinson’s Agents Therapeutic Class Review. August 23, 2013. RE-REVIEW: ANTI-ANXIETY AGENTS BACKGROUND
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) classifies anxiety disorders into several categories including: generalized anxiety disorder, panic disorder, agoraphobia without a history of panic disorder, phobic disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and acute stress disorder. For the purposes of this review, the background information will be limited to the agents not included in the previous review of this class by the PAC committee, specifically benzodiazepines. The benzodiazepines act on the benzodiazepine binding site on the chloride channel of the gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter receptor in the CNS, and increase the frequency of chloride channel opening. This hyperpolarizes the cell and prevents nerve firing/stimulation, resulting in generalized depression of spinal reflexes and the reticular activating system causing CNS depression. All agents in this class are indicated for the treatment of anxiety. Chlordiazepoxide, clorazepate, diazepam and oxazepam are additionally indicated for acute alcohol
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withdrawal. Clorazepate, diazepam and lorazepam are also indicated as adjunct therapy for the treatment of seizures. Diazepam can also be used as a muscle relaxant. Benzodiazepines are most commonly associated with CNS adverse events, including drowsiness and dizziness. For a complete list of adverse events, please refer to the Therapeutic Class Review Table. o Alprazolam, chlordiazepoxide, chlorazepate, diazepam, and lorazepam are contraindiated in acute narrow angle glaucoma. Diazepam is also contraindicated in severe hepatic insufficiency and myasthenia gravis. o Prolonged use of therapeutic doses of benzodiazepines can lead to dependence. Withdrawal syndrome has occurred after as little as 4 to 6 weeks treatment. o Pregnancy Category D o Concurrent use with other CNS depressants may result in additive respiratory depression. Alprazolam is contraindicated with concomitant use of ketoconazole or itraconazole. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders were updated in 2011 and recommend SSRIs and SNRIs as first line drugs for the treatment of anxiety disorders due to their favorable risk-benefit ratio. Furthermore, these guidelines recommend benzodiazepines should only be used for long-term treatment when other drugs or cognitive behavorial therapy (CBT) have failed.
RECOMMENDATION All agents in this class are indicated for the treatment of anxiety. Chlordiazepoxide, clorazepate, diazepam and oxazepam are additionally indicated for acute alcohol withdrawal. Clorazepate, diazepam and lorazepam are also indicated as adjunct therapy for the treatment of seizures. Diazepam can also be used as a muscle relaxant. SSRIs are recommended as first line therapy for anxiety disorders with SNRIs as second line agents; however, buspirone may be of benefit in patients who are not able to take either SSRIs or SNRIs. Meprobamate is not considered an agent of choice for the treatment of anxiety due to the considerable safety concerns and can be considered an inferior agent in this class. Agents, with the exception of buspirone, are schedule IV controlled substances, so addictive behaviors and withdrawal symptoms may occur. Safety profiles are similar among the benzodiazepines. Therefore, it is recommended that buspirone be available for use in patients with anxiety disorders. Additionally, due to the potential for abuse, it is recommended that the benzodiazepines should be subject to clinical criteria. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ANTI-ANXIETY AGENTS PREFERRED NON-PREFERRED PA, QL PA, QL alprazolam (compares to XANAX) alprazolam ER (compares to XANAX ER) PA, QL buspirone (compares to BUSPAR) alprazolam ODT (compares to NIRAVAM) PA, QL PA, QL chlordiazepoxide ATIVAN (lorazepam) PA, QL clorazepate (compares to TRANXENE-T) BUSPAR (buspirone) PA, QL diazepam (compares to VALIUM) meprobamate PA, QL PA, QL lorazepam (compares to ATIVAN) oxazepam PA, QL TRANXENE-T (chlorazepate) PA, QL VALIUM (diazepam) PA, QL XANAX (alprazolam) PA, QL XANAX ER (alprazolam XR)
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CNS AGENTS Prior Authorization Criteria for alprazolam(XANAX) and lorazepam (ATIVAN)
Diagnosis of anxiety disorder, AND o Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. Cognitive Behavioral Therapy, Worry Exposure, Applied Relaxation, Muscle Relaxation, Shortterm Psychodynamic Psychotherapy, Mindfulness-based Therapy), AND o Recipient has tried and failed, or have a contraindication or intolerance to: Two SSRIs (minimum trial duration of 3 weeks each) Two SNRIs (minimum trial duration of 3 weeks each) Buspirone Due to increased to increased risk of toxicity, o patient should not be pregnant OR concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse Must be prescribed by a Medicaid Provider
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for diazepam (VALIUM)
Diagnosis of seizure disorder AND recipient has tried and failed at least TWO preferred anticonvulsants AND must be used in conjunction with another anticonvulsant Diagnosis of muscle spasms Diagnosis of anxiety disorder, AND o Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. Cognitive Behavioral Therapy, Worry Exposure, Applied Relaxation, Muscle Relaxation, Shortterm Psychodynamic Psychotherapy, Mindfulness-based Therapy), AND o Recipient has tried and failed, or have a contraindication or intolerance to: Two SSRIs (minimum trial duration of 3 weeks each) Two SNRIs (minimum trial duration of 3 weeks each) Buspirone Due to increased to increased risk of toxicity, o patient should not be pregnant OR o concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates, AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse OR pt has diagnosis of acute alcohol withdrawal, AND Must be prescribed by a Medicaid Provider
COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CNS AGENTS Prior Authorization Criteria for chlordiazepoxide
Diagnosis of anxiety disorder, AND o Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. Cognitive Behavioral Therapy, Worry Exposure, Applied Relaxation, Muscle Relaxation, Shortterm Psychodynamic Psychotherapy, Mindfulness-based Therapy), AND o Recipient has tried and failed, or have a contraindication or intolerance to: Two SSRIs (minimum trial duration of 3 weeks each) Two SNRIs (minimum trial duration of 3 weeks each) Buspirone Due to increased to increased risk of toxicity, o patient should not be pregnant OR o concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates, AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse OR pt has diagnosis of acute alcohol withdrawal, AND Must be prescribed by a Medicaid Provider
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for clorazepate (TRANXENE-T)
Diagnosis of seizure disorder AND recipient has tried and failed at least TWO preferred anticonvulsants AND must be used in conjunction with another anticonvulsant Diagnosis of anxiety disorder, AND o Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. Cognitive Behavioral Therapy, Worry Exposure, Applied Relaxation, Muscle Relaxation, Shortterm Psychodynamic Psychotherapy, Mindfulness-based Therapy), AND o Recipient has tried and failed, or have a contraindication or intolerance to: Two SSRIs (minimum trial duration of 3 weeks each) Two SNRIs (minimum trial duration of 3 weeks each) Buspirone Due to increased to increased risk of toxicity, o patient should not be pregnant OR o concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates, AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse OR pt has diagnosis of acute alcohol withdrawal, AND Must be prescribed by a Medicaid Provider
COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CNS AGENTS Prior Authorization Criteria for alprazolam ODT (NIRAVAM)
Diagnosis of anxiety disorder, AND o Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. Cognitive Behavioral Therapy, Worry Exposure, Applied Relaxation, Muscle Relaxation, Shortterm Psychodynamic Psychotherapy, Mindfulness-based Therapy), AND o Recipient has tried and failed, or have a contraindication or intolerance to: Two SSRIs (minimum trial duration of 3 weeks each) Two SNRIs (minimum trial duration of 3 weeks each) Buspirone Due to increased to increased risk of toxicity, o patient should not be pregnant OR concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse Must be prescribed by a Medicaid Provider, AND Patient must be unable to swallow, OR unable to absorb medications through the GI tract.
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for alprazolam ER (XANAX XR)
Diagnosis of anxiety disorder, AND o Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. Cognitive Behavioral Therapy, Worry Exposure, Applied Relaxation, Muscle Relaxation, Shortterm Psychodynamic Psychotherapy, Mindfulness-based Therapy), AND o
Recipient has tried and failed, or have a contraindication or intolerance to: Two SSRIs (minimum trial duration of 3 weeks each) Two SNRIs (minimum trial duration of 3 weeks each) Buspirone Due to increased to increased risk of toxicity, o patient should not be pregnant OR concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse Must be prescribed by a Medicaid Provider, AND Patient must have tried and failed or have an allergy or intolerance to an inactive ingredient in immediate release alprazolam.
COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CNS AGENTS Quantity Limits alprazolam (XANAX, NIRAVAM) tablet/ODT alprazolam concentrate alprazolam solution alprazolam ER (XANAX XR) chlordiazepoxide clorazepate diazepam (VALIUM) tabs diazepam solution diazepam concentrate lorazepam (ATIVAN) tabs lorazepam concentrate oxazepam
3/day 6 mL/day 60 mL/day 1/day 4/day 3/day 2/day 10 mL/day 2 mL/day 3/day 1 mL/day 4/day
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. 3. Bandelow, et al. International Journal of Psychiatry in Clinical Practice, 2012; 16: 77–84
RE-REVIEW: ANTICONVULSANTS BACKGROUND
Epilepsy is one of the most common disorders of the central nervous system (CNS). It affects approximately three million Americans, with 200,000 new cases diagnosed each year. Goals of treating epilepsy are to reduce the frequency of seizure occurrence along with providing the best possible quality of life for the patient. Ideally, this would be achieved using a medication with minimal adverse effects and drug interactions. For the purposes of this review, the background information will be limited to the agents not included in the previous review of this class by the PAC committee, including phenobarbital, benzodiazepines and ezogabine. Barbiturates depress CNS activity by binding to the barbiturate site at the gammaaminobutyric acid (GABA) receptor complex, enhancing GABA activity. Barbiturates reduce monosynaptic and polysynaptic transmission resulting in decreased excitability of the entire nerve cell. They also increase the threshold for electrical stimulation of the motor cortex. Benzodiazepines potentiate the effects of GABA. Benzodiazepines suppress the spike and wave discharge associated with absence seizures. In vitro studies indicate that ezogabine enhances transmembrane potassium currents which are thought to stabilize the resting membrane potential and reduce brain excitability. In vitro data suggest that augmentation of GABA-mediated currents may also contribute to the therapeutic effects of ezogabine. Phenobarbital is indicated for the treatment of myoclonic, partial and tonic-clonic seizures. Phenobarbital is also indicated for treatment of status epilepticus; however, its full antiepileptic effect is not immediate. It is also indicated for the relief of anxiety, tension, and apprehension as well as for insomnia although the barbiturates are no longer used for this indication. Clonazepam is indicated for the treatment of absence and myoclonic seizures as well as for Lennox-Gastaut syndrome and panic disorder. Diazepam rectal gel is indicated for the management of selected, refractory patients on stable regimens of anti-epileptic agents who require intermittent use of diazepam to
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control bouts of increased seizure activity. Onfi is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. Ezogabine is indicated for adjunctive treatment for partial-onset seizures. Somnolence is the most common adverse event associated with the use of phenobarbital; other less common but serious adverse events include syncope, hallucinations and liver damage. Adverse events commonly associated with the use of benzodiazepines include somnolence and dizziness. o Barbiturates are contraindicated in patients with porphyria, marked impairment of liver function, or respiratory disease in which dyspnea or obstruction is evident. Benzodiazepines should not be used in patients with clinical or biochemical evidence of significant liver disease. They may be used in patients with open angle glaucoma who are receiving appropriate therapy but are contraindicated in acute narrow angle glaucoma. The most frequently reported adverse effects of ezogabine have been dizziness, somnolence and fatigue. Confusion, vertigo, tremor, abnormal coordination, disturbance in attention, gait disturbance, memory impairment, diplopia, blurred vision, asthenia, aphasia, dysarthria and balance disorder have also occurred. o Precautions/warnings: Phenobarbital may be habit forming, additive CNS depression may occur when used with other CNS depressants. Benzodiazepines may interfere with cognitive and motor functioning. Patients may become physically and psychologically dependent on benzodiazepines; tapering should occur slowly upon discontinuation to avoid withdrawal symptoms. During clinical trials, psychiatric symptoms including confusional state, psychotic symptoms, and hallucinations occurred more frequently in patients receiving ezogabine than placebo. Half of the patients in clinical trials who discontinued ezogabine due to hallucinations or psychosis required hospitalization, and two-thirds of patients with psychosis in clinical trials had no prior psychiatric history. A study of cardiac conduction showed QT prolongation occurring in healthy volunteers during administration of ezogabine. o Drug-Drug Interactions: Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response in oral anticoagulants (e.g., warfarin, acenocoumarol, dicoumarol and phenprocoumon). Phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. MAO inhibitors prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited. The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, anti-anxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs. Medications metabolized through CYP2D6 may need to be adjusted when administered with clobazam (Onfi). Additionally dosage adjustments of clobazam should occur when administered with strong inhibitors of CYP2C19 (e.g. fluconazole, fluvoxamine, ticlopidine), or moderate inhibitors (e.g. omeprazole). Administration with alcohol increases the maximum plasma exposure of clobazam by 50 percent. Due to the numerous agents, there is a large volume of clinical trial data available in this class; however, anticonvulsants have very little or no direct comparative data in the treatment of seizures or any other indication.
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Standard guidelines have not been created to help differentiate the superiority of one anticonvulsant agent over another agent. The reason for this is that there is a lack of comparative data on which to base such a guide. This was the recurring theme in an attempt by the International League Against Epilepsy (ILAE) to develop treatment guidelines in 2006. In 2007, the American Epilepsy Society (AES) and the American Academy of Neurology (AAN) developed a set of evidence-based guidelines to help healthcare professionals better understand the published research on the newer anticonvulsant agents. The guidelines summarize the use of the newer agents in patients newly diagnosed with seizures, patients with refractory seizures, and patients with refractory epilepsy. The guidelines suggest that gabapentin, lamotrigine, topiramate, and oxcarbazepine have enough supporting evidence to use as monotherapy in adolescents and adult patients newly diagnosed with partial or mixed seizures. They may also prove beneficial as adjunctive therapy in adult patients with partial seizures. Lamotrigine may be useful as monotherapy in children newly diagnosed with absence seizures. For adults and children with Lennox-Gastaut syndrome, the guidelines recommend that lamotrigine and topiramate may be used to control the “drop attacks.” The guidelines mention the option of using of felbamate in Lennox-Gastaut and partial seizures, but the guidelines suggest its use only when all other options have been exhausted due to the risks involved. The American Academy of Neurology (AAN) and the Child Neurology Society recommend low-dose ACTH as treatment of choice for infantile spasms. ACTH or vigabatrin may be useful for short-term treatment, with ACTH preferred. There is insufficient evidence that other anticonvulsants and combination therapy are effective for short-term treatment.
RECOMMENDATION All of the agents in this class are FDA approved for the prevention and/or treatment of various seizure disorders either as monotherapy or adjunctive therapy. Due to the lack of direct comparative data in the treatment of seizure, standard guidelines have not been created to help differentiate the superiority of one anticonvulsant agent over another agent. Patient responses may vary from agent to agent; therefore, it is necessary to have multiple agents for each seizure type. For this reason, it is recommended at least two agents for the treatment of each seizure type should all be available for use. Due to the significant safety concerns (aplastic anemia, hepatotoxicity), it is recommended felbamate be reserved for patients with refractory seizures in which the benefits of therapy outweigh the risks. Vigabatrin is FDA-approved for the treatment of infantile spasms but its use is associated with the potential for permanent vision loss; therefore, it is recommended vigabatrin be subject to step therapy criteria. In addition to its indication as adjunct therapy for the treatment of partial seizures, pregabalin is FDA-approved for the treatment of fibromyalgia, diabetic neuropathic pain and postherpetic neuralgia in adult patients. Given the differing place in therapy for pregabalin dependent on indication, it is recommended that pregabalin be subject to clinical criteria. Additionally, due to the potential for abuse, it is recommended that phenobarbital as well as the benzodiazepines should be subject to clinical criteria. COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CNS AGENTS RE-REVIEW: ANTICONVULSANTS PREFERRED NON-PREFERRED carbamazepine (compares to TEGRETOL) BANZEL (rufinamide) carbamazepine ER (excluding generic CARBAMAZEPINE ER (compares to Carbatrol) Carbatrol) CELONTIN (methsuximide) PA, QL Carbatrol (CARBAMAZEPINE ER) clonazepam (compares to KLONOPIN) PA, QL PA, QL Diastat (diazepam rectal gel) clonazepam ODT (compares to KLONOPIN DILANTIN 30 mg (phenytoin) RAPDIS) DILANTIN INFATAB (phenytoin) DEPAKENE (valproic acid) divalproex extended release (compares to DEPAKOTE (divalproex extended release) DEPAKOTE) DEPAKOTE ER (divalproex sodium extended release) divalproex DR sprinkles(compares to DEPAKOTE SPRINKLES (divalproex DR sprinkles) QL DEPAKOTE SPRINKLES) DIAZEPAM RECTAL GEL (compares to Diastat) divalproex sodium extended release DILANTIN-125 (phenytoin) (compares to DEPAKOTE ER) DILANTIN KAPSEAL 100 MG (Phenytoin) EQUETRO (carbamezepine) EPITOL (carbamazepine) PA ethosuximide (compares to ZARONTIN) felbamate (compares to FELBATOL) QL PA gabapentin caps (compares to FELBATOL (FELBAMATE) PA, QL NEURONTIN) gabapentin solution (compares to NEURONTIN lamotrigine chewable tabs (compares to solution) QL LAMICTAL) gabapentin tabs (compares to NEURONTIN) lamotrigine tabs(compares to LAMICTAL) GABITRIL(tiagabine) levetiracetam (compares to KEPPRA) KEPPRA (levetiracetam) levetiracetam ER (compares to KEPPRA KEPPRA XR (levetiracetam ER) XR) KLONOPIN (clonazepam) oxcarbazepine (compares to TRILEPTAL) LAMICTAL TABS (lamotrigine) PA phenobarbital LAMICTAL CHEWABLE TABS (lamotrigine) PA PHENYTEK (phenytoin ER) LAMICTAL ODT (lamotrigine) phenytoin (compares to DILANTIN) LAMICTAL XR (lamotrigine ER) primidone (compares to MYSOLINE) lamotrigine ER (compares to LAMICTAL XR) PA TEGRETOL XR 100 mg (carbamazepine ER) LYRICA (pregabalin) topiramate (compares to TOPAMAX) MYSOLINE (primidone) QL valproic acid (compares to DEPAKENE) NEURONTIN (gabapentin) PA PA, QL VIMPAT (lacosamide) NEURONTIN SOLUTION (gabapentin solution) PA zonisamide (compares to ZONEGRAN) ONFI (clobazam) OXTELLAR XR (oxcarbazepine extended release) PEGANONE (ethotoin) POTIGA (ezogabine) PA SABRIL (vigabatrin) STAVZOR (valproic acid, delayed release) TEGRETOL (carbamazepine) TEGRETOL XR 200 MG & 400 MG (carbamazepine ER) tiagabine(compares to GABITRIL) TOPAMAX (topiramate) TRILEPTAL (oxcarbazepine) PA TROKENDI XR (topiramate extended release) ZARONITN (ethosuximide) ZONEGRAN (zonisamide)
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CNS AGENTS Prior Authorization Criteria for clonazepam (KLONOPIN) Will be approved if ONE of the following criteria has been met: Diagnosis of seizure disorder AND recipient has tried and failed at least TWO preferred anticonvulsants Diagnosis of panic disorder AND recipient has tried and failed, or have a contraindication or intolerance to, at least TWO agents in each of the following classes: SSRIs (minimum trial duration of 3 weeks each) SNRIs (minimum trial duration of 3 weeks each) Additionally, due to increased to increased risk of toxicity, o Patient should not be pregnant OR o Concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates AND o Due to increased risk of dependency,patient does not have a history of alcohol or drug dependence/abuse Prescriber must be a Medicaid Provider. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for clonazepam ODT (KLONOPIN RAPDIS) Will be approved if ONE of the following criteria has been met: Diagnosis of seizure disorder AND recipient has tried and failed at least TWO preferred anticonvulsants Diagnosis of panic disorder AND recipient has tried and failed, or have a contraindication or intolerance to, at least TWO agents in each of the following classes: SSRIs (minimum trial duration of 3 weeks each) SNRIs (minimum trial duration of 3 weeks each) Additionally, due to increased to increased risk of toxicity, o Patient should not be pregnant OR o Concurrently taking CNS stimulants, opiates, carisoprodol, or barbiturates AND o Due to increased risk of dependency,patient does not have a history of alcohol or drug dependence/abuse Prescriber must be a Medicaid Provider, AND Patient must be unable to swallow, OR unable to absorb medications through the GI tract COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for Diastat (DIAZEPAM RECTAL GEL) -Prior Authorization will not be required for patients less than 21 years of age. -Patients 21 years of age & older: Will be approved for patients with a Diagnosis of Seizure Disorder or Epilepsy COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CNS AGENTS Prior Authorization Criteria for felbamate (FELBATOL) Will be approved if ONE of the following criteria has been met: Used as adjunctive therapy in Lennox‐Gastaut Syndrome with a contraindication to, or trial and failure of, TWO of the following: o Valproic acid/Divalproex sodium o Lamotrigine o Topiramate Used for the treatment of partial seizures with a contraindication to, or trial and failure of, THREE of the following: o Carbamazepine o Oxcarbamazepine o Phenytoin o Gabapentin o Lamotrigine o Topiramate o Valproic acid/divalproex sodium Note: Will not be approved if there is a history of blood dyscrasia or liver disease unless the prescriber can make a compelling clinical case demonstrating that the benefits of the drug outweigh the risks. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for gabapentin solution (NEURONTIN solution) Gabapentin solution will be approved for recipients who meet ALL of the following criteria: Inability to swallow solid oral dosage forms, AND Inability to open capsule and empty contents in food or drink Note: Prior authorization criteria is waived for recipients 12 years of age and under COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for LAMICTAL ODT Will be approved for patients who are: Unable to swallow, OR Unable to absorb medications through the GI tract COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for LYRICA ®
Lyrica will be approved if ONE of the following criteria has been met: Diagnosis of seizure disorder AND recipient has tried and failed at least TWO preferred anticonvulsants Diagnosis of diabetic peripheral neuropathy Diagnosis of fibromyalgia: o Recipient MUST have tried and failed, or have contraindication or intolerance to a tricyclic antidepressant, muscle relaxant, SSRI, SNRI, or gabapentin. Diagnosis of postherpetic neuralgia or other non‐diabetic peripheral neuropathy: o Recipient MUST have tried and failed, or have contraindication or intolerance to a tricyclic antidepressant OR gabapentin. Page 25 of 43
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CNS AGENTS COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for phenobarbital Will be approved for use ONLY in patients with diagnosis of seizure disorders COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for ONFI Will be approved for use as adjunctive therapy for Lennox‐Gastaut Syndrome when used in combination with at least one other anticonvulsant. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for TROKENDI XR TROKENDI XR will be approved for patients meeting the following criteria: Diagnosis of seizures or epilepsy, AND Trial and failure of immediate release topiramate OR allergy to inactive ingredient in immediate release product that is not in XR product
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for VIMPAT Will be approved for use as adjunctive therapy for partial seizures when used in combination with at least one other anticonvulsant. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for SABRIL ®
Sabril will be approved if ONE of the following criteria has been met: Diagnosis of seizure disorder AND recipient has tried and failed at least TWO preferred anticonvulsants Diagnosis of infantile spasms: o Recipient MUST have tried and failed, or have contraindication or intolerance to adrendocorticotropic hormone (ACTH) COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
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CNS AGENTS Quantity Limits clonazepam tabs, ODT (KLONOPIN) Diastat (diazepam rectal gel) gabapentin caps (NEURONTIN) gabapentin solution (NEURONTIN) gabapentin tabs (NEURONTIN)
3/day 2 packs per 30 days 100 mg: 6/day 300 & 400 mg: 9/day 72 mL/day 100 mg: 6/day 300 mg & 400mg: 3/day 600 mg: 6/day 800 mg: 4.5/day
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. 3. Magellan Medicaid Administration. Anticonvulsants, Oral Therapeutic Class Review. April 3, 2013. 4. Available at: http://www.epilepsy.com/epilepsy/medicine_guidelines. Accessed March 28, 2013. 5. Available at: http://aan.com/professionals/practice/pdfs/patient_ep_onset_c.pdf. Accessed March 28, 2013. 6. Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal S, Snead OC 3rd. Evidence-based guideline update: medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2012; 78(24): 1974-80. http://www.neurology.org/content/78/24/1974.full.pdf+html. Accessed March 28, 2013 RE-REVIEW: SEDATIVE HYPNOTICS BACKGROUND
Insomnia is a symptom complex that includes difficulties falling asleep, staying asleep or non-refreshing sleep in combination with daytime dysfunction or distress. The symptom complex can be an independent disorder (primary insomnia) or the result of another condition (secondary insomnia). Based on duration, insomnia may be classified into 3 categories: 1.) Transient insomnia, 2.) Short-term insomnia, and 3.) Chronic insomnia. Transient insomnia may last up to one week and is often referred to as adjustment sleep disorder because it is caused most often by an acute situational stress, such as a test or deadline. Transient insomnia is often recurrent with the same or similar stresses. The second type, short-term insomnia, lasts one to six months and is primarily associated with a more persistent stressful situational (death or illness) or environmental (noise) factors. Lastly, chronic insomnia involves symptoms that occur longer than six months duration. Insomnia treatment should first consist of identification and treatment/control of secondary causes. Whenever possible, use of non-pharmacological measures should be used to treat insomnia. Stimulus control, progressive muscle relaxation, sleep restriction, cognitive behavioral therapy (CBT), multicomponent therapy (without CBT), paradoxical intention, and biofeedback have been shown to be beneficial and are all recommended by the American Academy of Sleep Medicine (AASM). When non-pharmacological measures fail to adequately treat insomnia, the use of of pharmacologic hypnotics may be necessary.
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The benzodiazepines primarily differ in their duration of action. Triazolam has a short duration of action, while estazolam and temazepam are intermediate-acting agents. Flurazepam and quazepam are generally considered long-acting benzodiazepines. The benzodiazepines are thought to potentiate gamma aminobutyric acid (GABA) neuronal inhibition. The sedative and anticonvulsant actions of these drugs involve GABA receptors located in the limbic, neocortical, and mesencephalic reticular systems. At least two benzodiazepine (BZ) receptor subtypes have been identified in the brain, BZ-1 and BZ-2. BZ-1 is thought to be associated with sleep mechanisms while BZ-2 is thought to be associated with memory, motor, sensory, and cognitive functions. The non-benzodiazepine (Z drugs) sedative hypnotics are structurally different from benzodiazepines and from one another. This group of sedative hypnotics includes eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Ambien CR, Edluar, Zolpimist, and Intermezzo). These agents are all active at the GABA-BZ receptor complex and bind selectively to the BZ-1 receptor. Ramelteon (Rozerem) is a highly selective and potent agonist of the melatonin (MT) receptors, specifically MT1 and MT2 receptors, which are believed to be involved in the regulation of the circadian rhythm. The MT1 receptor is believed to regulate sleepiness, whereas the MT2 receptor is thought to help the body shift between day and night. Ramelteon has been reported to have a greater affinity, selectivity, and potency than melatonin for the MT1 receptor, resulting in a better ability to induce sleep onset. ® Doxepin (Silenor ) is a low dose formulation of the sedative tricyclic antidepressant, FDAapproved for treatment of insomnia, in particular those with sleep maintenance problems. Headache is the most common adverse event associated with the use of the sedative hypnotic agents. Other adverse events associated with this class include dizziness (with ® the exception of zolpidem [Intermezzo ]) and daytime drowsiness/somnolence (with the ® exception of zaleplon and Intermezzo ). In addition to those adverse events listed above the following agents are also associated with: Doxepin: mayalgia Eszopiclone: dose related unpleasant taste & respiratory infection, dry mouth and anxiety Zaleplon: myalgia and amnesia ® Zolpidem (except Intermezzo ): amnesia, BZs: amnesia or memory impairment, neonatal abstinence syndrome, physiological and psychological dependence o Benzodiazepines are contraindicated in patients with suspected or established sleep apnea. Doxepin is contraindicated in patients with untreated closed-angle glaucoma and severe urinary retention. o Zolpidem, zolpidem ER, doxepin, eszopiclone, ramelteon, and zaleplon are classified as pregnancy category C. While the other benzodiazepine hypnotics are pregnancy category X. o Precautions/warnings: The FDA-approved hypnotics (including non-benzodiazepine sedative hypnotics, hypnotics, and doxepin) includes a warning regarding complex sleep-related behaviors such as sleep-driving, making phone calls, sexual activity, and preparing and eating food while asleep and often patients have no memory of these events. These risks increase when the sedative-hypnotic is taken concurrently with alcohol or other CNS depressants. Benzodiazepines may interfere with cognitive and motor functioning. Patients may become physically and psychologically dependent on benzodiazepines; tapering should occur slowly upon discontinuation to avoid withdrawal symptoms. All of the sedative hypnotic agents with the exception of doxepin have a warning about their potential for anaphylaxis and angioedema, which can occur as early as the first dose.
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Ramelteon and zaleplon should not be used in patients with severe hepatic impairment. All sedative/hypnotics should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. In January 2013, the FDA announced lower dosing recommendations for zolpidem due to new data showing that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. Women appear to be more susceptible to this risk. o Drug Interactions: Increased CNS depressant effects of the benzodiazepines that are metabolized by oxidation have been reported when coadministered with isoniazid, oral contraceptives, cimetidine, and disulfiram. Concurrent administration of triazolam with efavirenz, delavirdine, azole antifungals, nefazodone, protease inhibitors, and any drugs that significantly impair the CYP3A mediated oxidative metabolism are contraindicated. Estazolam, eszopiclone, ramelteon and its active MII metabolite, triazolam, zaleplon, and zolpidem are substrates for the CYP450 3A4 enzyme. As such, inducers of CYP450 3A4 (e.g., rifampin) increase the clearance and reduce the bioavailability of these agents by approximately 80 percent. Inhibitors of CYP450 3A4 (e.g., cimetidine, clarithromycin, ketoconazole) increase the bioavailability of these drugs by up to 84 percent. Ramelteon is contraindicated for concomitant use with fluvoxamine, a strong CYP1A2 inhibitor. Administration of ramelteon with fluconazole increases the bioavailability of ramelteon and the MII metabolite by approximately 150 percent. Doxepin (Silenor) is primarily metabolized by CYP2C19 and CYP2D6 hepatic cytochrome P450 isozymes. Inhibitors of these isozymes may increase the exposure of doxepin in patients. Severe hypoglycemia has been reported with the simultaneous use of tolazamide. Using doxepin and cimetidine together has caused an increased exposure to doxepin.Patients should not use Monoamine Oxidase Inhibitor (MAOI) medications within 14 days of doxepin. There are very limited head-to-head clinical trials available that directly compare the benzodiazepines and non-benzodiazepine sedative hypnotics. One trial which evaluated the occurrence of rebound insomnia in 24 patients with moderate to severe chronic insomnia in a parallel, double-blind placebo-controlled trial. Patients were randomized to receive either triazolam 0.5 mg, zolpidem 10 mg, or placebo. Treatment duration was 27 nights, followed by three placebo-controlled withdrawal nights. Both drugs showed significant efficacy compared to placebo during the active treatment period. A trend toward tolerance was noted in the triazolam group but not in the zolpidem group. The increase in total sleep time in the zolpidem group was accompanied by an increase in the number of sleep cycles. When active treatment was discontinued, clear rebound insomnia was present in the triazolam group while it was not possible to observe any rebound in the placebo and zolpidem groups. The American Academy of Sleep Medicine treatment guidelines recommend a number of behavioral strategies and pharmacological agents for the treatment of insomnia. Further clinical guidance identifies psychological and behavioral strategies are effective in both primary and secondary insomnia as are pharmacological interventions. For the treatment of chronic insomnia, the guidelines do not distinguish amongst the pharmacological agents in this review. However, selection of an agent should take into consideration the patient’s specific symptom pattern, any comorbid disease states and concurrent medications, as well as the individual side effect profile for each option.
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CNS AGENTS RECOMMENDATION Insomnia is common and can cause significant impairment of functioning. Insomnia may be primary, in that there is no identifiable medical factor, or secondary in which a medical condition or drug is implicated as the cause. Current treatment guidelines suggest psychological/behavioral treatment as first-line treatment for insomnia. When initial therapy is ineffective, combination therapy with sedative hypnotics may be implemented. The American Academy of Sleep Medicine treatment guidelines recommend a number of behavioral strategies and pharmacological agents for the treatment of insomnia. Further clinical guidance identifies psychological and behavioral strategies are effective in both primary and secondary insomnia as are pharmacological interventions. For the treatment of chronic insomnia, the guidelines do not distinguish amongst the pharmacological agents in this review. Furthermore, the selection of an agent should take into consideration the patient’s specific symptom pattern, any comorbid disease states and concurrent medications, as well as the individual side effect profile for each option. It is recommended that sedative hypnotics should be available for use. Although benzodiazepines decrease the time for sleep onset and prolong the duration of sleep, the potential for dependency, tolerance, and risk of abuse, may outweigh their benefit as a sedative hypnotic. It is recommended that the benzodiazpine sedative hypnotics should be subject to prior authoriaztion criteria. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: SEDATIVE HYPNOTICS PREFERRED NON-PREFERRED QL QL zaleplon (compares to SONATA) AMBIEN (zolpidem) QL QL zolpidem (compares to AMBIEN) AMBIEN CR (zolpidem ER) PA, QL DORAL (quazepam) PA, QL EDLUAR (zolpidem SL) PA, QL flurazepam PA, QL estazolam PA, QL HALCION (triazolam) ® QL Intermezzo (zolpidem SL) QL LUNESTA (eszopiclone) PA, QL quazepam (compares to DORAL) PA, QL RESTORIL (temazepam) QL ROZEREM (ramelteon) PA, QL SILENOR (doxepin) QL SONATA (zaleplon) PA, QL temazepam (compares to RESTORIL) PA, QL temazepam (7.5mg & 22.5mg) PA, QL triazolam (compares to HALCION) QL zolpidem ER (compares to AMBIEN CR) PA, QL ZOLPIMIST (zolpidem) Prior Authorization Criteria for EDULAR , INTERMEZZO & ZOLPIMIST o
Approved only for patients with difficulty swallowing/absorption
COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
November 14, 2013 Tennessee PAC
CNS AGENTS Prior Authorization Criteria for flurazepam, estazolam, quazepam, temazepam (excludes 7.5mg/22.5mg) & triazolam Will be approved if ALL of the following criteria is met: Diagnosis of Insomnia AND Medical documentation that rules out other insomnia related disorders (e.g. movement, breathing, psychiatric disorders & medication) AND Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. stimulus control, sleep restriction, sleep hygiene measures & relaxation therapy) AND Use of 2 preferred agents, unless patient has a contraindication or allergy AND Due to increased to increased risk of toxicity, o patient should not be pregnant OR o concurrently taking CNS stimulants, opiates,carisoprodol & barbiturates AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse, AND Must be prescribed by a Medicaid Provider Note: Caution is warranted if patient is concurrently taking CYP3A4 inhibitors [e.g. fluvoxamine, intraconazole, ketoconazole] as patient is at increased risk of of toxicity. COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for temazepam 7.5mg & 22.5mg Will be approved if ALL of the following criteria is met: Diagnosis of Insomnia AND Medical documentation that rules out other insomnia related disorders (e.g. movement, breathing, psychiatric disorders & medication) AND Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. stimulus control, sleep restriction, sleep hygiene measures & relaxation therapy) AND Use of 2 preferred agents, unless patient has a contraindication or allergy AND Due to increased to increased risk of toxicity, o patient should not be pregnant OR o concurrently taking CNS stimulants, opiates, carisoprodol & barbiturates AND Due to increased risk of dependency, patient does not have a history of alcohol or drug dependence/abuse AND Trial and failure of temazepam 15mg and/or 30mg strength, AND Must be prescribed by a Medicaid Provider Note: Caution is warranted if patient is concurrently taking CYP3A4 inhibitors [e.g. fluvoxamine, intraconazole, ketoconazole] as patient is at increased risk of of toxicity. COMMITTEE VOTE: APPROVED
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DISAPPROVED
APPROVED with MODIFICATION
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CNS AGENTS Prior Authorization Criteria for DORAL, HALCION & RESTORIL Will be approved if ALL of the following criteria is met: Diagnosis of Insomnia AND Clinical documentation of functional impairment Medical documentation that rules out other insomnia related disorders (e.g. movement, breathing, psychiatric disorders & medication/substance use) AND Documented trial (at least 3 weeks) of non-pharmacological therapies (e.g. stimulus control, sleep restriction, sleep hygiene measures & relaxation therapy) AND Use of 2 preferred agents, unless patient has a contraindication or allergy AND Clinical reason as to why patient cannot use generic equivalent AND Due to increased to increased risk of toxicity, o patient should not be pregnant OR o concurrently taking CNS stimulants, opiates, carisoprodol & barbiturates AND Due to increased risk of dependency, o patient does not have a history of alcohol OR drug dependence/abuse
Note: Caution is warranted if patient is concurrently taking CYP3A4 inhibitors [e.g. fluvoxamine, intraconazole, ketoconazole] as patient is at increased risk of of toxicity.
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Prior Authorization Criteria for SILENOR o
Documented Trial/failure (defined as ≥ 1 week) at an appropriate dose of the doxepin 10mg/ml concentrated solution
COMMITTEE VOTE: APPROVED
DISAPPROVED
Quantity Limits AMBIEN (zolpidem) AMBIENCR, (zolpidem ER) EDLUAR,INTERMEZZO (zolpidem SL) DORAL (quazepam) flurazepam estazolam HALCION (triazolam) LUNESTA RESTORIL (temazepam) ROZEREM (ramelteon) SILENOR SONATA (zaleplon) ZOLPIMIST
APPROVED with MODIFICATION
14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 14 per 30 days 7.7mL per 60 days
COMMITTEE VOTE: APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References 1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2013. Accessed October, 2013. 2. Thompson MICROMEDEX on-line © 1974-2013. Accessed October, 2013. Page 32 of 43
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CNS AGENTS 3. Magellan Medicaid Administration. Sedative/Hypnotic Therapeutic Class Review. September 6, 2013. 4. Morgenthaler T, Kramer M, Alessi, et al. Practice Parameters for the Psychological and Behavioral treatment of Insomnia: An Update. An American Academy of Sleep Medicine Report. Sleep. 2006 (11) 1415-1419. 5. 19 Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008; 4(5):487-504.
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DERMATOLOGIC AGENTS RE-REVIEW: PEDICULOSIDES/SCABICIDES BACKGROUND
Pediculosis humanus capitis (head lice), are a worldwide public health concern affecting persons of all ages and socioeconomic backgrounds. In the U.S., it is most common among children three to 11 years old and accounts for six to 12 million annual infestations. Itching is the primary symptom of pediculosis which results from an allergic reaction to the saliva lice inject during feeding. The primary mode of head lice transmission is direct head-to-head contact. Lice crawl to move to their next location by using adapted claws. Head lice survive approximately 15 to 20 hours once they are removed from a host. Scabies is a major public health concern in many poor regions and can cause morbidity from secondary infections. Scabies is caused by an eight-legged obligate human parasitic mite, Sarcoptes scabiei and results in intense pruritus which is due to a delayed type-IV hypersensitivity reaction to the mite, its feces, and eggs. There is also a characteristic rash and distribution pattern. It can affect the entire body, but in adults, the head and neck are usually not affected. The female mite burrows under the skin and lays 10 to 25 eggs before dying. The eggs hatch typically in three days, leave the burrow for the skin surface, and mature into adults. Transmission of scabies is usually from direct person-to-person contact. The mites can survive off a host for 24 to 36 hours and longer in colder temperatures. Crusted scabies or Norwegian scabies, an aggressive form of scabies, can occur in immunocompromised patients. The agents reviewed in this class will include topical pediculosides/scabacides and ® ® ® include benzyl alcohol (Ulesfia ), crotamiton (Eurax ), Ivermectin (Sklice ), lindane, ® ® malathion (ovide ), permethrin (Elimite™), and spinosad (Natroba ). Crotamiton’s mechanism of action is not known. However, it has scabicidal activity against Propionibacterium acnes and S. scabiei, and possesses antipruritic actions. Benzyl alcohol inhibits lice from closing their respiratory spiracles, resulting in obstruction of the spiracles by the vehicle and subsequent asphyxiation of the lice. Due to its mechanism of action, the risk of resistance is low. However, its therapeutic effects are primarily directed at the louse and not the ovum and a full treatment course involves reapplication after seven days to ensure eradication of hatched ova. Ivermectin is a member of the avermectin class and primarily works by binding selectively and with high affinity to glutamate-gated chloride channels. This leads to an increase in permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, and results in paralysis and death of the parasite. Avermectin selectivity is attributed to some mammals not having glutamate-gated chloride channels and the avermectins have a low affinity for mammalian ligand-gated chloride channels. In humans, ivermectin does not cross the blood-brain barrier. Lindane is directly absorbed by parasites and their ova. It non-competitively inhibits gamma amino butyric acid (GABA) receptors. Lindane stimulates the nervous system, resulting in seizures and death of the parasites. Lindane resistance is thought to be via the GABA receptor becoming less sensitive to GABA antagonists. Malathion is an organophosphate which acts as a pediculicide by inhibiting cholinesterase activity in vivo. Permethrin, a synthetic pyrethroid which inhibits sodium ion influx through nerve cell membrane channels in ectoparasites, resulting in delayed repolarization and resultant paralysis and death of the parasites. Spinosad is a topical pediculicide that works by neuronal excitation in insects causing lice to become paralyzed and die. Although nit removal is not required, spinosad should be used in the context of an overall lice management program. Lindane is contraindicated for use in patients with an uncontrolled seizure disorder, crusted (Norwegian) scabies, or for use by persons who have extensive dermatitis (e.g. eczema, exfoliative dermatitis, psoriasis or any condition (e.g. burns, wounds) which may
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increase systemic absorption. Lindane should be used with extreme caution in patients with a preexisting seizure disorder or history of prior seizure. Malathion is contraindicated for use in infants and neonates because their scalps are more permeable which may lead to increased absorption. Malathion topical lotion also contains 78% isopropyl alcohol. The product is flammable and should not be used near heat or flame of any kind, including hair dryers, electric curlers, and tobacco smoking. Malathion labeling advises of the potential for second-degree chemical burns and stinging. Neonates (less than one month old or preterm infants with a corrected age of less than 44 weeks) can be at risk for gasping syndrome if treated with benzyl alcohol lotion. There are no reported drug interactions with the pediculoside/scabacide agents. However, increased toxicity has been reported with the use of lindane and drugs which can lower seizure threshold. Oils, creams, or ointments may enhance lindane absorption; concomitant use should be avoided. Drug interaction studies were not conducted for benzyl alcohol. FDA-Approved Indications: Drug benzyl alcohol crotamiton
Ivermectin lindane
malathion permethrin 5% spinosad
FDA-Approved Indication(s) Age 6 months and older Txmt of pediculosis Safety and effectiveness not established Txtmt of scabies Symptomatic treatment of pruritis Age 6 months and older Txtmt of pediculosis > 50kg (contraindicated in premature infants) Txmt of pediculosis and ova Txmt of scabies Age 6 years and older Txmt of pediculosis and ova Age 2 months and older Txmt of scabies Age 4 years and older Txmt of pediculosis
Adverse Events- The most common adverse events include: o benzyl alcohol: skin irritation, anesthesia, hypoesthesia, and local pain temporary pruritus, erythema, and ocular irritation o crotamiton: pruritus, rash (unspecified), atopic dermatitis, and allergic sensitivity o ivermectin: dermatitis, burning and stinging o lindane: dematitis, pruritus, rash, paresthesia, HA, and seizures o malathion: dermatitis, burning, and stinging o permethrin: pruritis, rash, burning, stinging, paresthesia, erythema, and HA o spinosad: erythema and ocular erythema Ivermectin should not be used in patients less than six months of age and should only be administered under adult supervision as accidental ingestion may occur in pediatric patients. Crotamiton, ivermectin, and lindane are classified as pregnancy category C. Benzyl alcohol, malathion, permethrin and spinosad are classifed as pregnancy category B agents. The 2010 American Academy of Pediatrics (AAP) Head Lice Guidelines and the 2012 AAP Redbook Report of the Committee on Infectious Diseases recommend topical OTC permethrin 1% or pyrethrins, which have good safety profiles, as first-line for head lice
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DERMATOLOGIC AGENTS when resistance to these products is not suspected. When resistance to these agents is confirmed or treatment fails, malathion can be used in children six years and older or benzyl alcohol can be used in children older than six months. o Lindane is no longer recommended by the AAP due to concerns with neurotoxicity, rare severe seizures in children, low ovicidal activity, and worldwide reports of resistance.
Two multicenter, randomized, investigator-blind, active-controlled studies (n=1,038) were conducted in patients six months of age and older with head lice infestation. Patients were randomized to spinosad 0.9% topical crème rinse or permethrin 1% crème rinse. All patients who were treated on day zero returned for efficacy evaluation at day seven. If live lice were present at day seven they received a second treatment. Patients who were lice free on day seven returned on day 14 for evaluation. Patients with live lice and who received a second treatment returned on days 14 and 21. Proportion of primary subjects who were free of live lice 14 days after the final treatment in the first study was 84.6 percent versus 44.9 percent for spinosad versus permethrin (p
