Clinical Pharmacist's Corner: A Look Back at 2008: A Synopsis of Noteworthy FDA Approvals

Nelda Murri


AccessMedicine from McGraw-Hill 

The FDA approved 33 drugs of note in 2008. Most are pharmacologically similar to others already marketed in the United States (see Table 1 ).

Among the remainder are truly new medicines heralding the market debut of new pharmacologic drug classes to be employed for hereditary angioedema, chronic idiopathic thrombocytopenia, improving the yield of harvested stem cells, and blocking the undesired effects of opioids while preserving analgesia (see Table 2 and the discussion that follows).

Also noteworthy in 2008:

  • AdreView® (iobenguane I123) is a radiolabeled norepinephrine (NE) mimetic with a chemical structure similar to guanethedine. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues such as the adrenal medulla, salivary glands, heart, liver, spleen, lungs, and tumors derived from the neural crest. Radiolabeled iobenguane was licensed for use as an adjunct to other tests for the diagnosis of pheochromocytoma and neuroblastoma (see 11th edition of Goodman & Gilman, page 164).

  • Banzel® (rufinamide), a presumed sodium channel modulator, was licensed for use as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (see 11th edition of Goodman & Gilman, pages 501-525).

  • OraVerse® (phentolamine) was licensed for the reversal of dental (local) anesthesia (see 11th edition of Goodman & Gilman, page 268-269).

  • Sancuso® (a transdermal formulation of granisetron) was licensed for the prevention of nausea and vomiting in patients receiving emetogenic chemotherapy (see 11th edition of Goodman & Gilman, page 1001-1003).

  • Vimpat® (lacosamide), a "functionalized" amino acid,[1] was licensed for adjunctive therapy of partial-onset seizures. Lacsamide modulates sodium channels and also binds to collapsin response mediator protein 2 (CRMP2).[2] CRCMP2 is involved in neuronal differentiation, axonal outgrowth and possibly epileptogenesis[3] (see 11th edition of Goodman & Gilman, pages 501-525).

  • Zolpimist® (a spray formulation of zolpidem) was licensed for insomnia (see 11th edition of Goodman & Gilman, page 412-413).

In addition, three new pediatric vaccines were licensed in 2008:

  • Oral rotavirus vaccine, live (RotaRix®).

  • Diphtheria & tetanus toxoids, acellular pertussis, and inactivated poliovirus vaccine (Kinrix®).

  • Diphtheria & tetanus toxoids, acellular pertussis, inactivated poliovirus and Haemophilus b conjugate vaccine (Pentacel®).

New Pharmacological Drug Classes Introduced in 2008

Alvimopan (Entereg®) is a peripherally acting µ-opioid receptor antagonist indicated to accelerate gastrointestinal tract recovery following bowel surgery. To assure that patients receive only short-term therapy with alvimopan, access to the drug requires enrollment in the manufacturer's E.A.S.E. risk-mitigation program. Use of the drug beyond 7 days is not recommended because of adverse findings related to cardiovascular events (2.6% vs. 1.12%) and cancer rates (2.8% vs. 0.7%) among a cohort of study patients receiving off-label alvimopan vs. placebo for opioid-induced constipation.[4,5] Alvimopan is a zwitterion with a relatively high molecular weight (461 Da) and low lipophilicity; these physical characteristics hinder penetration of the drug into the central nervous system and account for the predominantly peripheral action.[6] On average, post-operative patients receiving alvimopan recover GI function 17 hours earlier than patients given placebo. While a faster recovery logically translates to a reduction in the length of hospitalization due to postoperative ileus, the clinical and economic significance of the improved outcome remains unproven.[7] (See Figure 1.) (CID: 5488547)

Figure 1.

Chemical structure of alvimopan.

The FDA-approved dose of alvimopan is 12 mg. The drug is given by mouth shortly before surgery and twice daily for a total of no more than 15 doses. During pre-marketing clinical trials, the most common adverse reactions among bowel resection patients receiving alvimopan were anemia, dyspepsia, hypokalemia, back pain, and urinary retention. Vigorous gastrointestinal side effects (including abdominal pain, nausea, vomiting, and diarrhea) can be expected when opioid-tolerant patients are given alvimopan, so patients who have taken opioids for the 7 consecutive days immediately prior to surgery should not be considered candidates for the drug.

The oral bioavailability of alvimopan is low (~6%). An active metabolite is formed in the gut by intestinal microflora. Since both the parent and metabolite are p-glycoprotein substrates, clinically significant drug interactions may surface with strong p-glycoprotein inhibitors (e.g., verapamil, cyclosporine, amiodorone, itraconazole, quinine, spironolactone, quinidine, diltiazem, and bepridil). Biliary secretion is the primary pathway of elimination for unabsorbed alvimopan and the metabolite formed in the gut is eliminated in the feces and urine as unchanged metabolite, the glucuronide conjugate, and other minor metabolites.[8] The half-life of alvimopan and the gut metabolite ranges from 10 to 18 hours. The drug accumulates approximately 10-fold in patients with severe hepatic impairment, thereby precluding administration to this group.[8]

Label approved on 5/20/08 for ENTEREG, NDA no. 021775

C1 inhibitor (Cinryze®) is licensed for the routine prophylaxis against angioedema attacks in patiets with hereditary angioedema (HAE). Application for licensure as a treatment for acute angioedema attacks is pending.[9] The identification of HAE dates back to the late 1500s.[10] The absence of functional complement 1 (C1) inhibitor activity, a plasma protein, was identified in the 1960s as the main biochemical deficit in type 1 and type 2 HAE, but not type 3 (estrogen-exacerbated) HAE.[10,11] Clinically, loss of C1 inhibitor activity can be acquired, but the condition is most commonly an autosomal dominant inherited disease occurring with a prevalence between 1:10,000 to 1:150,000.[11] C1 inhibitor regulates complement activation and also plays a role in the intrinsic cogulation and fibrinolytic systems.[12] The edema of HAE attacks is mediated by unregulated production of bradykinin with significant clinical implications because of the variety of medications known to precipitate attacks in susceptible patients (e.g., birth control pills, angiotensin converting enzyme inhibitors, angiotensin II antagonists, antidepressants, non-steroidal anti-inflammatory drugs, statins, proton pump inhibitors, serotonin reuptake inhibitors).[13] FDA approval of C1 inhibitor replacement therapy offers patients a targeted alternative to traditional therapy with anabolic androgens. C1 inhibitor is prepared from pooled plasma and is administered as an IV infusion of 1000 units every 3-4 days as needed. Hypersensitivity reactions have been reported during administration and thrombotic events have followed the administration of super-pharmacologic doses.

Label approved on 10/10/08 for CINRYZE, Biologic license no. 1780

Eltrombopag (Promacta®) is an orally available non-peptide thrombopoietin (TPO) receptor agonist licensed for the treatment of thrombocytopenia in patients with refractory chronic immune thrombocytopenic purpura. Eltrombopag is considered a second-generation thrombopoietin agent that does not lead to the development of TPO-neutralizing antibodies.[14,15] Administration of eltrombopag produces a dose-dependent rise in platelet counts via JAK2 and STAT5 signaling pathways.[14,15] The drug is a hydrazone compound and carries a black box warning regarding hepatotoxicity. As a class, TPO receptor agonists are thought to increase the risk for development of bone marrow fibrosis and may increase the risk for hematologic malignancies. Eltrombopaq may also promote the development of cataracts. Eltrombopag is extensively metabolized and eliminated via the feces and urine. The drug is a substrate of CYP1A2 and CYP2C8; an inhibitor of organic anion transporting polypeptide OATP1B1; and an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B, and UGT2B15. Therefore, a multitude of significant drug-drug interactions is likely to occur clinically in patients receiving concomitant medications. In addition, the drug chelates polyvalent cations (e.g., iron, calcium) and must not be administered within 4 hours of antacids, dairy products, or mineral supplements. The dose of eltrombopaq is adjusted to the lowest dose necessary to reduce the risk of bleeding and achieve a platelet count >50 x 109/L. A maximum daily dose of 75 mg is recommended with therapy discontinued if the platelet count does not increase sufficiently within 4 weeks of initiating therapy. The starting dose must be reduced 50% in East Asian patients because of a 70% higher systemic exposure following drug administration. Discontinuation of therapy poses a risk for worsening of thrombocytopenia below baseline, which may result in hemorrhage. Patients receiving eltrombopag must be monitored prior to initiation of therapy, frequently during treatment, and following cessation of therapy. Not surprisingly, prescribing of eltrombopaq is restricted to prescribers enrolled in the manufacturer's CARES risk-mitigation program. (See Figure 2.) (CID: 9915926)

Figure 2.

Chemical structure of eltrombopag.

Label approved on 11/20/08 for PROMACTA, NDA no. 022291

Methylnaltrexone (Relistor®) is a peripherally acting µ-opioid receptor antagonist FDA approved for the treatment of refractory opioid-induced constipation in patients with advanced illness (e.g., cancer, AIDS) who are receiving palliative care. Administered subcutaneously no more frequently than once per day, methylnaltrexone stimulates laxation within 4 hours in approximately 60% of patients. Clinical experience confirms a much more rapid onset of action in patients who are opioid tolerant.[6] Methylnaltrexone is a quaternary amine derivative of naltrexone with a limited ability to penetrate into the central nervous system. Side effects are largely extensions of normal gastrointestinal functions: abdominal pain, flatulence, nausea, and diarrhea. The drug is a weak CYP2D6 inhibitor with no known drug-drug interactions. Methylnaltrexone undergoes hepatic metabolism; however, N-demethylation to naltrexone is not thought to be a significant pathway.[6] Renal excretion of unchanged drug is the dominant route of elimination. The usual dose of methylnaltrexone is 8-12 mg, depending on body weight. Therapy for longer than 4 months in the target population of patients with terminal illness is unstudied. Methylnaltrexone was investigated as a treatment for postoperative ileus, but with disappointing results.[6] (See Figure 3.) (CID:5361918)

Figure 3.

Chemical structure of methylnaltrexone.

Label revised 5/08 for RELISTOR, NDA no. 021964

Plerixa (plerixafor, Mozobil®) started out as an investigational anti-retroviral drug for the treatment of AIDS.[16] An unexpected finding of increased CD34+ hematopoietic stem cell counts in the peripheral blood of subjects exposed to the drug[16] eventually lead to its licensing for use in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection prior to autologous transplantation in patients with non-Hodgkin´s lymphoma and multiple myeloma. Plerixa is an inhibitor of the CXCR4 chemokine receptor. CXCR4, is normally responsible for "homing" (anchoring) stem cells in the bone marrow.[16] Plerixa antagonizes the interaction between CXCR4 and its cognate ligand, stromal cell-derived factor-1a. Plerixa works synergistically with G-CSF and is given after "priming" with 4 daily doses of G-CSF. Plerixa is administered subcutaneously, in a dose of 0.24 mg/kg (up to 40 mg), approximately 11 hours prior to an apheresis session, in conjuction with additional daily G-CSF, for up to 4 consecutive days. Approximately 1/2 of non-Hodgkins lymphoma patients receiving plerixa will achieve a yield >5 x 106 CD34+ cell harvests after 2 apheresis sessions. Data for patients with multiple myeloma suggests that approximately 75% will achieve a yield >6 x 106 CD34+ cell harvests after 2 apheresis sessions. Plerixa is primarily eliminated by the kidneys. Drug-drug interactions may result from coadministration with drugs that reduce renal function or compete for active tubular secretion. (See Figure 4.) (CID: 16727404)

Figure 4.

Chemical structure of plerixa.

The most common adverse reactions reported in patients who received plerixa in conjunction with G-CSF and aphresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, vomiting, abdominal pain, hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, hypoesthesia, constipation, dyspepsia, and musculoskeletal pain. Less common (<1%) were urticaria, periorbital swelling, dyspnea, and hypoxia. The product labeling warns of the risk of vasovagal reactions, orthostatic hypotension, syncope, tumor cell mobilization, increased circulating leukocytes, decreased platelet counts, and splenic enlargement.

Label approved on 12/15/08 for MOZOBIL, NDA no. 022311

Romiplostim (Nplate®) is an fusion protein (peptibody) that contains two identical single-chain subunits, each consisting of a human immunoglobulin IgG1 Fc domain covalently linked to a peptide containing two TPO receptor-binding domains. The drug is licensed for the treatment of thrombocytopenia in patients with refractory chronic immune thrombocytopenic purpura and acts as a thrombopoietin (TPO) receptor agonist to activate intracellular transcriptional pathways leading to increased platelet production.[14,15] As a class, TPO receptor agonists are thought to increase the risk for development of bone marrow fibrosis and may increase the risk for hematologic malignancies. Access to the drug is restricted to prescribers enrolled in the NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) risk-mitigation program. Romiplostim is administered as a subcutaneous injection with the dose adjusted to the lowest dose necessary to reduce the risk of bleeding and achieve a platelet count = 50 x 109/L. A maximum weekly dose of 10 mcg/kg is recommended with therapy discontinued if the platelet count does not increase sufficiently within 4 weeks of therapy. Hyporesponsiveness or failure to maintain a platelet response may signal the development of neutralizing antibodies. Discontinuation of therapy poses a risk for worsening of thrombocytopenia below baseline, with subsequent hemorrhage. Patients receiving romiplostim must be monitored prior to initiation of therapy, frequently during treatment, and for 2 weeks following cessation of therapy.

Label approved on 8/22/08 for NPLATE, NDA no. 125268


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