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P T. 2010 March; 35(3): 162–164.
PMCID: PMC2844048

Pharmaceutical Approval Update

Marvin M. Goldenberg, PhD, RPh, MS

Dalfampridine (Ampyra) Extended-Release Tablets

Manufacturer: Elan, Ireland, and Acorda Therapeutics, Hawthorne, N.Y.

Indication: Dalfampridine is approved to improve walking in patients with multiple sclerosis (MS). The approval was based on an increase in walking speed in treated patients compared with those receiving placebo.

Drug Class: Dalfampridine is a broad-spectrum potassium channel blocker. Its chemical name is 4-aminopyridine. Each tablet contains 10 mg of dalfampridine in an extended-release formulation for twice-daily oral administration.

Uniqueness of Product: The mechanism by which dalfampridine exerts its therapeutic effect has not been fully elucidated. In animal studies, dalfampridine increased conduction of action potentials in demyelinated axons through inhibition of potassium channels.

Warnings and Precautions:

Seizures. Dalfampridine is contraindicated in patients with a history of seizures. An increased incidence of seizures was observed at 20 mg twice daily in controlled clinical studies of 9 to 14 weeks’ duration with dalfampridine in patients with MS. Dalfampridine has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an electroencephalogram, because these patients were excluded from clinical trials. Dalfampridine should be discontinued and should not be restarted in patients who experience a seizure during treatment.

Renal impairment. Dalfampridine is eliminated through the kidneys primarily unchanged. It is not indicated for patients with moderate-to-severe renal impairment. The risk of seizures in patients with mild renal impairment (creatinine clearance, 51–80 mL/minute) is unknown, but plasma levels of dalfampridine in these patients may approach those seen with 15 mg twice daily, a dose that may be associated with an increased risk of seizures.

Concurrent treatment with other forms of 4-amino-pyridine. Dalfampridine should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), because the active ingredient is the same.

Urinary tract infections. Urinary tract infections were reported more frequently as adverse reactions in controlled studies in patients receiving dalfampridine 10 mg twice daily (12%) compared with those receiving placebo (8%).

Dosage and Administration: The maximum recommended dose is one 10-mg tablet twice daily, taken with or without food. Doses should be taken about 12 hours apart. Patients should not take double or extra doses if a dose is missed.

Commentary: MS is a chronic, often disabling disease that affects the central nervous system (brain, spinal cord, and optic nerves). Approximately 400,000 people in the U.S. and 2.5 million people worldwide have MS. Dalfampridine is the first medication indicated to improve walking, one of the greatest challenges associated with MS.

Acorda has announced that the wholesale acquisition cost for dalfampridine extended-release tablets will be $1,056 for a 30-day supply (60 tablets per bottle) at an annual cost of $12,850. Does the cost of the drug outweigh its potential utility? For the MS patient, the tablet is definitely an advantage because it means improvements in walking speed; this benefit, for example, can help patients reach a bathroom in time or cross a street before the light changes. However, the drug is not always effective, and the disease may become refractory to therapy over time. Justifying an annual price tag of $12,000 (or more) to insurers and altering the prescribing habits of neurologists will require more than the endorsement of the MS lobby.

The company is also launching services to ensure that patients have access to the drug and to assistance and copay programs.

Source: www.ampyra.com/local/files/PI.pdf

Tocilizumab (Actemra) Injection

Manufacturer: Roche Group/Genentech, South San Francisco, Calif.

Indication: Tocilizumab for intravenous (IV) infusion is indicated for adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.

Biological Class: Tocilizumab is a humanized monoclonal antibody interleukin-6 (IL-6) receptor inhibitor.

Uniqueness of Drug: Tocilizumab is the first IL-6 receptor-inhibiting monoclonal antibody approved to treat RA. It may be used alone or in combination with methotrexate or other disease modifying anti-rheumatic drugs (DMARDs).

Boxed Warning: Patients receiving tocilizumab are at an increased risk for serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking a concomitant immunosuppressant such as methotrexate or corticosteroids. If a serious infection develops, tocilizumab therapy should be interrupted until the infection is controlled. Reported infections may include:

  • active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB before and during therapy. Treatment for latent infection should begin before tocilizumab is used.
  • invasive fungal infections (candidiasis, aspergillosis, and pneumocystis). Patients with invasive fungal infections may present with disseminated rather than localized disease.
  • bacterial, viral, and opportunistic infections.

The risks and benefits of tocilizumab should be carefully considered before therapy is begun in patients with chronic or recurrent infection. Patients should be closely monitored for signs and symptoms during and after treatment with tocilizumab.

Warnings and Precautions:

Serious infections. Serious and sometimes fatal infections resulting from bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents, including tocilizumab for RA. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis.

Gastrointestinal perforation. Tocilizumab should be used with caution in patients who may be at increased risk for gastrointestinal (GI) perforation, which has been reported as a complication of diverticulitis.

Laboratory parameters:

Neutrophils. Tocilizumab was associated with a higher incidence of neutropenia. It is recommended that tocilizumab treatment not be initiated in patients with an absolute neutrophil count of less than 2,000/mm3. Neutrophil counts should be monitored every four to eight weeks.

Platelets. Tocilizumab was related to a reduction in platelet counts. Patients with a platelet count below 100,000/mm3 should not initiate therapy.

Liver function tests. A higher incidence of transaminase elevations was noted in patients taking tocilizumab. The frequency and magnitude of these elevations increased when potentially hepatotoxic drugs (e.g., methotrexate) were used in combination with tocilizumab.

Lipids. Patients receiving tocilizumab experienced increases in lipid parameters such as total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol-C (HDL-C). Lipid values should be assessed every four to eight weeks.

Immunosuppression. As an immunosuppressant, tocilizumab may cause an increased risk of malignancy. All patients should be monitored for active TB.

Hypersensitivity reactions. Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with infusions of tocilizumab.

Demyelinating disorders. Patients should be closely monitored for signs and symptoms that might be indicative of demyelinating disorders.

Active hepatic disease. Tocilizumab is not recommended in patients with active hepatic disease.

Vaccinations. Vaccines should not be given concurrently with tocilizumab.

Dosage and Administration: Tocilizumab may be used alone or with methotrexate or other DMARDs. When it is used with DMARDs or as monotherapy, the recommended starting dose is 4 mg/kg, followed by an increase to 8 mg/kg based on the patient’s clinical response.

Commentary: RA is a chronic, progressive inflammatory disease of the joints and surrounding tissues. It is associated with intense pain, irreversible joint destruction, and systemic complications. Several key cytokines (proteins) are involved in the inflammatory process, including IL-6. Research shows that IL-6 levels are elevated in patients with RA. Tocilizumab is the first medication designed to inhibit the biological activity of IL-6 and the first humanized IL-6 receptor-inhibiting monoclonal antibody. Substantial adverse effects are associated with laboratory changes in patients receiving tocilizumab, as outlined in the warnings.

The drug is a once-monthly IV therapy for moderately to severely active RA in adults who have not responded to TNF antagonists. However, the FDA limited the approval because of serious safety concerns, including elevated liver enzymes, elevated LDL-C levels, hypertension, and GI perforation. Therefore, physicians and patients must be aware of the product’s limitations.

Source: www.gene.com/gene/products/information/actemra/pdf/pi.pdf

Aliskiren and Valsartan (Valturna) Tablets

Manufacturer: Novartis Pharmaceuticals, East Hanover, N.J.

Indication: Valturna is a combination of aliskiren (Tekturna) and valsartan (Diovan). The tablets are indicated for the treatment of hypertension in patients whose blood pressure is not adequately controlled with monotherapy.

Drug Class: Aliskiren is a direct renin inhibitor, and valsartan is an angiotensin II receptor blocker (ARB).

Uniqueness of Drug: Aliskiren decreases plasma renin activity and inhibits the conversion of angiotensinogen to angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure.

Valsartan inhibits the vasoconstrictor and aldosterone-secreting effects of Ang II by selectively blocking the binding of Ang II to the AT1 (angiotensin) receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Ang II is formed from Ang I in a reaction catalyzed by ACE (kininase II). The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor.

Boxed Warning. When pregnancy is detected, Valturna should be discontinued as soon as possible. When Valturna is used in pregnancy during the second and third trimester, drugs that act directly on the renin–angiotensin system can cause injury and death to the developing fetus.

Warnings and Precautions:

Fetal or neonatal morbidity and mortality. Valturna can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

Head and neck angioedema. Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with aliskiren and has led to the need for hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors or ARBs. Prompt administration of subcutaneous (SQ) epinephrine solution 1:1000 (0.3–0.5 mL) and measures to ensure a patent airway may be necessary.

Hypotension. In controlled trials, an excessive fall in blood pressure was rarely seen (in fewer than 0.5% of cases) in patients with uncomplicated hypertension who received Valturna. In patients with an activated RAAS, such as volume-depleted or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving RAAS blockers. Therapy should be administered cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis.

Severe renal impairment:

Valturna. Patients with severe renal impairment were excluded from clinical trials of Valturna for hypertension.

Aliskiren. Patients with severe renal dysfunction, a history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical trials of aliskiren in hypertension. Severe renal dysfunction was defined as a creatinine level of 1.7 mg/dL for women and 2 mg/dL for men or an estimated glomerular filtration rate below 30 mL/minute.

Valsartan. In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Valsartan has not been used over the long term in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated. As a consequence of inhibiting the RAAS, changes in renal function may occur, particularly in volume-depleted patients. In patients with severe heart failure whose renal function may depend on the activity of the RAAS, treatment with ACE inhibitors and ARBs has been associated with oliguria or progressive azotemia and rarely with acute renal failure or death. Similar outcomes have been reported with valsartan.

Hepatic impairment. Because most of the valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance—that is, higher area-under-the-curve (AUC) concentrations.

Congestive heart failure and postmyocardial infarction. Some patients with heart failure have experienced increases in BUN, serum creatinine, and potassium levels with valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reductions, discontinuation of the diuretic or valsartan, or both, may be required.

Serum electrolyte abnormalities. In short-term controlled trials of various doses of Valturna, the incidence of hyperkalemia (a serum potassium level above 5.5 mEq/L) was about 1% to 2% higher with the combination compared with aliskiren or valsartan alone or with placebo. In a long-term, uncontrolled study with median treatment duration of about one year, about 4% of the patients had at least one serum potassium level above 5.5 mEq/L at some time during the study; about 0.8% of patients discontinued treatment with Valturna and had a high serum potassium level at some point during the study. Periodic determinations of serum electrolytes to detect possible electrolyte imbalances are advised. Caution is advised with the concomitant use of Valturna and potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels.

Renal artery stenosis:

Aliskiren. No data are available on the use of aliskiren in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Valsartan. In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. Long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis has not been reported, but an effect similar to that seen with ACE inhibitors should be anticipated.

Cyclosporine. When aliskiren was given with cyclosporine, blood concentrations of aliskiren were significantly increased. The concomitant use of aliskiren with cyclosporine is not recommended.

Dosage and Administration:

Dose selection. The recommended once-daily dose of Valturna is 150/160 mg or 300/320 mg. The recommended initial once-daily dose is 150/160 mg. Titration should be performed as needed to a maximum of 300/320 mg. Patients switched from monotherapy, on average, experience greater blood pressure reductions with use of the combination product.

Dose titration. The antihypertensive effect of Valturna is largely attained within two weeks. If blood pressure remains uncontrolled after two to four weeks of therapy, the dose may be titrated up to a maximum of 300/320 mg.

Add-on therapy. A patient whose blood pressure is not adequately controlled with aliskiren alone or valsartan (or with another ARB) alone may be switched to combination therapy. The usual recommended starting dose is 150/160 mg once daily, as needed.

Replacement therapy. For convenience, patients using aliskiren and valsartan as separate tablets may prefer to receive a single tablet of the combination product containing the same component doses.

Initial therapy. The usual recommended starting dose of Valturna is 150/160 mg once daily, as needed, to control blood pressure. The dose may be titrated up to a maximum of 300/320 mg once daily. The combination product is not recommended for use as initial therapy in patients with intra-vascular volume depletion.

Commentary: Valturna combines valsartan, an ARB, and aliskiren, the only approved direct renin inhibitor. It is the first therapy to target two points within the RAAS, which plays a key role in regulating blood pressure. The combination product offers greater blood pressure reduction than either valsartan or aliskiren alone; however, it is associated with serious warnings and precautions. A patient whose blood pressure is not adequately controlled with aliskiren alone or valsartan (or another ARB alone) may be switched to Valturna.

Source: www.pharma.us.novartis.com/product/pi/pdf/valturna.pdf


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