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Pharmaceutical Approval Update May 2014
Manufacturer: Chelsea Therapeutics, Charlotte, North Carolina
Date of Approval: February 18, 2014
Indication: For the treatment of neurogenic orthostatic hypotension (NOH), a rare, chronic, and often debilitating drop in blood pressure upon standing that is associated with Parkinson’s disease, multiple-system atrophy, and pure autonomic failure.
Drug Class: Droxidopa is a (–)-threo-3-(3,4-dihydroxyphenyl) derivative of the natural amino acid L-serine. In the body, droxidopa is metabolized by a vitamin B6-dependent enzyme, aromatic amino acid decarboxylase (DOPA decarboxylase) into the neurotransmitter norepinephrine [4-(2-amino-1-hydroxyethyl)-1,2-benzenediol], by removal of the single carboxylic acid group of L-serine.
The chemical structure of droxidopa is (2R,3S)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid with a molecular mass of 213.18734 g/mol. It is a synthetic precursor of nor epinephrine.
Uniqueness of Drug: Droxidopa is a prodrug of norepinephrine and epinephrine used to increase the concentrations of these neurotransmitters in the body and brain. Droxidopa is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as dopa decarboxylase (DDC). Patients with NOH have depleted concentrations of nor epinephrine and epinephrine, which leads to hypotension upon orthostatic challenge.
Droxidopa works by increasing the concentrations of norepinephrine and epinephrine in the peripheral nervous system. This induces tachycardia and increased blood pressure, enabling the body to maintain blood flow upon and while standing.
Droxidopa can also cross the blood–brain barrier, where it is converted to norepinephrine and epinephrine from within the brain. Droxidopa elicits beta-1 and alpha-adrenergic effects and moderate beta-2 effects, which increase cardiac output and heart rate, decrease renal perfusion and pulmonary vascular resistance, and cause variable blood pressure effects.
Boxed Warning: Monitor supine blood pressure prior to and during treatment, and more frequently when increasing doses. Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position. If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue droxidopa.
Warnings and Precautions:
Supine hypertension. Droxidopa therapy may cause or exacerbate supine hypertension in patients with NOH. Patients should be advised to elevate the head of the bed when resting or sleeping. Monitor blood pressure, both in the supine position and in the recommended elevated sleeping position. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well managed, droxidopa may increase the risk of cardiovascular events.
Hyperpyrexia and confusion. Postmarketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with droxidopa use. Observe patients carefully when the dosage of droxidopa is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients.
Pregnancy. There have been no adequate, well-controlled trials of droxidopa in pregnant women. Women who are nursing should choose between nursing and droxidopa. The safety and effectiveness of droxidopa in pediatric patients have not been established.
Age. Patients with symptomatic NOH ages 75 years and older were included in the droxidopa clinical program. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal clearance. Droxidopa and its metabolites are primarily cleared renally. No clinical trials were conducted with droxidopa in patients with severely decreased renal function (glomerular filtration rate [GFR] less than 20 mL/min). Patients with mild or moderate renal impairment (GFR greater than 20 mL/min) were included in clinical trials and did not have an increase in associated adverse events.
Dosage and Administration: Droxidopa is available in three dosages, including 100-mg, 200-mg, and 300-mg capsules. The recommended starting dose of droxidopa is 100 mg, taken orally three times a day: upon rising in the morning, at midday, and in the late afternoon at least three hours prior to bedtime. Administer with or without food.
Commentary: Northera (droxidopa) is indicated for the treatment of orthostatic dizziness, lightheadedness, or a feeling of an impending blackout in adult patients with symptomatic NOH.
The Food and Drug Administration approved droxidopa under the accelerated approval program, which authorizes a drug to treat a serious disease based on clinical data showing that the drug has an effect on an intermediate clinical measure (in this case, short-term relief of dizziness) that is reasonably likely to predict the outcome of ultimate interest (in this case, relief of dizziness during chronic treatment). This program provides patient access to promising drugs while the company conducts postapproval clinical trials to verify the drug’s clinical benefit, in this case long-term effect on NOH symptoms.
Source: Chelsea Therapeutics
Elosulfase Alfa (Vimizim)
Manufacturer: BioMarin Pharmaceutical, Novato, California
Date of Approval: February 19, 2014
Indication: Treatment of mucopolysaccharidosis type IVA (MPS IVA), Morquio A syndrome.
Drug Class: N-acetylgalactosamine-6-sulfatase is an enzyme that catalyzes the chemical reaction of cleaving off the 6-sulfate groups of the N-acetyl-D-galactosamine 6-sulfate units of the macromolecule chondroitin sulfate and, similarly, of the D-galactose 6-sulfate units of the macromolecule keratan sulfate. This enzyme belongs to the family of hydrolases, specifically those acting on sulfuric ester bonds. The systematic name of this enzyme class is N-acetyl-D-galactosamine-6-sulfate 6-sulfohydrolase. This enzyme participates in glycosaminoglycan degradation and degradation of glycan structures.
Uniqueness of Drug: Absence of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which normally clears out long chains of sugar molecules, leads to Morquio A syndrome, a rare, autosomal recessive lysosomal storage disease. Morquio A syndrome presents problems with bone development, growth, and mobility. Elosulfase alfa is intended to provide the exogenous enzyme GALNS that will be taken up into the lysosomes and increase the catabolism of glycosaminoglycans keratan sulfate and chondroitin 6 sulfate.
Boxed Warning: Life-threatening anaphylaxis can occur during elosulfase alfa infusions. Typical signs of anaphylaxis include cough, rash, throat tightness, hives, flushing, changes in skin color, low blood pressure, shortness of breath, chest pain, and gastrointestinal symptoms such as nausea, abdominal pain, retching, and vomiting. Patients who experience these symptoms during or after elosulfase alfa infusions should contact their doctor or seek medical help immediately. People with a respiratory illness may be at risk for a sudden worsening of their condition and may require additional monitoring.
Warnings and Precautions:
Anaphylaxis and hypersensitivity reactions. Life-threatening anaphylaxis can occur during elosulfase alfa infusions. Due to the potential for anaphylaxis, appropriate medical support should be readily available when elosulfase alfa is administered and for an appropriate period following administration. Hypersensitivity reactions have been observed as early as 30 minutes after the start of elosulfase alfa infusion but as late as six days after infusion. Frequent symptoms of hypersensitivity reactions included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing.
Risk of acute respiratory complications. Because of the potential for hypersensitivity reactions, administer anti-histamines with or without antipyretics prior to infusion. If severe hypersensitivity reactions occur, immediately stop the infusion and initiate appropriate treatment. Patients with acute febrile or respiratory illness at the time of elosulfase alfa infusion may be at higher risk of life-threatening complications from hypersensitivity reactions.
Sleep apnea. Sleep apnea is common in Morquio A syndrome patients. Evaluation of airway patency should be considered prior to initiation of treatment with elosulfase alfa. Patients using supplemental oxygen or continuous positive airway pressure during sleep should have these treatments readily available during infusion in the event of an acute reaction or extreme drowsiness/sleep induced by antihistamine use.
Spinal or cervical cord compression (SCC). This known and serious complication of MPS IVA may occur as part of the natural history of the disease. In clinical trials, SCC was observed both in patients receiving elosulfase alfa and patients receiving placebo. Patients with MPS IVA should be monitored for signs and symptoms of SCC (including back pain, paralysis of limbs below the level of compression, and urinary and fecal incontinence) and given appropriate clinical care.
Dosage and Administration: The usual adult dose of elosulfase alfa for MPS IVA is 2 mg per kilogram of body weight administered once every week as an intravenous infusion. The usual pediatric dose for patients 5 years of age or older is 2 mg/kg administered once every week as an intravenous infusion.
Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion in adults and children.
Commentary: Vimizim is the first FDA-approved drug for Morquio A syndrome, an enzyme deficiency that interferes with skeletal development and can trigger a host of other health problems. About 800 people suffer from the disease in the U.S., with 3,000 patients in the developed world.
A year’s supply of Vimizim will cost about $380,000, bringing in $400 million to $500 million annually for BioMarin, analysts predict. Still, Vimizim’s steep price ranks it only third on the list of the most costly medications. Alexion Pharmaceuticals’ Soliris, which treats paroxysmal nocturnal hemoglobinuria and other rare illnesses, is first at $440,000 a year. Second-place Cinryze treats hereditary angioedema at an annual cost of $417,000, while another orphan drug, Hunter syndrome therapy Elaprase, is fourth at $375,000.
Sources: Medical News Today, MediLexicon, FiercePharma, San Francisco Business Times
Sodium Hyaluronate in Phosphate-Buffered Saline (Monovisc)
Manufacturer: Anika Pharmaceuticals, Bedford, Massachusetts
Date of Approval: March 3, 2014
Indication: Monovisc is a single-injection regimen to treat knee pain and improve joint mobility in patients who have osteoarthritis (OA) of the knee.
Drug Class: Sodium hyaluronate (NaHA) is a high-molecular-weight polysaccharide composed of sodium glucuronate and N-acetylglucosamine. The NaHA in Monovisc is derived from bacterial fermentation. Hyaluronic acid (HA) is ubiquitously distributed throughout the body and is present in high concentrations in some tissues, such as vitreous humor, synovial fluid, the umbilical cord, and dermis. NaHA functions as a tissue lubricant and plays an important role in modulating the interactions between adjacent tissues. Different NaHA preparations may have different molecular weights, but they have the same chemical structure. This cross-linked NaHA injection is biocompatible, noninflammatory, and nonpyrogenic.
Uniqueness of Drug: Joints affected by OA typically have lower concentrations of HA in the synovial fluid. As a result, the synovial fluid has lower viscosity and elasticity than healthy synovial fluid, decreasing its ability to lubricate the joint and absorb shocks. Viscosupplements such as this are designed to replace the body’s natural HA, providing significant pain relief from OA symptoms. The actions of this injection are lubrication and mechanical support. NaHA preparations have been shown to be well tolerated in osteoarthritic synovial joints.
Warnings and Precautions:
General precautions should be considered during injection of substances into joints. The amount of Monovisc that should be injected depends on the site, the patient’s anatomy, and his or her needs. An excess quantity of NaHA should not be used and patients should be monitored closely. The synovial space should not be overfilled. If pain increases during the injection procedure, the injection should be stopped and the needle should be withdrawn.
Common needle gauges for injections into the knee are sizes 18 to 21. The needle selection for any procedure is determined by the physician. Ensure proper penetration into the joint’s synovial space prior to injection.
Dosage and Administration: The required amount of the preparation is injected into the selected joint space through a sterile, disposable hypodermic needle of suitable gauge. One injection is given every four to six months.
This sterile, viscoelastic preparation is supplied in a disposable glass syringe delivering 4 mL. Each milliliter of the pre-filled syringe contains 15 mg to 25 mg of lightly cross-linked NaHA dissolved in phosphate-buffered saline. It is manufactured from ultra-pure, high-molecular-weight NaHA produced by bacterial fermentation. HA is a natural complex polysaccharide of the glycosaminoglycan family.
Commentary: OA of the knee afflicts more than 5% of the world’s population, making it the most common joint disease. Typically affecting middle-aged and older people, OA can range from very mild to very severe. Risk factors include being overweight, joint injury, muscle weakness, having other forms of arthritis, and heredity. Approximately 10 million Americans suffer from OA of the knee, and that number is expected to increase.
OA of the knee is characterized by the breakdown of cartilage, the part of the joint that cushions the ends of bones, causing bones to rub against each other, resulting in pain and loss of movement. Degradation changes in the synovial fluid contained in the joint may also play a role in OA. Synovial fluid, which mostly consists of hyaluronan, lubricates the joint and is needed to facilitate movement of the joint.
Monovisc is the only single-injection viscosupplement approved for relief of joint pain in all synovial joints. It is specially formulated for single-injection treatment by lightly cross-linking the HA polymers using a proprietary technology. Light cross-linking stabilizes the HA polymers for durability while retaining all of the HA’s natural benefits.