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Pharmaceutical Approval Update June 2013

Marvin M. Goldenberg PhD, RPh, MS

Carbinoxamine Maleate Oral Suspension Extended-Release (Karbinal ER)

Manufacturer: Tris Pharma, Monmouth Junction, N.J.

Indication: Carbinoxamine maleate, a mildly sedating anti-histamine, has been approved to treat seasonal and perennial allergic rhinitis in children 2 years of age and older. It is also used to treat vasomotor rhinitis, conjunctivitis, hives, angioedema, and dermatographism (a form of hypersensitive urticaria).

Drug Class: Carbinoxamine is a histamine receptor– blocking agent. It is freely soluble in water. The chemical name is 2-[(4-chlorophenyl)-2-pyridinylmethoxy]- N,N-dimethylethanamine (Z)-2-butenedioate (1:1). The structural formula is C16H19CIN2O • C4H4O4. The molecular weight is 406.86 g/mol.

Uniqueness of Drug: Carbinoxamine is the first sustained-release histamine-blocking agent indicated for symptoms of allergic rhinitis. The drug–polistirex complex is formed with carbinoxamine maleate, USP, and sodium polystyrene sulfonate, USP. Karbinal ER contains 4 mg of carbinoxamine maleate per 5 mL. OralXR+ technology allows the drug ingredients to be delivered over time. The coating masks any unpleasant-tasting drug particles. The viscous suspension has a strawberry– banana flavor.

Warnings and Precautions:

Anticholinergic effects. Possible effects include dryness of the mouth, nose, and throat; dysuria; and urinary retention. This product should be used with extreme caution, if at all, in patients with angle-closure glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, or bladder neck obstruction.

Concomitant diseases. Caution is recommended in patients with elevated intraocular pressure, hyperthyroidism, cardiovascular disease, and hypertension. Antihistamines are not recommended in asthmatic patients who have experienced a serious antihistamine-induced adverse bronchopulmonary effect. This product should not be used to treat lower respiratory tract symptoms, including asthma.

Central nervous system effects. Because of a risk of drowsiness, patients should use caution when driving or operating machinery. Excitability, especially in children, has been documented. The use of other central nervous system (CNS) depressants may have additive depressant effects on the CNS.

Contraindications: Karbinal ER should not be prescribed for children younger than 2 years of age (deaths have been reported in this age group). The drug is also contraindicated for nursing mothers; individuals who are hypersensitive to carbinoxamine maleate or the drug’s inactive ingredients; and patients taking monoamine oxidase inhibitors.

Dosage and Administration: Karbinal ER is an extended-release oral suspension containing 4 mg of carbinoxamine maleate per 5 mL. The dosage should be tailored to patients according to their condition and response to therapy. Lower doses should be given initially and increased as needed and as tolerated. An accurate milliliter-measuring device (not a household teaspoon) should be used to prevent an overdose. A pharmacist can provide an appropriate device. Doses are as follows:

  • Adults and adolescents 12 years of age and older:7.5–20 mL (6–16 mg) every 12 hours
  • Children: 2–11 years: about 0.2–0.4 mg/kg per day
    • 2–3 years: 3.75 –5 mL (3–4 mg) every 12 hours
    • 4–5 years: 3.75–10 mL (3–8 mg) every 12 hours
    • 6–11 years: 7.5–15 mL (6–12 mg) every 12 hours

Commentary: Karbinal ER is a new formulation of carbinoxamine maleate. Before 2006, carbinoxamine was widely used in many combinations, but most older products had not been approved by the FDA. Following the FDA’s Drug Efficacy Study Implementation (DESI) review, the agency removed all unapproved products except two immediate-release formulations. The FDA had initiated the DESI program in the 1960s.

Approximately 30% of allergic patients do not obtain adequate relief from nonsedating antihistamines. The dosing schedule for carbinoxamine ER is convenient for those who do not respond to second-generation antihistamines.


Brinzolamide 1.0%/Brimonidine Tartrate 0.2% Ophthalmic Suspension (Simbrinza)

Manufacturer: Alcon/Novartis, Fort Worth, Texas

Indication: Simbrinza helps to reduce intraocular pressure (IOP) in primary open-angle glaucoma or ocular hypertension.

Drug Class: Brinzolamide is a carbonic anhydrase inhibitor; brimonidine tartrate is an alpha2-adrenergic receptor agonist. Brinzolamide is described chemically as (R)-(+)-4-ethylamino-2-(3-methoxypropyl)-3,4dihydro-2H-thieno [3,2-e]-1,2-thiazine-6-sulfonamide-1,1- dioxide. Its empirical formula is C12H21N3O5S3. The molecular weight is 383.5. Brimonidine tartrate is described chemically as 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline l-tartrate. Its empirical formula is C11H10BrN5–C4H6O6. The molecular weight is 442.2.

Uniqueness of Drug: This is the only fixed-dose combination for glaucoma in the U.S. that does not include a beta blocker.

Warnings and Precautions:

Hypersensitivity. Sulfonamide hypersensitivity reactions may occur because of the brinzolamide component.

Cornea. Endothelial cells of the cornea may be lost.

Renal impairment. Severe renal impairment may limit the metabolism of brinzolamide.

Glaucoma. Therapeutic interventions, in addition to ocular hypotensive agents, are required for patients with acute angle-closure glaucoma. Simbrinza has not been studied in patients with this type of glaucoma.

Contact lenses. The preservative (benzalkonium chloride) in Simbrinza may be absorbed by soft contact lenses. The lenses should be removed during instillation of the medication and may be reinserted 15 minutes after instillation.

Cardiovascular disease. In clinical studies, brimonidine caused a decrease in blood pressure in fewer than 5% of patients 2 hours after administration. Caution should be exercised in patients with severe cardiovascular disease.

Hepatic impairment. Brimonidine has not been studied in patients with hepatic impairment. It should be prescribed with caution in these patients.

Vascular insufficiency. Brimonidine may potentiate syndromes associated with vascular insufficiency. It should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans (Buerger’s disease).

Contaminated ophthalmic products. Bacterial keratitis has been associated with the use of multiple-dose containers of topical ophthalmic products when the containers were inadvertently contaminated by patients with concurrent corneal disease or with disruption of the ocular epithelial surface.

Dosage and Administration: Simbrinza contains 10 mg/mL of brinzolamide and 2 mg/mL of brimonidine. The bottle should be shaken well before use. One drop is instilled into the affected eye three times daily. If more than one topical ophthalmic drug is being used, the drugs should be taken at least 5 minutes apart.

Commentary: More than 67 million people worldwide have glaucoma, the second-leading cause of preventable blindness. Untreated, the condition can result in a gradual, irreversible loss of vision. Elevated IOP is considered a risk factor for glaucoma. In rare cases, even a normal IOP can result in the disease.

In clinical trials, the suspension was found to decrease elevated IOP by 21% to 35%.


Cysteamine Bitartrate (Procysbi)

Manufacturer: Raptor Pharmaceuticals, Novato, Calif.

Indication: Cysteamine bitartrate helps to reduce cystine levels, potentially delaying kidney and other damage. The medication is used in the management of nephropathic cystinosis, a rare genetic condition, in adults and children 6 years of age and older. It was granted an orphan product designation. Nephropathic cystinosis is the most common form of cystinosis, in which toxic levels of cystine, a naturally occurring non-essential amino acid, build up in the body’s cells and organs.

Drug Class: Procysbi contains the bitartrate salt of cysteamine. The chemical name for cysteamine bitartrate is ethanethiol, 2-amino, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt). The molecular formula is C2H7NS • C4H6O6, and the molecular weight is 227.

Uniqueness of Drug: This medication is the only delayed-release formulation of cysteamine bitartrate in a capsule form. It is a highly water-soluble white powder.

Warnings and Precautions:

Skin. If a skin rash develops, cysteamine bitartrate should be withheld until the rash clears. If a severe skin rash develops (erythema multiforme bullosa or toxic epidermal necrolysis), the medication should not be readministered. Serious skin lesions have also been reported in patients receiving high doses of cysteamine bitartrate or other cysteamine salts. Physicians should routinely monitor the skin and bones of patients.

Central nervous system. Seizures, lethargy, somnolence, depression, and encephalopathy have been associated with cysteamine. If symptoms develop, the patient should be carefully evaluated and the dose should be adjusted as necessary.

Benign intracranial hypertension. There have been reports of pressure within the brain in the absence of a tumor, also known as pseudotumor cerebri (PTC). PTC may be more common in cystinotic patients because of concomitant medications and renal transplantation. Patients should be advised to report headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye, or pain with eye movement. A periodic eye examination is needed to identify PTC early in order to prevent vision loss.

Gastrointestinal system. Gastrointestinal (GI) ulceration and bleeding have been reported in patients receiving cysteamine bitartrate. Physicians should remain alert for signs of ulceration and bleeding and should inform the patient’s caregiver about the signs and symptoms of serious GI toxicity and what steps to take if they occur. Nausea, vomiting, anorexia, and abdominal pain, sometimes severe, have been associated with cysteamine. If any these symptoms develop, therapy may have to be interrupted and the dose might need to be adjusted.

Hematology and hepatology. Cysteamine has occasionally been associated with reversible leukopenia and abnormal hepatic function results. Therefore, blood counts and liver function studies should be monitored.

Dosage and Administration: The delayed-release capsules are available in strengths of 25 mg and 75 mg. The total daily dose is 1.3 g/m2 per day in two divided doses every 12 hours. The goal of therapy is to maintain a white blood cell cystine level less than 1 nmol ½ cystine per milligram of protein or a plasma cysteamine concentration of greater than 0.1 mg/L.

Mylan’s cysteamine bitartrate immediate-release product (Cystagon) is the current standard of care, but it is taken every 6 hours whereas Procysbi is taken every 12 hours.

Commentary: Cystinosis affects an estimated 500 patients in the U.S. and from 2,000 to 3,000 patients worldwide. The condition is fatal if not treated in early childhood. Cystine buildup in the cells causes urinary loss of sugar, proteins, and salts, leading to slow body growth and small stature; weak bones; and worsening kidney failure. Nephropathic cystinosis, the most severe type, can severely damage the kidneys.

Procysbi (RP-103) is a reformulation of Cystagon, approved in 1994. Sigma-Tau’s ophthalmic solution (Cystaran), approved in 2012, is used to treat corneal cystine crystal accumulation.

In a phase 3 study, Procysbi brought about consistent cystine depletion over the full 12-hour period. Sustained levels of cysteamine, which historically have not been achieved in this patient population, may help to delay kidney dysfunction, transplantation, dialysis, organ failure, and premature death.

The estimated cost will be $350,000 per patient per year.