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P T. 2010 May; 35(5): 288–290.
PMCID: PMC2873704

Pharmaceutical Approval Update

Marvin M. Goldenberg, PhD, RPh, MS

Carglumic Acid Tablets (Carbaglu)

Manufacturer: Orphan Europe SARL, Paris, France

Indication: Carglumic acid tablets are indicated as an adjunctive therapy and as a maintenance therapy for children and adults with acute hyperammonemia caused by a deficiency in the hepatic enzyme N-acetylglutamate synthase (NAGS). During acute episodes of elevated ammonia levels, the concomitant administration of Carbaglu with other ammonia-lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction are recommended. During maintenance therapy, the concomitant use of other ammonia-lowering therapies and protein restriction may be reduced or discontinued, depending on the patient’s plasma ammonia levels.

Drug Class: The chemical formula of this carbamoyl phosphate synthetase 1 (CPS1) activator is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid. The molecular weight is 190.16.

Uniqueness of Product: Carbaglu is a synthetic structural analogue of N-acetylglutamate (NAG), an essential allosteric activator of CPS1 in liver mitochondria. CPS1 is the first enzyme of the urea cycle, which converts ammonia into urea. NAG is the product of NAGS, a mitochondrial enzyme. Carbaglu acts as a replacement for NAG in NAGS deficiency patients by activating CPS1.

Warnings and Precautions:

Hyperammonemia. Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Dialysis (preferably hemodialysis) may be required to remove a large burden of ammonia. Uncontrolled hyperammonemia can rapidly result in brain injury or death, and the prompt use of all therapies necessary to reduce plasma ammonia levels is essential.

Hyperammonemia caused by NAGS deficiency should be managed in coordination with medical personnel experienced in treating metabolic disorders. Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests and clinical responses in patients receiving Carbaglu is crucial to assess patient response to treatment.

Therapeutic monitoring. Plasma ammonia levels should be maintained within the normal range by means of individual dose adjustments according to the patient’s age.

Nutritional management. During acute hyperammonemic episodes, protein restriction and hypercaloric intake are recommended to block ammonia-generating catabolic pathways. When plasma ammonia levels have returned to normal, protein intake can usually be increased, with the goal of unrestricted protein intake.

Adverse Reactions: In clinical trials, the most common reactions occurring in 13% of patients or more, regardless of the cause, were vomiting, abdominal pain, pyrexia, tonsillitis, anemia, ear infections, diarrhea, nasopharyngitis, and headache.

Dosage and Administration: Carbaglu is a 200-mg tablet that may be divided into two or four doses per day. If a dose is missed, it should be taken as soon as possible. If it is almost time for the next scheduled dose, the patient should skip the missed dose and should wait to return to the regular dosing schedule. The dose should not be doubled.

Treatment should be initiated by a health care practitioner experienced in metabolic disorders.

Adults:

Initial and maintenance therapy. The recommended initial dose for acute hyperammonemia is 100 to 250 mg/kg per day. The concomitant administration of other ammonia-lowering therapies is recommended. Dosing should be titrated based on the individual’s plasma ammonia levels and clinical symptoms.

The recommended maintenance dose should be titrated to target normal plasma ammonia levels according to the patient’s age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg per day. The total daily dose should be divided into two to four doses and rounded off to the nearest 100 mg (i.e., half a tablet).

Oral administration. The tablets should not be swallowed whole or crushed. Each 200-mg tablet should be dispersed in a minimum of 2.5 mL of water and taken immediately. Because the tablets do not dissolve completely in water, undissolved particles may remain in the mixing container. To ensure complete delivery of the dose for pediatric patients, the clinician should rinse the mixing container with additional volumes of water. The contents should be swallowed immediately. The use of Carbaglu in food has not been studied and is therefore not recommended.

Nasogastric tube administration. For adult patients with a nasogastric tube in place, each 200-mg tablet should be mixed in a minimum of 2.5 mL of water. The solution should be shaken gently to allow for quick dispersal. The dispersion should be given immediately through the tube. The tube should be flushed with additional water to clear it.

Pediatrics:

Initial and maintenance therapy. The recommended initial dose for acute hyperammonemia is 100 to 250 mg/kg per day. The concomitant administration of other ammonia-lowering therapies is recommended. Dosing should be titrated according to each patient’s ammonia level and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia concentrations according to the patient’s age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg per day. The total daily dose should be divided into two to four doses.

Oral administration using an oral syringe. For administration via oral syringe, each 200-mg Carbaglu tablet should be mixed in 2.5 mL of water in a container to yield a concentration of 80 mg/mL. The solution is shaken gently to allow for quick dispersal. The appropriate volume of dispersion is drawn in an oral syringe and administered immediately. The unused portion should be discarded. The oral syringe is refilled with a minimum volume of water (1–2 mL) and administered immediately.

Nasogastric tube administration. For pediatric patients with a nasogastric tube in place, each 200-mg tablet should be mixed in 2.5 mL of water in a mixing container to yield a concentration of 80 mg/mL. The solution should be shaken gently to allow for quick dispersal. The appropriate volume of dispersion is drawn and administered immediately through a nasogastric tube. The unused portion should be discarded. To clear the tube, the clinician should flush it with additional water.

Commentary: NAGS deficiency is a rare genetic disorder that can be present soon after birth. NAGS deficiency and the resulting hyperammonemia can be fatal if they are not treated quickly. DNA testing can confirm the diagnosis. The safety and efficacy of Carbaglu were studied in 23 patients for periods ranging from six months to 21 years. The medication reduced blood ammonia concentrations within 24 hours and normalized them within three days. Most patients maintained normal ammonia levels over the long term. Only physicians experienced in treating metabolic disorders should administer this drug.

Sources: FDA, March 18, 2010, www.accessdata.fda.gov/drugsatfda_docs/label/2010/022562lbl.pdf; www.drugs.com

Adapalene Topical 0.1% Lotion (Differin)

Manufacturer: Galderma Pharmaceuticals, Princeton, N.J.

Indication: Adapalene lotion 0.1% is indicated for the treatment of acne vulgaris in patients 12 years of age and older. It can be used on the face and other affected areas.

Drug Class: The chemical formula is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, and the molecular weight is 412.52. A chemically stable, retinoid-like compound, adapalene is a modulator of cellular differentiation, keratinization, and inflammatory processes, all representing features in the pathology of acne vulgaris.

Uniqueness of Drug: Adapalene binds to specific retinoic and nuclear receptors, but it does not bind to the cytosolic receptor protein. Although the exact mechanism of action is unknown, topical adapalene may normalize the differentiation of follicular epithelial cells, resulting in decreased formation of micro-comedones. Adapalene inhibits the directional and random responses of human polymorphonuclear leukocytes; it also blocks the metabolism of arachidonic acid, by lipoxygenation, to inflammatory mediators.

Warnings: The lotion should be discontinued if patients experience hypersensitivity to any of the ingredients. Patients with sunburn should not use the lotion until the skin is fully recovered.

Precautions: Patients should apply the lotion to the affected area once per day, avoiding the eyes, lips, and mucous membranes. The most common adverse event reported with use of adapalene lotion 0.1% was mild-to-moderate dryness, which may be managed with moisturizers. Redness, scaling, stinging, and burning have also been reported. These effects typically resolve during the first two weeks of treatment, but a physician should be consulted if they persist.

Patients should avoid excessive exposure to sunlight and sunlamps while they are using the lotion. Sunscreen products and protective clothing are recommended. Irritating topical products that contain resorcinol, salicylic acid, or sulfur should not be used during adapalene therapy. Patients should avoid applying the lotion to areas that have been treated with a depilatory product such as wax. This lotion has not been tested in pregnant or nursing women or in elderly patients.

Teratogenic effects. The product is a Pregnancy Category C medication. No teratogenic effects were seen in rats at oral doses of 0.15 to 5 mg/kg per day, which was up to 120 times the maximal daily human topical dose. Teratological studies of the cutaneous route, conducted in rats and rabbits at doses of 0.6, 2, and 6 mg/kg per day (up to 150 times the maximal daily human topical dose) exhibited no fetotoxicity and only minimal increases in supernumerary ribs in rats. No adequate or well-controlled studies have been conducted in pregnant women. Adapalene should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. The product has not been tested in pregnant women, nursing mothers, or elderly patients.

Dosage and Administration: The lotion is formulated for tolerable efficacy; it spreads easily and is available in a convenient, easy-to-use pump dispenser.

After washing gently with a mild, soapless cleanser, patients apply a thin film of the lotion to the entire face or affected areas once daily. Three to four activations of the pump (about the size of a nickel) are used. Areas of the skin around the eyes, lips, and mucous membranes should be avoided.

Commentary: Adapalene is a third-generation synthetic retinoid that produces less irritation compared with other topical retinoids. In addition to having efficacy equivalent to that of tretinoin (Retin-A, Ortho), adapalene has potent anti-inflammatory activity of its own. Because of its reduced potential for irritation, adapalene is well suited for use in combination regimens, particularly with benzoyl peroxide (e.g., Benzac, Galderma; Benzagel, Dermik; Desquam, Westwood-Squibb), which is potentially irritating. Topical retinoids add comedolytic activity to the benzoyl peroxide/clindamycin (BenzaClin, Dermik) regimen.

Adapalene is also sold as a gel and a cream; this new approval is the first lotion formulation of this product for the treatment of acne. No studies have compared the efficacy and safety of the cream versus the lotion formulation. With combination therapy the standard of care in the management of acne vulgaris, it remains to be determined whether the manufacturer might contemplate producing a combination product.

Sources: www.differin.com; www.pharmqd.com; www.drugs.com

Velaglucerase alfa for Injection (VPRIV)

Manufacturer: Shire Human Genetic Therapies, Inc., Cambridge, Mass.

Indication: VPRIV is designed for long-term enzyme replacement therapy in pediatric and adult patients with type-1 Gaucher disease.

Drug Class: This product is a hydrolytic lysosomal glucocerebroside-specific enzyme.

Uniqueness of Drug: The active ingredient, velaglucerase alfa, is produced by gene activation technology in a human fibroblast cell line. This glycoprotein has 497 amino acids and a molecular weight of approximately 63 kD. Velaglucerase alfa has the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. The product contains five potential N-linked glycosylation sites; four of these sites are occupied by glycan chains.

VPRIV contains predominantly high-mannose-type N-linked glycan chains; these chains are specifically recognized and internalized via the mannose receptor present on the surface on macrophages, the cells that accumulate glucocerebroside in Gaucher disease. VPRIV catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide in the lysosome.

Warnings and Precautions:

Hypersensitivity reactions. Patients receiving the medication with any intravenous (IV) protein product have reported hypersensitivity reactions. For this reason, appropriate medical support should be readily available when VPRIV is administered. If a severe reaction occurs, current medical standards for emergency treatment should be followed. Caution is recommended for patients who have experienced symptoms of hypersensitivity to the active ingredient or excipients in the drug or to other enzyme replacement therapy.

Infusion-related reactions. The most commonly observed adverse reactions in patients receiving VPRIV have been infusion-related. Symptoms have included headache, dizziness, hypotension, hypertension, nausea, fatigue and asthenia, and pyrexia. Generally, these reactions were mild; in treatment-naive patients, the onset of symptoms usually occurred during the first six months of treatment and tended to occur less frequently with time.

The management of these reactions should be based on the severity of the reaction, such as slowing the infusion rate; using antihistamines, antipyretics, or corticosteroids; or stopping and resuming treatment with an increased infusion time. Pretreatment with antihistamines or cortico steroids may prevent subsequent reactions if symptomatic treatment has been necessary. During clinical studies, patients were not routinely premedicated before they received VPRIV therapy.

Dosage and Administration: The recommended dose is 60 units/kg every other week as a 60-minute IV infusion. Patients being treated with imiglucerase (Cerezyme, Genzyme) for type-1 Gaucher disease may be switched to VPRIV. It is recommended that patients who previously received a stable dose of imiglucerase begin treatment with VPRIV at that same dose when they make this switch.

Dosage adjustments can be made based on the achievement and maintenance of each patient’s therapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 units/kg every other week. VPRIV should be administered under the supervision of a health care professional.

Aseptic use is required. VPRIV alfa is a lyophilized powder that must be reconstituted and diluted. It is intended for IV infusion only. This product contains no preservatives, and vials are for a single use only. Any unused solution should be discarded. The number of vials to be reconstituted is based on each patient’s weight and the prescribed dose. Table 1 presents instructions for reconstitution.

Table 1
Instructions for Reconstitution Of Velaglucerase alfa (VPRIV)

Upon reconstitution in the vials, the solution should be clear to slightly opalescent and colorless, and it should not be used if it is discolored or if it contains foreign particulate matter. The calculated volume of drug is withdrawn from the appropriate number of vials, and the total volume required in 100 mL of 0.9% sodium chloride solution suitable for IV administration is diluted. The solution is mixed gently; it should not be shaken.

VPRIV is administered over a period of 60 minutes. It should not be infused with other products in the same infusion tubing, because the compatibility in solution with other products has not been evaluated. The diluted solution should be filtered through an in-line, low-protein-binding, 0.2-micron filter during administration.

VPRIV contains no preservatives and should be used immediately after it is reconstituted. If this is not possible, the reconstituted or diluted product may be stored for up to 24 hours at 2° to 8°C (36°–46°F). VPRIV should not be frozen, and it should be kept protected from light. The infusion should be completed within 24 hours of reconstitution of the vials.

Commentary: Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene, which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam (Gaucher) cells. In patients with this lysosomal storage disorder, clinical features reflect the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of these cells in the liver and spleen leads to organomegaly, and their accumulation in the bone marrow and spleen lead to anemia and thrombocytopenia. VPRIV catalyzes the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside.

VPRIV provides long-term enzyme replacement therapy for type-1 Gaucher disease. It is an alternative to imiglucerase, which had been in short supply. Patients who previously received imiglucerase can safely switch to VPRIV.

Sources: Medicus Life Brands, http://medicuslb.com; www.fdanews.com; www.shire.com


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