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Pharmaceutical Approval Update February 2011

Marvin M. Goldenberg PhD, RPh, MS

Gardasil Vaccine for Anal Cancer

Manufacturer: Merck &Co., Whitehouse Station, N.J.

Indication: Gardasil has a new approval for the prevention of anal cancer caused by human papillomavirus (HPV) types 16 and 18 in females and males 9 through 26 years of age as well as for the prevention of grades 1, 2, and 3 anal intraepithelial neoplasia caused by HPV types 6, 11, 16 and 18. Earlier indications are discussed in the Commentary.

Biological Class: This non-infectious recombinant quadrivalent vaccine is prepared from purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and are self-assembled into VLPs. S. cerevisiae is grown on fermentation media that include vitamins, amino acids, mineral salts, and carbohydrates.

VLPs are released from the yeast cells by cell disruption and are purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed amorphous aluminum hydroxyphosphate sulfate, an aluminum-containing adjuvant. The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.

Uniqueness of Biological Product: Only humans are affected by HPV. Studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines involves the development of humoral immune responses. Humans develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.

Warnings and Precautions:

Syncope. Because syncope may occur after inoculation, possibly resulting in falls, it is recommended that the person be observed for 15 minutes after the injection. Syncope, sometimes associated with tonic–clonic movements and other seizure-like activity, has occurred following vaccination with Gardasil. When syncope is associated with tonic–clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion if the patient maintains a supine or Trendelenburg position.

Allergic reactions. Appropriate medical treatment and supervision must be available in case of anaphylactic reactions following the administration of Gardasil.

Adverse effects. In general, events included headache, fever, nausea, dizziness, injection-site reactions consisting of pain, swelling, erythema, and bruising.

Dosage and Administration: Gardasil 0.5 mL is given in a three-dose series administered by intramuscular (IM) injection in the upper arm. The second and third doses should be administered two and six months after the first dose. The minimum interval between the first and second doses is four weeks.

The vaccine should be agitated thoroughly immediately before administration to maintain suspension. After agitation, it becomes a white cloudy liquid. Gardasil should not be diluted or mixed with other vaccines. The vaccine should not be used if particulates are present or if it appears discolored.

Commentary: Anal cancer affects both men and women, but the incidence is highest among men who have sex with men, according to the National Cancer Institute (NCI). The American Cancer Society states that 60% of cases occur in women. It was estimated that anal cancer would be diagnosed in approximately 2,000 men and 3,000 women during 2010. There is no standardized screening for the general population for anal cancer, and the disease is often discovered when it is more advanced. Although this cancer is less common than other types, its incidence is increasing.

In 2006, Gardasil was approved to prevent cervical, vulvar, and vaginal cancers in females and genital warts in males and females. It does not prevent the development of anal pre-cancerous lesions that already exist at the time of vaccination.


Testosterone Gel (Fortesta)

Manufacturer: Endo Pharmaceuticals, Chadds Ford, Pa.

Indication: Fortesta Gel is an androgen to be used as a replacement therapy in men with a deficiency or absence of endogenous testosterone resulting from:

  • congenital or acquired primary hypogonadism: testicular failure resulting from cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Kline-felter’s syndrome, chemotherapy, or toxicity from alcohol or heavy metals. Serum testosterone levels are usually low, but gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels—are above the normal range.
  • congenital or acquired hypogonadotropic hypogonadism: idiopathic gonadotropin or luteinizing hormone–releasing hormone (LHRH) deficiency or pituitary–hypothalamic injury from tumors, trauma, or radiation. Serum testosterone levels are low, but gonadotropins are in the normal or low range.

Drug Class: The gel’s active ingredient is testosterone, a whitish powder. It is described chemically as 17-beta hydroxyandrost-4-en-3-one.

Uniqueness of Drug: Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for the maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the onset of male hair distribution; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.

Boxed Warning: Virilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using this gel. Patients are advised to adhere to recommended instructions for use.

Warnings and Precautions:

Risks of prostate enlargement and prostate cancer. Men with benign prostatic hyperplasia (BPH) who are treated with androgens should be monitored for worsening of signs and symptoms of BPH. Because men receiving androgens may be at increased risk for prostate cancer, screening for the presence of prostate cancer before and during treatment with androgens is appropriate.

Secondary exposure to the gel. Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. These signs and symptoms usually regressed with removal of the exposure to testosterone gel. In a few cases, enlarged genitalia did not fully return to age-appropriate normal size and bone age remained modestly greater than chronological age. In some cases, the risk of transfer was increased when the patient or family members did not adhere to precautions concerning the appropriate use of topical testosterone. Children and women should avoid contact with unwashed or unclothed application sites in men using Fortesta.

If inappropriate changes are observed in genital size or the development of pubic hair or libido in children, or if changes are noted in body hair distribution, an increase in acne, or other signs of virilization in adult women, the possibility of secondary exposure to testosterone gel should be brought to the attention of a physician. The gel should be promptly discontinued until the cause of virilization has been identified.

Polycythemia. In patients with an elevated hematocrit, which reflects an increased red blood cell (RBC) mass, the testosterone dose may need to be lowered or the product may need to be discontinued. The hematocrit should be checked before treatment is initiated and three to six months and annually after treatment is started. If the hematocrit becomes elevated, therapy should be stopped until a lower, acceptable level is observed. An increase in RBC mass may increase the risk of thromboembolic events.

Use in women. Owing to a lack of controlled studies in women and potential virilizing effects, testosterone gel is not indicated for use in women.

Potential for adverse effects on spermatogenesis. With large doses of exogenous androgens, including testosterone gel, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH, which can lead to adverse effects on semen parameters, including sperm count.

Adverse hepatic effects. Prolonged use of high doses of orally active 17α-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic effects, including peliosis hepatitis, which can be life-threatening or fatal; hepatic neoplasms; cholestatic hepatitis; and jaundice. Long-term therapy with testosterone enanthate has produced multiple hepatic adenomas. Testosterone gel is not known to cause these effects.

Edema. Androgens, including testosterone gel, may promote the retention of sodium and water. With or without congestive heart failure, edema may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease.

Gynecomastia. Enlarged breasts may develop and persist in patients using androgens, including testosterone gel, for hypogonadism.

Sleep Apnea. Testosterone may potentiate sleep apnea in some patients, especially patients with risk factors such as obesity or chronic lung diseases.

Lipids. If changes in the serum lipid profile occur, dose adjustments or discontinuation of testosterone therapy may be required.

Hypercalcemia. Androgens, including testosterone gel, should be used with caution in cancer patients at risk of hypercalcemia and associated hypercalciuria.

Decreased thyroxine-binding globulin. Androgens, including testosterone gel, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total thyroxine T4 serum concentrations and increased resin uptake of tri-iodothyronine (T3) and T4.

Flammability. Alcohol-based products, including testosterone gel, are flammable; therefore, patients should be advised to avoid smoking and to keep away from fire or flames until the gel has dried.

Dosage and Administration: The recommended starting dose is 40 mg (four activations of the metered-dose pump) in the morning. One pump activation delivers 10 mg of testosterone. The dose can be adjusted between a minimum of 10 mg and a maximum of 70 mg. The gel is applied once daily, directly to clean, dry, intact skin in the morning. The patient should use one finger to gently rub the gel evenly onto the front and inner area of each thigh. The gel should not be applied to the genitals or other parts of the body. When the application site is dry, it should be covered with clothing.

Commentary: Hypogonadism affects nearly 14 million American men. Declining blood levels of testosterone can occur in men beginning as early as age 40. Symptoms of low testosterone can be nonspecific and are often associated with other chronic medical problems. Symptoms include erectile dysfunction, decreased sexual desire, fatigue, loss of energy, depression, regression of secondary sexual characteristics, and osteoporosis.


Baclofen Injection (Gablofen)

Manufacturer: CNS Therapeutics, St. Paul, Minn.

Indications: Gablofen is used to manage severe spasticity in adults and children four years of age and older. For spasticity of spinal cord origin, chronic infusions of the product via an implantable pump should be reserved for patients who are not responding to oral baclofen.

Drug Class: Baclofen is a gamma-aminobutyric acid (GABA)-ergic agonist. The chemical name is 4-amino-3-(4-chlorophenyl)butanoic acid. The molecular weight is 213.66.

Uniqueness of Drug: The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. The agent inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals; however, actions at supraspinal sites may also occur and may contribute to its clinical effect. Baclofen is a structural analogue of the inhibitory neurotransmitter GABA and may exert its effects by stimulation of the GABA-B receptor subtype.

Boxed Warning: Gablofen should not be discontinued abruptly. Sudden discontinuation of intrathecal baclofen has resulted in high fever; altered mental status; exaggerated rebound spasticity; and muscle rigidity, resulting in rhabdomyolysis, multiple organ-system failure, and death. Preventing abrupt withdrawal of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be informed about the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk.

Warnings and Precautions:

Risk of life-threatening overdose during pump refills. Extreme caution must be used during filling of the Medtronic SynchroMed II programmable pump. The pump is equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a life-threatening overdose. Only fully trained and qualified personnel should refill the reservoir. Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection.

Training and screening after implantation. Gablofen is available as single-bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) as well as in the implantable Medtronic programmable pump or other pumps labeled for intrathecal administration of this product. Because of the possibility of potentially life-threatening central nervous system (CNS) depression, cardiovascular collapse, or respiratory failure, physicians must be adequately trained in administering chronic intrathecal infusion therapy. The pump system should not be implanted until the patient’s response to a bolus Gablofen injection is adequately evaluated.

Resuscitative equipment. Following surgical implantation of the pump, especially during the initial phases of pump use, patients should be monitored closely until their responses to the infusion are reasonably stable.

Overdose. Signs of overdose may appear suddenly or gradually. An acute massive overdose may be manifested as coma. If an overdose appears likely, the patient should be taken immediately to a hospital for assessment and the pump reservoir should be emptied.

Extreme caution must be used during filling of the implantable pump. The Medtronic pump should be refilled only through the reservoir refill septum. The pump has a catheter access port that allows direct access to the intrathecal catheter; however, direct injection into this catheter access port may cause a life-threatening overdose.

Gablofen withdrawal. Abrupt withdrawal of intrathecal baclofen has resulted in fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity that progressed to rhabdomyolysis, multiple organ-system failure, and death.

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Rapid, accurate diagnosis and treatment in the emergency department or intensive-care unit are important in order to prevent the potentially life-threatening CNS and systemic effects of withdrawal. Oral or enteral baclofen alone should not be relied on to halt the progression of intrathecal baclofen withdrawal.

Seizures have been reported during overdoses of baclofen, after withdrawals of intrathecal baclofen, and with maintenance therapeutic doses.

Psychosis, schizophrenia, and confusion. Patients with psychotic disorders, schizophrenia, or confusional states should be treated cautiously with intrathecal baclofen and should be kept under careful surveillance. Exacerbations of these conditions have been observed with oral administration of baclofen.

Fatalities. In premarketing and postmarketing studies, 16 deaths were reported among the 576 patients receiving intrathecal baclofen.

Spasticity of cerebral origin. In pre-marketing studies, three patients among the 211 patients treated with intrathecal baclofen died, although these deaths were not attributed to the therapy.

Autonomic dysreflexia. Gablofen should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or the abrupt withdrawal of Gablofen may cause an autonomic dysreflexic episode.

Infections. Patients should be free of infection before the screening trial with Gablofen. The presence of a systemic infection may interfere with an assessment of the patient’s response to the bolus.

Drowsiness. Drowsiness has been reported in patients receiving intrathecal baclofen. Patients should be cautioned about operating automobiles or dangerous machinery.

Intrathecal masses. Cases of an intrathecal mass at the tip of the implanted catheter have been reported. Most instances involved pharmacy-compounded analgesic admixtures.

Ovarian cysts. A dose-related increase in incidence of ovarian cysts was observed in female rats that received chronic therapy with oral baclofen.

Dosage and Administration: Gablofen should be used only with Medtronic’s SynchroMed II programmable pump or other pumps labeled for intrathecal administration of Gablofen. It is important to select the appropriate refill kit for the pump. Gablofen should not be compounded with other medications.

Screening phase. Before the pump is implanted and chronic infusions of Gablofen are initiated, patients must demonstrate a positive clinical response to a Gablofen bolus dose at a concentration of 50 mcg/mL, given intrathecally in a screening trial. A 1-mL (50-mcg/mL) syringe is available for use in the trial. The patient is observed over the next four to eight hours.

A positive response consists of a significant decrease in muscle tone or in the frequency or severity of spasms. If the initial response is less than desired, a second bolus injection may be administered 24 hours after the first. The second screening bolus dose consists of 75 mcg in 1.5 mL. Again, the patient should be observed for an interval of four to eight hours. If the response is still inadequate, a final bolus screening dose of 100 mcg/2 mL may be given 24 hours later.

Pediatric patients. The starting screening dose for pediatric patients is the same as that for adults (50 mcg). For very small patients, a screening dose of 25 mcg may be tried first. Patients who do not respond to an intrathecal bolus of 100 mcg should not be considered candidates for chronic infusion with an implanted pump.

Dose Titration:

After implantation. To determine the initial total daily dose following implantation, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period unless the efficacy of the bolus dose was maintained for more than eight hours. In that case, the starting daily dose should be the screening dose, delivered over a 24-hour period. No dose increases should be given in the first 24 hours until the steady state is achieved. In most patients, it is necessary to increase the dose gradually over time to maintain effectiveness. A sudden requirement for substantial dose escalation typically indicates a catheter complication such as kinking or dislodgment.

Adults with spasticity of spinal cord origin. After the first 24 hours, the daily dosage should be increased slowly by increments of 10% to 30% and only once every 24 hours until the desired clinical effect is achieved.

Adults with spasticity of cerebral origin. After the first 24 hours, the daily dose should be increased slowly by 5% to 15% only once every 24 hours until the desired clinical effect is achieved.

Pediatric patients. After the first 24 hours, the daily dose should be increased slowly by 5% to 15% only once every 24 hours until the desired clinical effect is achieved.

Other adjustments. The dose should be titrated carefully when spasticity is necessary to sustain upright posture and balance in locomotion or when spasticity is necessary for optimal function and care.

Commentary: The approval of Gablofen for use in the management of severe spasticity offers an easy-to-administer, cost-effective option. Severe spasticity is a movement disorder that affects more than 500,000 patients in the U.S. alone. It is often triggered by multiple sclerosis, cerebral palsy, spinal cord injury, brain trauma, and stroke.

Gablofen is compatible with Medtronic’s programmable drug pump and is available in the same standard concentrations as Lioresal Intrathecal Injection (Novartis). Gablofen is sold in ready-to-use vials and prefilled syringes, providing a clear advantage over glass ampules, including less refill preparation time and a reduced risk of drug contamination.

Approximately 150,000 patients in the U.S. have intrathecal drug pump implants. Although there is no cure for spasticity, physicians are managing the condition with baclofen, which can be delivered orally or intrathecally. In the U.S., approximately 60,000 patients have been treated with intrathecal baclofen.